Compounds and compositions for treating glucose hypometabolic disorders

Abstract

The present disclosure provides systems, methods, compositions, and algorithms for treating a subject diagnosed with a glucose hypometabolic disorder (e.g., Alzheimer's disease, Parkinson's disease, or heart failure).

Description

Attomey Docket No. FRD-002WO COMPOUNDS AND COMPOSITIONS FOR TREATING GLUCOSE HYPOMETABOLIC DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 778,042, filed March 26, 2025, and U.S. Provisional Patent Application No.63 / 920,843, filed November 19, 2025, the contents of each of which are hereby incorporated by reference in their entirety.BRIEF SUMMARY

[0002] Described herein are compounds and compositions for treating a common underlying metabolic mechanism in diverse diseases. Specifically, the compounds and compositions described herein are useful for treating glucose hypometabolism and the resultant cellular energy crisis found in neurodegenerative, cardiovascular, and metabolic disorders that were previously considered unrelated.FIELD OF THE INVENTION

[0003] This application relates to compounds and compositions, specifically ketone bodies conjugated to biologically active carriers, for treating neurological, cardiovascular, metabolic, psychiatric, inflammatory, and neuromuscular disorders characterized by glucose hypometabolism.BACKGROUND

[0004] Diseases and disorders have historically been classified based on presenting symptoms and affected organs rather than underlying molecular and metabolic mechanisms. For example, the symptomatic presentations of Alzheimer's disease (memory loss), heart failure (reduced cardiac output), and Parkinson's disease (motor dysfunction) appear entirely distinct, masking their shared metabolic pathophysiology. A unifying feature of these conditions is impaired glucose utilization at the cellular level, often due to reduced glucose uptake or utilization in affected regions. Despite decades of research in each of these disease areas, this unifying mechanism - glucose hypometabolism - has remained unrecognized due to several key factors, including entrenched medical specialization silos, lack of previous cross-disease metabolic comparisons, and technological limitations to precisely measure and quantify tissue-specific glucose metabolism. In Alzheimer's disease, the dominant amyloid hypothesis has guided therapeutic development for decades, despite consistent failures. In Parkinson's disease, focus has remained on dopaminergic therapies despite their inability to modify disease progression. In heart failure, hemodynamic approaches have predominated despite incomplete efficacy. ThereAttorney Docket No. FRD-002WO remains a need to develop a unifying therapeutic approach to address the common underlying pathophysiology - glucose hypometabolism and resultant cellular energy crisis - behind these and other traditionally considered distinct and unrelated disorders, including neurodegenerative, cardiovascular, and metabolic disorders.

[0005] Ketone bodies, namely P-hydroxybutyrate ( HB) and acetoacetate (AcAc), represent an alternative energy source for the brain that can bypass defects in glucose metabolism. During fasting or ketogenic diets, the liver produces ketone bodies which can supply up to two-thirds of the brain’s energy. Importantly, ketones produce more ATP per unit oxygen than glucose and generate fewer reactive oxygen species (ROS) during metabolism , thereby offering a dual benefit of efficient energy and reduced oxidative stress. Preclinical and clinical evidence suggests ketone supplementation can lead to significant cognitive or metabolic improvements in patients with mild cognitive impairment and Alzheimer’ s disease, improvement in non-motor symptoms in patients with Parkinson’s disease, and reduction in hospitalization risk in patients with heart failure.

[0006] However, administration of ketone bodies in therapeutic amounts presents formulation and stability challenges. Free ketone bodies are rapidly cleared from circulation, limiting their therapeutic efficacy. Additionally, high concentrations of free ketone salts can cause gastrointestinal distress and electrolyte imbalances. Prior approaches to ketone supplementation have included ketone salts, ketone esters, medium-chain triglycerides, and specialized ketogenic diets. However, these approaches suffer from limitations including poor palatability, gastrointestinal side effects, limited bioavailability, and challenges in achieving sustained therapeutic ketosis. Therefore, there remains a need for novel compositions that can effectively deliver therapeutic quantities of ketone bodies to tissues affected by glucose hypometabolism, with improved bioavailability, targeted delivery, and minimal side effects.SUMMARY OF THE DISCLOSURE

[0007] Disclosed herein, in certain embodiments, are compounds and compositions for treating a subject diagnosed with a glucose hypometabolic disorder (e.g., Alzheimer’s disease, Parkinson’s disease, heart failure, or other diseases and disorders described herein).

[0008] In one aspect provided is a compound of Formula (A):(A),or a pharmaceutically acceptable salt or solvate thereof, whereinAttorney Docket No. FRD-002WO R1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- , -S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0009] In certain embodiments, R1is selected from the group consisting of trehalose, myoinositol, D-ribose, inulin, creatine, glycine, carnitine, taurine, glycerol, allulose, aspartic acid, and carnosine.

[0010] In another aspect, the invention provides pharmaceutical formulations comprising a compound of Formula (A) and pharmaceutically acceptable excipients suitable for oral, enteral, parenteral, or intravenous delivery.

[0011] In yet another aspect, the invention provides methods for treating glucose hypometabolic disorders by administering to a patient an effective amount of a compound of Formula (A), wherein the disorders include Alzheimer's disease, Parkinson's disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any condition exhibiting impaired glucose utilization.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0013] FIG.1 is a bar graph showing dose-dependent effects of acetoacetate (AcAc) on neuronal viability in Alzheimer’s disease (AD) neurons. Neurons were treated with amyloid beta (A01-42) and increasing concentrations of AcAc (approximately 0.1 mM, 0.5 mM, 1 mM, 10 mM, and 100 mM). Cell viability was measured using a luminescence-based live / dead assay (CellTiter-Glo). Increasing concentrations of AcAc progressively improve viability relative to untreated AD neurons exposed to Af>, approaching levels observed in healthy control neurons.Attorney Docket No. FRD-002WO

[0014] FIG.2 is a bar graph showing dose-dependent effects of acetoacetate (AcAc) on reactive oxygen species (ROS) levels in AD neurons. Neurons were treated with amyloid beta (Api-42) and increasing concentrations of AcAc (approximately 0.1 mM to 100 mM). ROS levels were measured using MitoSOX staining. Increasing concentrations of AcAc reduce MitoSOX fluorescence intensity relative to untreated AD neurons, indicating a dose-dependent reduction in oxidative stress.

[0015] FIG.3 is a bar graph showing effects of multiple ketone bodies, including D-0-hydroxybutyrate (D-BHB), L-P-hydroxybutyrate (L-BHB), and acetoacetate (AcAc), on ROS levels in AD neurons under amyloid beta stimulation. Ketone treatment reduces ROS relative to untreated AD neurons, demonstrating a class-wide effect of ketones on oxidative stress reduction.

[0016] FIG.4 is a set of fluorescence microscopy images showing mitochondrial structure and oxidative stress in neurons under amyloid beta-induced conditions. Neurons were treated with 1 pM amyloid beta (Api-42) in the presence or absence of P-hydroxybutyrate (P-OHB) at concentrations of approximately 250 pM and 500 pM. MitoTracker staining (green) indicates mitochondrial structure and integrity, while MitoSOX staining (red) indicates mitochondrial reactive oxygen species (ROS) production. Ketone-treated cells exhibit reduced MitoSOX signal intensity and improved mitochondrial morphology relative to amyloid-treated cells without ketone treatment, indicating reduced oxidative stress and preservation of mitochondrial integrity.

[0017] FIG.5 is a bar graph quantifying mitochondrial oxidative stress in neurons under amyloid beta-induced conditions. Neurons were treated with 1 pM amyloid beta (Api-42) in the presence or absence of P-hydroxybutyrate (P-OHB) at concentrations of approximately 250 pM and 500 pM. Reactive oxygen species (ROS) levels were measured using MitoSOX staining and normalized to MitoTracker signal. Treatment with P-OHB reduced MitoSOX fluorescence intensity relative to amyloid-treated cells without ketone treatment, indicating reduced mitochondrial oxidative stress. Lower values correspond to reduced oxidative stress.

[0018] FIG.6 is a bar graph showing dose-dependent effects of acetoacetate (AcAc) on intracellular ATP levels in Alzheimer’s disease (AD) neurons. Neurons were treated with 1 pM amyloid beta (Api-42) and increasing concentrations of AcAc (approximately 0.1 mM, 0.5 mM, 1 mM, 10 mM, and 100 mM). Intracellular ATP levels were measured using an ATP-dependent luminescence assay and are presented relative to healthy control neurons. AD neurons exhibit reduced ATP levels relative to healthy controls, while treatment with increasing concentrations of AcAc results in a dose-dependent increase in ATP levels, indicating restoration of cellular energy metabolism.Attorney Docket No. FRD-002WO

[0019] FIG.7 is a bar graph showing neuronal viability under basal and amyloid betastimulated conditions in AD neurons. Neurons were treated with 1 pM amyloid beta (A 1-42) in the presence or absence of ketone bodies, including D-0-hydroxybutyrate (D-BHB), L-P-hydroxybutyrate (L-BHB), and acetoacetate (AcAc), at approximately 5 mM for 14 days. Cell viability was measured using a CellTiter-Glo Live / Dead assay. Amyloid beta exposure reduces viability relative to basal conditions, while ketone treatment restores viability to varying extents.

[0020] FIG.8 is a bar graph showing apoptosis levels in AD neurons as measured by Annexin V staining. Neurons were treated with 1 pM amyloid beta (Api-42) in the presence or absence of ketone bodies (D-BHB, L-BHB, and AcAc) at approximately 5 mM for 14 days. The percentage of Annexin V-positive cells is increased following amyloid beta exposure and reduced following ketone treatment, indicating decreased apoptotic signaling.

[0021] FIG. 9 is a graph showing oxygen consumption rate (OCR) over time in AD neurons as measured by a Seahorse XF Mito Stress Test. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). OCR was measured across sequential additions of mitochondrial modulators, including oligomycin, FCCP, and rotenone / antimycin A. Ketone -treated neurons exhibit increased mitochondrial respiration relative to untreated AD neurons.

[0022] FIG. 10 is a bar graph showing ATP-linked respiration in AD neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc) and ATP concentration was measured. Ketone-treated neurons exhibit increased ATP relative to untreated AD neurons.

[0023] FIG. 11 is a bar graph showing basal respiratory capacity in AD neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). Basal respiration was determined using Seahorse XF Mito Stress Test analysis. Ketone-treated neurons exhibit increased basal respiratory capacity relative to untreated AD neurons, indicating improved mitochondrial function.

[0024] FIG. 12 is a bar graph showing neuronal viability in Parkinson’s disease (PD) neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). Cell viability was measured using a CellTiter-Glo Live / Dead assay. PD neurons exhibit reduced viability relative to healthy controls, and ketone treatment improves viability, with AcAc demonstrating a comparatively strong effect.

[0025] FIG. 13 is a bar graph showing apoptosis levels in PD neurons as measured by Annexin V staining. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). PD neurons exhibit increased percentages of Annexin V-positive cells relative to healthy controls, and ketone treatment reduces apoptotic signaling.Attorney Docket No. FRD-002WO

[0026] FIG. 14 is a bar graph showing reactive oxygen species (ROS) levels in PD neurons as measured by MitoSOX staining. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). PD neurons exhibit elevated ROS levels relative to healthy controls, and ketone treatment reduces ROS levels to varying extents.

[0027] FIG. 15 is a graph showing oxygen consumption rate (OCR) over time in PD neurons as measured by a Seahorse XF Mito Stress Test. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). OCR was measured across sequential additions of mitochondrial modulators, including oligomycin, FCCP, and rotenone / antimycin A. Ketone-treated neurons exhibit increased mitochondrial respiration relative to untreated PD neurons.

[0028] FIG. 16 is a bar graph showing ATP production in PD neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). ATP-linked respiration was derived from Seahorse XF Mito Stress Test measurements. Ketone treatment increases ATP production relative to untreated PD neurons.

[0029] FIG. 17 is a bar graph showing basal respiratory capacity in PD neurons. Neurons were treated with ketone bodies (D-BHB, L-BHB, and AcAc). Basal respiration was determined using Seahorse XF Mito Stress Test analysis. Ketone treatment increases basal respiratory capacity relative to untreated PD neurons.

[0030] FIG. 18 is a bar graph showing uptake of amyloid beta (Api-42) by microglia treated with ketone esters. Microglia were treated with ketone esters and exposed to fluorescently labeled Ap 1 -42 for approximately 1 hour. Following acid wash to remove non-internalized amyloid, intracellular fluorescence was measured. Increased fluorescence intensity indicates enhanced internalization of amyloid beta in ketone-treated microglia relative to untreated controls.

[0031] FIG. 19 is a bar graph showing clearance of amyloid beta (Api-42) by microglia following ketone treatment. Microglia were treated with ketone esters and exposed to fluorescently labeled Api-42 for approximately 24 hours. Residual extracellular amyloid beta was quantified by fluorescence analysis. Reduced fluorescence intensity indicates decreased residual amyloid beta and enhanced clearance relative to untreated controls.

[0032] FIG.20 is a line graph showing the relative kinetics of amyloid beta (Api-42) clearance in microglia over time. Microglia were treated with acetoacetate (AcAc) and exposed to amyloid beta, and clearance was monitored over a time course of approximately 0 to 30 hours. Ketone-treated microglia exhibit enhanced uptake at early time points and acceleratedAttorney Docket No. FRD-002WO clearance relative to vehicle-treated controls, resulting in improved overall amyloid clearance kinetics.

[0033] FIG.21 displays a graph demonstrating the mean time-plasma BHB concentration following a representative compound of Formula (A), TrehaAce, PO dosing in mice.DETAILED DESCRIPTION

[0034] Provided herein, in certain embodiments, are systems, methods, compositions, and algorithms for treating a subject diagnosed with a glucose hypometabolic disorder (e.g., Alzheimer’s disease, Parkinson’s disease, heart failure, or other diseases and disorders described herein). The contemplated systems, methods, compositions, and algorithms disclosed herein are useful in a diagnostic-therapeutic platform for identifying and treating glucose hypometabolism and resultant cellular energy crisis in subjects by quantitatively measuring tissue-specific glucose metabolism deficits and administering precisely calibrated exogenous ketone formulations to compensate for these deficits.Certain Terminology

[0035] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. Generally, nomenclatures utilized in connection with, and techniques of, immunology, oncology, cell and tissue culture, molecular biology, and protein and oligo- or polynucleotide chemistry and hybridization described herein are those well-known and commonly used in the art. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0036] The articles “a” and “an” are used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.Chemical Definitions

[0037] Definitions of specific functional groups and chemical terms are described in more detail below.

[0038] In some embodiments, compounds described herein comprise one or more asymmetric centers, and thus exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, in some embodiments, the compounds described herein are in the form of an individual enantiomer, diastereomer or geometric isomer, or are in the form of a mixture ofAttorney Docket No. FRD-002WO stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. In some embodiments, isomers are isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric syntheses. The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0039] In some embodiments, compounds described herein also comprise one or more isotopic substitutions. For example, in some embodiments, H is in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C is any isotopic form, including12C,13C, and14C; O is in any isotopic form, including16O and18O; F is in any isotopic form, including18F and19F; and the like.

[0040] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, Ci-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0041] As used herein, “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1-C20 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-C10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-C9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-Cs alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-C7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci Ce alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of Ci-Ce alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0042] As used herein, “alkylene,” refers to a divalent radical of an alkyl group. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. In some embodiments, “alkylene” group is substituted or unsubstituted with one or more substituents as described herein.

[0043] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 u electrons shared in a cyclicAttorney Docket No. FRD-002WO array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“Ce-i4 aryl”).

[0044] As used herein, “heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In some embodiments, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits.

[0045] In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0046] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.

[0047] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-10, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "Cs-Ciocycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.

[0048] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms,Attorney Docket No. FRD-002WO wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In some embodiments, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment is a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and is saturated or is partially unsaturated. In some embodiments, heterocyclyl bicyclic ring systems include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more phenyl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably.

[0049] In some embodiments, a heterocyclyl group is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 3-7 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-7 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.Attorney Docket No. FRD-002WO

[0050] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. In some embodiments, hetero is applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl; cycloalkyl, e.g., heterocyclyl; aryl, e.g., heteroaryl; and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0051] The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I). In certain embodiments, the halo group is either fluoro or chloro.

[0052] The term “haloalky 1” includes mono, poly, and perhaloalkyl groups substituted with one or more halogen atoms where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0053] The term “oxo” as used herein refers to =0.

[0054] The term “hydroxyl” as used herein refers to -OH.

[0055] In general, the term “substituted,” whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

[0056] Nitrogen atoms are substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.

[0057] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.Other Definitions

[0058] As used herein, the term “about” when modifying a numeric value means within a reasonable range of the stated value, typically ±10% unless otherwise specified. This term accounts for normal experimental or biological variability around the precise value.

[0059] As used herein, “pharmaceutically acceptable excipient” refers to any substance in a pharmaceutical formulation other than the active pharmaceutical ingredient(s). ExemplaryAttorney Docket No. FRD-002WO pharmaceutical excipients include those that aid the manufacturing process; protect, support or enhance stability; increase bioavailability; or increase patient acceptability. They may also assist in product identification or enhance the overall safety or function of the product during storage or use.

[0060] As used herein, “pharmaceutically acceptable salt’’ refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0061] As used herein, a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments,Attorney Docket No. FRD-002WO the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” “individual” and “subject” are used interchangeably herein. None of the terms require the supervision of medical personnel.

[0062] The terms “disease”, “disorder”, and “condition” are used interchangeably herein.

[0063] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition.

[0064] As used herein, and unless otherwise specified, a “therapeutically effective amount” or an “effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount or an effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. In some embodiments, the term “therapeutically effective amount” or “effective amount” encompasses an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0065] As used herein, the term “ketone body”, “exogenous ketone” or “exogenous ketone body” means a compound or species which is a ketone or a ketone body precursor, that is, a compound or species which is a precursor to a ketone and which may be converted or metabolized to a ketone. Ketone bodies are produced when fatty acids levels are raised in the body and are metabolized by the body for energy. Ketone bodies have been disclosed as being suitable for reducing the levels of free fatty acids circulating in the plasma of a subject and that ingestion of ketone bodies can lead to various clinical benefits, including an enhancement of cognitive performance and treatment of cardiovascular conditions, diabetes and treatment of mitochondrial dysfunction disorders and in treating muscle fatigue and impairment. Examples of ketone bodies include, but are not limited to, beta-hydroxybutyrate (“PHB”) and acetoacetate (“AcAc”).

[0066] For consistency, the terms “administering” and “delivering” (with respect to providing a therapeutic composition to a subject) are used interchangeably herein. Likewise, terms like “exogenous ketone therapy,” “ketone composition,” or “ketone formulation” refer to the use of one or more ketone compounds (or precursors) administered to the subject as described.Attorney Docket No. FRD-002WO

[0067] As used herein, the term “glucose hypometabolic disorder” refers to any disease, disorder, or condition in which one or more tissues exhibit a chronically reduced capacity to utilize glucose relative to normal physiology. Examples of glucose hypometabolic disorders include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any other condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

[0068] As used herein, the term “glucose metabolism deficit,” abbreviated as “G_Diff,” refers to the quantitative shortfall in glucose utilization by a tissue (or entire subject) compared to a nonual or baseline value. G_Diff may be expressed as a percentage below a normal glucose metabolic rate, an absolute deficit in terms of glucose consumption (e.g., milligrams per deciliter lower than normal), or an energy equivalent. For example, a G_Diff of 20% indicates the tissue is only achieving about 80% of the glucose uptake / usage observed in a healthy reference under the same conditions.

[0069] The term “module” (as in “diagnostic module,” “computational module,” etc.) refers broadly to a component or combination of components — implemented in hardware, software, firmware, or any combination thereof — configured to perform a specified function. For example, a “diagnostic module” may be a physical device or instrament (such as an imaging scanner or a biosensor array) or a software algorithm that processes data from an instrament to yield a diagnostic result. Modules can be distributed or integrated; a module’s function can be executed on a local machine or via a remote / cloud-based service, as long as it performs the recited function.Compounds and CompositionsCompounds

[0070] Disclosed herein, in certain embodiments, are compounds of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;Attorney Docket No. FRD-002WO R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0071] As generally defined above R1is a polyol, amino acid, or a derivative thereof. In certain embodiments, R1is a polyol. A polyol is a compound containing two or more hydroxy (OH) groups. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.Attomey Docket No. FRD-002WO

[0072] In certain embodiments, R1is a polyol which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0073] In certain embodiments, R1is a carbohydrate. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable ofAttorney Docket No. FRD-002WO delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0074] In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an carbohydrate which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an carbohydrate which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.Attomey Docket No. FRD-002WO

[0075] In certain embodiments, R1is an amino acid or a derivative thereof. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0076] In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 10 g or more of ketone bodies to a subjectAttomey Docket No. FRD-002WO diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an amino acid or a derivative thereof which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an amino acid or a derivative thereof which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0077] In certain embodiments, R1is selected from the group consisting of trehalose, inositol, ribose, inulin, creatine, glycine, carnitine, and taurine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, taurine, glycerol, allulose, aspartic acid, and carnosine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine. In certain embodiments, R1is D-ribose. In certain embodiments, R1is inulin. In certain embodiments, R1is creatine. In certain embodiments, R1is glycine. In certain embodiments, R1is carnitine. In certain embodiments, R1is taurine. In certain embodiments, R1is glycerol. In certain embodiments, R1is allulose. In certain embodiments, R1is aspartic acid. In certain embodiments, R1is carnosine.

[0078] In certain preferred embodiments, R1is trehalose, myo-inositol, or D-ribose. In certain embodiments, R1is myo-inositol or trehalose. In certain embodiments, R1is myo-inositol. In certain embodiments, R1is trehalose.

[0079] As generally defined above, X is a covalent linker joining selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH- -NH-C(O)-, -C(O)-S- -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-Attorney Docket No. FRD-002WO NH- , - O- , -NH- ,— S— , and -S-S-. In certain embodiments, X is -O-C(O)-. In certain embodiments, X is -C(O)-O- In certain embodiments, X is -C(O)-NH-. In certain embodiments, X is -NH-C(O)-. In certain embodiments, X is -C(O)-S- In certain embodiments, X is -S-C(O)-. In certain embodiments, X is -O-C(O)-O- . In certain embodiments, X is -O-C(O)-NH- or -NH-C(O)-O- . In certain embodiments, X is -O-PIO?)-O- . In certain embodiments, X is -O-SO2-O- . In certain embodiments, X is -C=N- In certain embodiments, X is -C=N-NH- . In certain embodiments, X is O . In certain embodiments, X is -NH- . In certain embodiments, X is -S- . In certain embodiments, X is-S-S- . In preferred embodiments, X is -O- or -NH-.

[0080] As generally defined above R2is a ketone body moiety selected from P-hydroxybutyryl (BHB), acetoacetyl (AcAc), or a derivative thereof. In certain embodiments, R2is f>-hydroxybutyryl (BHB) or a derivative thereof. In certain embodiments, R2is P-hydroxybutyryl (BHB). In certain embodiments, R2is a acetoacetyl (AcAc) or a derivative thereof. In certainembodiments, R2is a acetoacetyl (AcAc). In certain embodiments, R2is. In certainembodiments, R2isIn certain embodiments, R2is. In certainembodiments,R2is

[0081] As generally defined above, n is an integer from 1 to 50. In certain embodiments, n is an integer from 1 to 20. In specific embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In certain embodiments n is 1. In certain embodiments n is 2. In certain embodiments n is 3. In certain embodiments n is 4. In certain embodiments n is 5. In certain embodiments n is 6. In certain embodiments n is 7. In certain embodiments n is 8. In certain embodiments n is 9. In certain embodiments n is 10. In certain embodiments n is 11. In certain embodiments n is 12. In certain embodiments n is 13. In certain embodiments n is 14. In certain embodiments n is 15. In certain embodiments n is 16. In certain embodiments n is 17. In certain embodiments n is 18. In certain embodiments n is 19. In certain embodiments n is 20. In certain embodiments, n is an integer which is equal to the number of hydroxy groups in R1.

[0082] In certain embodiments, the compound is compound of Formula (A):Attorney Docket No. FRD-002WO or a pharmaceutically acceptable salt or solvate thereof, whereinR1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O , O -P(O2) O , O SO2 O , C=N , -C=N NH , O , NH , S , and S S ;R2is a ketone body moiety selected from |3-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0083] In certain embodiments, the compound is compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine;X is -O- or -NH-;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0084] In certain embodiments, the compound is compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is trehalose, myo-inositol, or D-ribose;Attorney Docket No. FRD-002WO X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S- -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from -hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 8, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0085] In certain embodiments, the compound is compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is trehalose, myo-inositol, or D-ribose;X is -O-C(O)- ;R2is a ketone body moiety selected from -hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 8, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.In certain embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof. It is understood that each of these compounds may exist in partially esterified / amidated forms where not all available hydroxyl or amine groups are conjugated to ketone bodies. Additionally, mixed conjugates are contemplated wherein some attachment sites contain P-hydroxybutyrate moieties while others contain acetoacetate moieties on the same carrier molecule.Attorney Docket No. FRD-002WO Table 1. List of compounds.CompoundName StructureNo.1 HO,H01HO- / o V\ A \ HO V ° 0 JTrehalose-BHBH0fr-o,, X . Oz, / L 1 O | o | | o Ester (TrehaBHB) ''O' ' ' \ 7°H" 7 u 6 \0H 0>0 / ^OHX CLTrehalose-0;=Y c>° y~0z, Oz, A. .D2 Acetoacetate Ester01 ? I I / ° (TrehaAce) 'v ' ' ^O' / ^'° x J3'' 0u2=0 / 0HO^ / 1 0^ / HOH01Inositol-BHB Ester o^o^ A ^o73 I [ 0(InosBHB) ^ P'' OH -V x0 x— ( OH ° >°XVoHAttorney Docket No. FRD-002WOAttorney Docket No. FRD-002WOCompoundName StructureNo.o’Carnitine- 0^ 0 08 Acetoacetate Ester(CarnAce) / NtxrTaurine- 9 AcetoacetateAmide (TaurAce)oo y CD —Inositol- ' oZ < o oDD C C —10 Acetoacetate Ester \ \ oK °(InosAce) < > o p o—( \ \o°o o=- — — / \ TZ / O o") \ °0— A '>■\( b < oo y o-,' SA0 0 Z ' o° 0== o / oZEGlycerol- Z o «>O=11 Acetoacetate Ester °<sx° D < (GlycAce)Allulose- 12 Acetoacetate Ester(AllAce)0Aspartic Acid-HOYV13 Acetoacetate Ester O NH<OH(AspAce) l ^0^ <3Attorney Docket No. FRD-002WOCompoundName StructureNo.Glycerol- BHB14Ester (GlycBHB)Carnosine-BHB HHH* 1 EsteHOY^N^Yy 5 rOH0 0(CarnosBHB) V NHN= /

[0086] The compounds of Formula (A) described herein offer certain advantages over simpler ketone supplements (such as monomeric ketone esters or salts). By attaching multiple ketone zbody moieties (R2) to a single polyol backbone (R1), a sin yg OO=le compound can deliver a higher ( o o —payload of ketone equivalents per molecule, potentially increasing the efficiency of raising blood ketone levels. Additionally, the use of a polyol backbone can impart favorable pharmacokinetic properties - for instance, as the conjugate is metaboliz oed, it may release ketone bodies gradually, acting as a built-in sustained-release mechanism. This could help maintain therapeutically relevant ketone concentrations over a longer duration com £pared to a rapid spike from a simple ketone salt. In some embodiments, such multi-ketone conjugates may also improve tolerability or palatability: by distributing the ketone load across a larger molecule, peak gastrointestinal irritation or the strong taste associated with free ketones or salts might be reduced. While the invention is not bound by theory, these potential benefits illustrate the innovative nature of the polyol-based ketone conjugates, which go beyond conventional monomeric ketone compounds.Compositions

[0087] Another aspect of the invention provides compositions comprising one or more compounds of Formula (A). In certain embodiments, the comprises at least two compounds from Table 1.

[0088] In certain embodiments, the composition comprises Compound 1 and Compound 2. In certain embodiments, the composition comprises Compound 1 and Compound 3. In certain embodiments, the composition comprises Compound 1 and Compound 4. In certain embodiments, the composition comprises Compound 1 and Compound 5. In certain embodiments, the composition comprises Compound 1 and Compound 6. In certainAttomey Docket No. FRD-002WO embodiments, the composition comprises Compound 1 and Compound 7. In certain embodiments, the composition comprises Compound 1 and Compound 8. In certain embodiments, the composition comprises Compound 1 and Compound 9. In certain embodiments, the composition comprises Compound 1 and Compound 10. In certain embodiments, the composition comprises Compound 1 and Compound 11. In certain embodiments, the composition comprises Compound 1 and Compound 12. In certain embodiments, the composition comprises Compound 1 and Compound 13. In certain embodiments, the composition comprises Compound 1 and Compound 14. In certain embodiments, the composition comprises Compound 1 and Compound 15.

[0089] In certain embodiments, the composition comprises Compound 2 and Compound 3. In certain embodiments, the composition comprises Compound 2 and Compound 4. In certain embodiments, the composition comprises Compound 2 and Compound 5. In certain embodiments, the composition comprises Compound 2 and Compound 6. In certain embodiments, the composition comprises Compound 2 and Compound 7. In certain embodiments, the composition comprises Compound 2 and Compound 8. In certain embodiments, the composition comprises Compound 2 and Compound 9. In certain embodiments, the composition comprises Compound 2 and Compound 10. In certain embodiments, the composition comprises Compound 2 and Compound 11. In certain embodiments, the composition comprises Compound 2 and Compound 12. In certain embodiments, the composition comprises Compound 2 and Compound 13. In certain embodiments, the composition comprises Compound 2 and Compound 14. In certain embodiments, the composition comprises Compound 2 and Compound 15.

[0090] In certain embodiments, the composition comprises Compound 3 and Compound 4. In certain embodiments, the composition comprises Compound 3 and Compound 5. In certain embodiments, the composition comprises Compound 3 and Compound 6. In certain embodiments, the composition comprises Compound 3 and Compound 7. In certain embodiments, the composition comprises Compound 3 and Compound 8. In certain embodiments, the composition comprises Compound 3 and Compound 9. In certain embodiments, the composition comprises Compound 3 and Compound 10. In certain embodiments, the composition comprises Compound 3 and Compound 11. In certain embodiments, the composition comprises Compound 3 and Compound 12. In certain embodiments, the composition comprises Compound 3 and Compound 13. In certain embodiments, the composition comprises Compound 3 and Compound 14. In certain embodiments, the composition comprises Compound 3 and Compound 15.Atorney Docket No. FRD-002WO

[0091] In certain embodiments, the composition comprises Compound 4 and Compound 5. In certain embodiments, the composition comprises Compound 4 and Compound 6. In certain embodiments, the composition comprises Compound 4 and Compound 7. In certain embodiments, the composition comprises Compound 4 and Compound 8. In certain embodiments, the composition comprises Compound 4 and Compound 9. In certain embodiments, the composition comprises Compound 4 and Compound 10. In certain embodiments, the composition comprises Compound 4 and Compound 11. In certain embodiments, the composition comprises Compound 4 and Compound 12. In certain embodiments, the composition comprises Compound 4 and Compound 13. In certain embodiments, the composition comprises Compound 4 and Compound 14. In certain embodiments, the composition comprises Compound 4 and Compound 15.

[0092] In certain embodiments, the composition comprises Compound 5 and Compound 6. In certain embodiments, the composition comprises Compound 5 and Compound 7. In certain embodiments, the composition comprises Compound 5 and Compound 8. In certain embodiments, the composition comprises Compound 5 and Compound 9. In certain embodiments, the composition comprises Compound 5 and Compound 10. In certain embodiments, the composition comprises Compound 5 and Compound 11. In certain embodiments, the composition comprises Compound 5 and Compound 12. In certain embodiments, the composition comprises Compound 5 and Compound 13. In certain embodiments, the composition comprises Compound 5 and Compound 14. In certain embodiments, the composition comprises Compound 5 and Compound 15.

[0093] In certain embodiments, the composition comprises Compound 6 and Compound 7. In certain embodiments, the composition comprises Compound 6 and Compound 8. In certain embodiments, the composition comprises Compound 6 and Compound 9. In certain embodiments, the composition comprises Compound 6 and Compound 10. In certain embodiments, the composition comprises Compound 6 and Compound 11. In certain embodiments, the composition comprises Compound 6 and Compound 12. In certain embodiments, the composition comprises Compound 6 and Compound 13. In certain embodiments, the composition comprises Compound 6 and Compound 14. In certain embodiments, the composition comprises Compound 6 and Compound 15.

[0094] In certain embodiments, the composition comprises Compound 7 and Compound 8. In certain embodiments, the composition comprises Compound 7 and Compound 9. In certain embodiments, the composition comprises Compound 7 and Compound 10. In certain embodiments, the composition comprises Compound 7 and Compound 11. In certainAtorney Docket No. FRD-002WO embodiments, the composition comprises Compound 7 and Compound 12. In certain embodiments, the composition comprises Compound 7 and Compound 13. In certain embodiments, the composition comprises Compound 7 and Compound 14. In certain embodiments, the composition comprises Compound 7 and Compound 15.

[0095] In certain embodiments, the composition comprises Compound 8 and Compound 9. In certain embodiments, the composition comprises Compound 8 and Compound 10. In certain embodiments, the composition comprises Compound 8 and Compound 11. In certain embodiments, the composition comprises Compound 8 and Compound 12. In certain embodiments, the composition comprises Compound 8 and Compound 13. In certain embodiments, the composition comprises Compound 8 and Compound 14. In certain embodiments, the composition comprises Compound 8 and Compound 15.

[0096] In certain embodiments, the composition comprises Compound 9 and Compound 10. In certain embodiments, the composition comprises Compound 9 and Compound 11. In certain embodiments, the composition comprises Compound 9 and Compound 12. In certain embodiments, the composition comprises Compound 9 and Compound 13. In certain embodiments, the composition comprises Compound 9 and Compound 14. In certain embodiments, the composition comprises Compound 9 and Compound 15.

[0097] In certain embodiments, the composition comprises Compound 10 and Compound 11. In certain embodiments, the composition comprises Compound 10 and Compound 12. In certain embodiments, the composition comprises Compound 10 and Compound 13. In certain embodiments, the composition comprises Compound 10 and Compound 14. In certain embodiments, the composition comprises Compound 10 and Compound 15.

[0098] In certain embodiments, the composition comprises Compound 11 and Compound 12. In certain embodiments, the composition comprises Compound 11 and Compound 13. In certain embodiments, the composition comprises Compound 11 and Compound 14. In certain embodiments, the composition comprises Compound 11 and Compound 15.

[0099] In certain embodiments, the composition comprises Compound 12 and Compound 13. In certain embodiments, the composition comprises Compound 12 and Compound 14. In certain embodiments, the composition comprises Compound 12 and Compound 15.

[0100] In certain embodiments, the composition comprises Compound 13 and Compound 14. In certain embodiments, the composition comprises Compound 13 and Compound 15.

[0101] In certain embodiments, the composition comprises Compound 14 and Compound 15.Attorney Docket No. FRD-002WO

[0102] In certain embodiments, the composition comprises at least two compounds of Formula (A). In certain embodiments, each compound of Formula (A) has the same R1and X.

[0103] As generally defined above R1is a polyol, amino acid, or a derivative thereof. In certain embodiments, R1is a polyol. A polyol is a compound containing two or more hydroxy (OH) groups.

[0104] In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0105] In certain embodiments, R1is a polyol which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 5 g or more of ketone bodiesAttomey Docket No. FRD-002WO to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a polyol which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0106] In certain embodiments, R1is a carbohydrate. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucoseAttorney Docket No. FRD-002WO hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0107] In certain embodiments, R1is a carbohydrate which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an carbohydrate which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an carbohydrate which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a carbohydrate which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0108] In certain embodiments, R1is an amino acid or a derivative thereof. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.Attomey Docket No. FRD-002WO In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 5 g, about 5 g to 10 g, about 10 g to 15 g, about 15 g to 20 g, about 20 g to 25 g, about 25 g to 30 g, about 30 g to about 35 g, about 35 g to 40 g, about 40 g to 45 g, or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g to 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 5 g to 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 10 g to 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 15 g to 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 20 g to 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 25 g to 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 30 g to about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 35 g to 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 40 g to 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 45 g to 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0109] In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 1 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 5 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 10 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 15 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is anAttorney Docket No. FRD-002WO amino acid or a derivative thereof which is capable of delivering about 20 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 25 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is an amino acid or a derivative thereof which is capable of delivering about 30 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 35 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering about 40 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 45 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder. In certain embodiments, R1is a amino acid or a derivative thereof which is capable of delivering or about 50 g or more of ketone bodies to a subject diagnosed with a glucose hypometabolic disorder.

[0110] In certain embodiments, R1is selected from the group consisting of trehalose, inositol, ribose, inulin, creatine, glycine, carnitine, and taurine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, taurine, glycerol, allulose, aspartic acid, and carnosine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine.

[0111] In certain embodiments, R1is selected from the group consisting of trehalose, inositol, ribose, inulin, creatine, glycine, carnitine, and taurine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, taurine, glycerol, allulose, aspartic acid, and carnosine. In certain embodiments, R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine.

[0112] In certain preferred embodiments, R1is trehalose, myo-inositol, or D-ribose. In certain embodiments, R1is myo-inositol or trehalose. In certain embodiments, R1is myo-inositol. In certain embodiments, R1is trehalose. In certain embodiments, R1is D-ribose. In certain embodiments, R1is inulin. In certain embodiments, R1is creatine. In certain embodiments, R1is glycine. In certain embodiments, R1is carnitine. In certain embodiments, R1is taurine. In certain embodiments, R1is glycerol. In certain embodiments, R1is allulose. In certain embodiments, R1is aspartic acid. In certain embodiments, R1is carnosine.Attorney Docket No. FRD-002WO

[0113] As generally defined above, X is a covalent linker joining selected from the group consisting of-O-C(O)- -C(O)-O- -C(O)-NH- -NH-C(O)-, -C(O)-S- -S-C(O)- -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , — O~ , -NH- ,-S- , and -S-S-. In certain embodiments, X is -O-C(O)-. In certain embodiments, X is -C(O)-O- In certain embodiments, X is -C(O)-NH-. In certain embodiments, X is -NH-C(O)-. In certain embodiments, X is -C(O)-S- In certain embodiments, X is -S-C(O)-. In certain embodiments, X is -O-C(O)-O- . In certain embodiments, X is -O-C(O)-NH- or -NH-C(O)-O- . In certain embodiments, X is -O-P(O2)-O- . In certain embodiments, X is -O-SO2-O- . In certain embodiments, X is -C=N- In certain embodiments, X is -C=N-NH- . In certain embodiments, X is -O- . In certain embodiments, X is -NH- . In certain embodiments, X is -S- . In certain embodiments, X is-S-S- . In preferred embodiments, X is -O- or -NH-.

[0114] In certain preferred embodiments, R1is trehalose, myo-inositol, or D-ribose. In certain embodiments, R1is myo-inositol or trehalose. In certain embodiments, R1is myo-inositol. In certain embodiments, R1is trehalose. In certain embodiments, R1is D-ribose. In certain embodiments, R1is inulin. In certain embodiments, R1is creatine. In certain embodiments, R1is glycine. In certain embodiments, R1is carnitine. In certain embodiments, R1is taurine. In certain embodiments, R1is glycerol. In certain embodiments, R1is allulose. In certain embodiments, R1is aspartic acid. In certain embodiments, R1is carnosine.

[0115] In certain embodiments, the composition comprises at least two unique compounds of Formula (A). In certain embodiments, the composition comprises one unique compound of Formula (A) is:or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl or a derivative thereof; andAttorney Docket No. FRD-002WO n is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1, andwherein the other unique compound of Formula (A) is:or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from acetoacetyl (AcAc) or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1..

[0116] .

[0117] The compounds of Formula (A) may be formulated as pharmaceutical compositions by combining the compound with pharmaceutically acceptable carriers, excipients, and / or diluents. Such compositions may be formulated for oral, enteral, parenteral, or intravenous administration.

[0118] For oral administration, the compounds may be formulated as tablets, capsules, powders, solutions, suspensions, or emulsions. For parenteral administration, the compounds may be formulated as solutions, suspensions, or emulsions in aqueous or oil vehicles.Therapeutic Applications and Advantages

[0119] The compounds and compositions of the present disclosure provide significant therapeutic advantages for treating glucose hypometabolic disorders:

[0120] Enhanced Bioavailability: By conjugating ketone bodies to carrier molecules via stable linkers (e.g., ester or amide bonds), the compounds and compositions exhibit improved absorption, extended circulation time, and enhanced tissue penetration compared to free ketone bodies.Attomey Docket No. FRD-002WO

[0121] Increased Ketone Payload: In certain embodiments, the multi-esterification design allows delivery of multiple ketone moieties per carrier molecule, maximizing the therapeutic effect while minimizing excipient load.

[0122] Targeted Delivery: Specific carrier molecules can preferentially direct ketones to tissues most affected by glucose hypometabolism. For example, trehalose-based conjugates may have enhanced blood-brain barrier penetration for neurological conditions.

[0123] Controlled Release: The linkers (e.g., the ester or amide bonds) are enzymatically hydrolyzed in vivo, providing sustained release of ketone bodies over time rather than the sharp peaks and troughs seen with direct ketone salt administration.

[0124] Synergistic Effects: The carrier molecules themselves often have complementary therapeutic effects. For example, inositol supports membrane stabilization and signaling, while creatine enhances cellular energy reserves.

[0125] Reduced Side Effects: The conjugate formulations minimize gastrointestinal distress and electrolyte imbalances commonly associated with ketone salt administration.

[0126] Dosing Convenience: The stable solid formulations allow for convenient oral dosing, improving patient compliance compared to liquid formulations or dietary interventions.Mechanisms of Action

[0127] The compounds and compositions of the present disclosure work through multiple complementary mechanisms:

[0128] Metabolic Bypass: The released ketone bodies provide an alternative energy substrate that bypasses the impaired glucose metabolism pathways seen in conditions like Alzheimer's disease, Parkinson's disease, and heart failure.

[0129] Enhanced Energetic Efficiency: Ketone bodies produce more ATP per oxygen molecule compared to glucose (2.5 vs 2.25 ATP / O), providing energetic advantages in oxygenlimited or mitochondrially compromised tissues.

[0130] Reduced Oxidative Stress: Ketone metabolism produces fewer reactive oxygen species than glucose or fatty acid oxidation, reducing oxidative damage in affected tissues.

[0131] Signaling Effects: Beyond serving as energy substrates, ketone bodies (particularly -hydroxybutyrate) activate beneficial signaling pathways, including those related to mitochondrial biogenesis, antioxidant defense, and epigenetic regulation through histone deacetylase inhibition.Attorney Docket No. FRD-002WO

[0132] Neuroprotection: In neurodegenerative conditions, ketone bodies provide neuroprotection through multiple mechanisms, including reduced excitotoxicity, enhanced GABA signaling, and stabilization of neuronal membrane potentials.

[0133] Cardiac Protection: In heart failure, ketone bodies improve cardiac efficiency, reduce fibrosis, and enhance calcium handling in cardiomyocytes.Methods

[0134] Disclosed herein, in certain embodiments, are methods of treating a subject diagnosed with a glucose hypometabolic disorder (e.g., Alzheimer’s disease, Parkinson’s disease, or heart failure) comprising administering a therapeutically effective amount of a compound of Formula (A):2)f R TR'n(A),or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SOz-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0135] Also disclosed herein, in certain embodiments, are methods for diagnosing and quantifying glucose hypometabolism in a subject comprising administering a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;Attorney Docket No. FRD-002WO X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S- -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryI, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1,n some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:

[0136] In another aspect, provided herein is a method for treating Alzheimer’s disease, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryI, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0137] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0138] In another aspect, provided herein is a method for treating Parkinson’s disease, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0139] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0140] In another aspect, provided herein is a method for treating Huntington’ s disease, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0141] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0142] In another aspect, provided herein is a method for treating heart failure, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0143] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0144] In another aspect, provided herein is a method for treating stroke, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0145] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0146] In another aspect, provided herein is a method for treating spinal cord injury, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0147] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0148] In another aspect, provided herein is a method for treating type 2 diabetes, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0149] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0150] In another aspect, provided herein is a method for treating obesity, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0151] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0152] In another aspect, provided herein is a method for treating non-alcoholic fatty liver disease (NAFLD), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0153] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0154] In another aspect, provided herein is a method for treating non-alcoholic steatohepatitis (NASH), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0155] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0156] In another aspect, provided herein is a method for treating polycystic ovarian syndrome (PCOS), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0157] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0158] In another aspect, provided herein is a method for treating epilepsy, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0159] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0160] In another aspect, provided herein is a method for treating traumatic brain injury (TBI), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0161] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0162] In another aspect, provided herein is a method for treating amyotrophic lateral sclerosis (ALS), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0163] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0164] In another aspect, provided herein is a method for treating cancer, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0165] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0166] In another aspect, provided herein is a method for treating cancer cachexia, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0167] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0168] In another aspect, provided herein is a method for treating peripheral vascular disease, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0169] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0170] In another aspect, provided herein is a method for treating mitochondrial disorders, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0171] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0172] In another aspect, provided herein is a method for treating chronic fatigue syndrome, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0173] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0174] In another aspect, provided herein is a method for treating metabolic syndrome, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0175] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0176] In another aspect, provided herein is a method for treating bipolar disorder, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0177] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0178] In another aspect, provided herein is a method for treating major depressive disorder, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0179] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0180] In another aspect, provided herein is a method for treating anxiety disorders, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0181] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0182] In another aspect, provided herein is a method for treating schizophrenia, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0183] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0184] In another aspect, provided herein is a method for treating autism spectrum disorder, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0185] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0186] In another aspect, provided herein is a method for treating attention deficit hyperactivity disorder (ADHD), the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A)Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N-, -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from 0-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0187] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WO

[0188] In another aspect, provided herein is a method for treating any condition in which a subject’s tissue exhibits a quantifiable reduction in glucose utilization, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

[0189] In some embodiments, the compound of Formula (A) is a compound in Table 1. In some embodiments, the compound is selected from the group consisting of:Attorney Docket No. FRD-002WOAttorney Docket No. FRD-002WO Precise Measurement of Glucose Hypometabolism Across Conditions

[0190] Comprehensive, quantitative evidence demonstrates remarkably consistent patterns of glucose hypometabolism across diverse disorders:Alzheimer's Disease:

[0191] FDG-PET studies demonstrate 15-25% lower regional glucose metabolism in temporal, parietal, and posterior cingulate regions compared to age-matched controls. Early-onset AD shows even more dramatic declines, with 40-45% global cerebral metabolic rate glucose reduction. The degree of hypometabolism correlates strongly with cognitive impairment, with correlation coefficients between regional FDG uptake and cognitive scores of r ~ 0.5-0.7.Hypometabolism manifests 5-10 years before clinical dementia in sporadic AD and 13 years before expected symptom onset in familial AD.Parkinson's Disease:

[0192] Substantia nigra shows 15-20% lower FDG uptake in PD patients compared to controls (effect size d~l .0). The PD-related metabolic pattern (PDRP) network expression correlates with motor UPDRS scores at r = 0.62, p<0.005. Correlation between glucose metabolism deficits and dopaminergic neuron loss (DAT binding r ~0.6)Heart Failure:

[0193] Cardiac glucose oxidation rates in failing hearts are 30-40% lower than in healthy hearts. Glucose's contribution to cardiac ATP production falls from approximately 30% in healthy hearts to 10-15% in severe heart failure. Myocardial phosphocreatine-to-ATP ratio (PCr / ATP) is reduced by 25-30% in dilated cardiomyopathy, correlating with LVEF at r -0.6 Convergent Enzymatic and Mitochondrial Defects

[0194] A particularly surprising finding is the convergent pattern of enzymatic deficiencies across these diverse conditions:Attorney Docket No. FRD-002WO Table 2. Comparison of Enzymatic Deficiencies in Alzheimer’s Disease, Parkinson’s Disease, and Heart FailurePrimary Key Enzyme Magnitude of Energy Reserve DiseaseTissue Defect Defect DeficitAlzheimer's -20% ATP Brain cortex PDH complex -50% reductionDisease reductionParkinson's Substantia -10-15% ATP Complex I -30% reductionDisease nigra reduction30-40% reduced -30% ATP Heart Failure Cardiac tissue PDH complexflux reduction

[0195] In one aspect, provided herein a method of treating a glucose hypometabolic disorder in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0196] In certain embodiments, the glucose hypometabolic disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, heart failure, stroke, spinal cord injury, type 2 diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), polycystic ovary syndrome (PCOS), epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer, cancer cachexia, peripheral vascular disease, mitochondrial disorders, chronic fatigue syndrome, metabolic syndrome, bipolar disorder, major depressive disorder, anxiety disorders, schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

[0197] In certain embodiments, the glucose hypometabolic disorder is Alzheimer’s disease. In certain embodiments, the glucose hypometabolic disorder is Parkinson’s disease. In certain embodiments, the glucose hypometabolic disorder is Huntington’s disease. In certain embodiments, the glucose hypometabolic disorder is heart failure. In certain embodiments, the glucose hypometabolic disorder is stroke. In certain embodiments, the glucose hypometabolic disorder is spinal cord injury. In certain embodiments, the glucose hypometabolic disorder is type 2 diabetes. In certain embodiments, the glucose hypometabolic disorder is obesity. In certain embodiments, the glucose hypometabolic disorder is non-alcoholic fatty liver disease (NAFLD). In certain embodiments, the glucose hypometabolic disorder is non-alcoholicAttorney Docket No. FRD-002WO steatohepatitis (NASH). In certain embodiments, the glucose hypometabolic disorder is polycystic ovary syndrome (PCOS). In certain embodiments, the glucose hypometabolic disorder is epilepsy. In certain embodiments, the glucose hypometabolic disorder is traumatic brain injury. In certain embodiments, the glucose hypometabolic disorder is amyotrophic lateral sclerosis. In certain embodiments, the glucose hypometabolic disorder is cancer. In certain embodiments, the glucose hypometabolic disorder is cancer cachexia. In certain embodiments, the glucose hypometabolic disorder is peripheral vascular disease. In certain embodiments, the glucose hypometabolic disorder is a mitochondrial disorder. In certain embodiments, the glucose hypometabolic disorder is chronic fatigue syndrome. In certain embodiments, the glucose hypometabolic disorder is metabolic syndrome. In certain embodiments, the glucose hypometabolic disorder is bipolar disorder. In certain embodiments, the glucose hypometabolic disorder is major depressive disorder. In certain embodiments, the glucose hypometabolic disorder is an anxiety disorder. In certain embodiments, the glucose hypometabolic disorder is schizophrenia. In certain embodiments, the glucose hypometabolic disorder is autism spectrum disorder. In certain embodiments, the glucose hypometabolic disorder is attention deficit hyperactivity disorder (ADHD). In certain embodiments, the glucose hypometabolic disorder is any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

[0198] In some embodiments, increasing glucose metabolism comprises increasing the activity of a glucose hypometabolic enzyme. In some embodiments, increasing glucose metabolism comprises increasing the activity of a pyruvate dehydrogenase complex (PDH complex).

[0199] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased byAttorney Docket No. FRD-002WO about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0200] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0201] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%,. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0202] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%.Attorney Docket No. FRD-002WO In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0203] In another aspect, provided herein is a method of treating Alzheimer's Disease in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue. In some embodiments, increasing glucose metabolism comprises increasing the activity of a glucose hypometabolic enzyme. In some embodiments, increasing glucose metabolism comprises increasing the activity of a pyruvate dehydrogenase complex (PDH complex).

[0204] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0205] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, theAttorney Docket No. FRD-002WO glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0206] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0207] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by aboutAttorney Docket No. FRD-002WO 45%. In some embodiments, the production of ATP is increased by about 50%. In another aspect, provided herein is a method of treating Parkinson’s Disease in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue. In some embodiments, increasing glucose metabolism comprises increasing the activity of a glucose hypometabolic enzyme. In some embodiments, increasing glucose metabolism comprises increasing the activity of a pyruvate dehydrogenase complex (PDH complex).

[0208] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0209] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In someAttomey Docket No. FRD-002WO embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0210] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0211] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0212] In another aspect, provided herein is a method of treating Huntington’ s Disease in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0213] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35%Attorney Docket No. FRD-002WO to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0214] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0215] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%. about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In someAttorney Docket No. FRD-002WO embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0216] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0217] In another aspect, provided herein is a method of treating heart failure in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises heart tissue. In some embodiments, increasing glucose metabolism comprises increasing the activity of a glucose hypometabolic enzyme. In some embodiments, increasing glucose metabolism comprises increasing the activity of a pyruvate dehydrogenase complex (PDH complex).

[0218] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments,Attorney Docket No. FRD-002WO the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0219] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0220] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In someAttorney Docket No. FRD-002WO embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0221] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0222] In another aspect, provided herein is a method of treating stroke in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0223] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0224] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,Attorney Docket No. FRD-002WO about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0225] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0226] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP isAttorney Docket No. FRD-002WO increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0227] In another aspect, provided herein is a method of treating spinal cord injury in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0228] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0229] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolismAttorney Docket No. FRD-002WO is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0230] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0231] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0232] In another aspect, provided herein is a method of treating type 2 diabetes in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0233] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism isAttorney Docket No. FRD-002WO increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0234] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0235] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP isAttorney Docket No. FRD-002WO increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0236] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0237] In another aspect, provided herein is a method of treating obesity in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0238] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.Attorney Docket No. FRD-002WO

[0239] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0240] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0241] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In someAttorney Docket No. FRD-002WO embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0242] In another aspect, provided herein is a method of treating non-alcoholic fatty liver disease (NAFLD) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0243] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0244] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In someAttomey Docket No. FRD-002WO embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0245] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0246] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0247] In another aspect, provided herein is a method of treating non-alcoholic steatohepatitis (NASH) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0248] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35%Attorney Docket No. FRD-002WO to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0249] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0250] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%. about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In someAttorney Docket No. FRD-002WO embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0251] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0252] In another aspect, provided herein is a method of treating polycystic ovarian syndrome (PCOS) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0253] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased byAttorney Docket No. FRD-002WO about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0254] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0255] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0256] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%.Attorney Docket No. FRD-002WO In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0257] In another aspect, provided herein is a method of treating epilepsy in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0258] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0259] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In someAttorney Docket No. FRD-002WO embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0260] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0261] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.Attorney Docket No. FRD-002WO

[0262] In another aspect, provided herein is a method of treating traumatic brain injury (TBI) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0263] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0264] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by aboutAttorney Docket No. FRD-002WO 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0265] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0266] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0267] In another aspect, provided herein is a method of treating amyotrophic lateral sclerosis (ALS) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0268] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism isAttorney Docket No. FRD-002WO increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0269] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0270] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP isAttorney Docket No. FRD-002WO increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0271] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0272] In another aspect, provided herein is a method of treating cancer in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0273] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.Attorney Docket No. FRD-002WO

[0274] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0275] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0276] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In someAttorney Docket No. FRD-002WO embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0277] In another aspect, provided herein is a method of treating cancer cachexia in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0278] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0279] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, theAttorney Docket No. FRD-002WO glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0280] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0281] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0282] In another aspect, provided herein is a method of treating peripheral vascular disease in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0283] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, aboutAttorney Docket No. FRD-002WO 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0284] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0285] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%. about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments,Attorney Docket No. FRD-002WO the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0286] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0287] In another aspect, provided herein is a method of treating mitochondrial disorders in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0288] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% toAttorney Docket No. FRD-002WO 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0289] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0290] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0291] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments,Attorney Docket No. FRD-002WO the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0292] In another aspect, provided herein is a method of treating chronic fatigue syndrome in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0293] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0294] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, theAttorney Docket No. FRD-002WO glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0295] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0296] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0297] In another aspect, provided herein is a method of treating metabolic syndrome in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.Attorney Docket No. FRD-002WO

[0298] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0299] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0300] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP isAttorney Docket No. FRD-002WO increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0301] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0302] In another aspect, provided herein is a method of treating bipolar disorder in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0303] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments,Attorney Docket No. FRD-002WO the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0304] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0305] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In someAttomey Docket No. FRD-002WO embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0306] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0307] In another aspect, provided herein is a method of treating major depressive disorder in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0308] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0309] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,Attorney Docket No. FRD-002WO about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0310] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0311] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP isAttorney Docket No. FRD-002WO increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0312] In another aspect, provided herein is a method of treating anxiety disorders in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0313] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0314] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by aboutAttorney Docket No. FRD-002WO 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0315] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0316] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0317] In another aspect, provided herein is a method of treating schizophrenia in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject. In some embodiments, the one or more tissues comprises brain tissue.

[0318] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism isAttorney Docket No. FRD-002WO increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0319] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0320] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP isAttorney Docket No. FRD-002WO increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0321] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0322] In another aspect, provided herein is a method of treating autism spectrum disorder in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0323] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In someAttorney Docket No. FRD-002WO embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0324] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0325] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0326] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATPAttorney Docket No. FRD-002WO is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0327] In another aspect, provided herein is a method of treating attention deficit hyperactivity disorder (ADHD) in a subject, the method comprising increasing glucose metabolism in one or more tissues of the subject.

[0328] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0329] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolismAttorney Docket No. FRD-002WO is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0330] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP is increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0331] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0332] In another aspect, provided herein is a method of treating any condition in which a subject’s tissue exhibits a quantifiable reduction in glucose utilization, the method comprising increasing glucose metabolism in one or more tissues of the subjectAttorney Docket No. FRD-002WO

[0333] In some embodiments, the glucose metabolism is increased by about 5% to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, or about 70 to 75%. In some embodiments, the glucose metabolism is increased by about 5% to 10%. In some embodiments, the glucose metabolism is increased by about 10% to 15%. In some embodiments, the glucose metabolism is increased by about 15% to 20%. In some embodiments, the glucose metabolism is increased by about 20% to 25%. In some embodiments, the glucose metabolism is increased by about 25% to 30%. In some embodiments, the glucose metabolism is increased by about 30% to 35%. In some embodiments, the glucose metabolism is increased by about 35% to 40%. In some embodiments, the glucose metabolism is increased by about 40% to 45%. In some embodiments, the glucose metabolism is increased by about 45% to 50%. In some embodiments, the glucose metabolism is increased by about 50% to 55%. In some embodiments, the glucose metabolism is increased by about 55% to 60%. In some embodiments, the glucose metabolism is increased by about 60% to 65%. In some embodiments, the glucose metabolism is increased by about 65% to 70%. In some embodiments, the glucose metabolism is increased by about 70 to 75%.

[0334] In some embodiments, the glucose metabolism is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, or about 75%. In some embodiments, the glucose metabolism is increased by about 5%. In some embodiments, the glucose metabolism is increased by about 10%. In some embodiments, the glucose metabolism is increased by about 15%. In some embodiments, the glucose metabolism is increased by about 20%. In some embodiments, the glucose metabolism is increased by about 25%. In some embodiments, the glucose metabolism is increased by about 30%. In some embodiments, the glucose metabolism is increased by about 35%. In some embodiments, the glucose metabolism is increased by about 40%. In some embodiments, the glucose metabolism is increased by about 45%. In some embodiments, the glucose metabolism is increased by about 50%. In some embodiments, the glucose metabolism is increased by about 55%. In some embodiments, the glucose metabolism is increased by about 60%. In some embodiments, the glucose metabolism is increased by about 65%. In some embodiments, the glucose metabolism is increased by about or about 70%. In some embodiments, the glucose metabolism is increased by about 75%.

[0335] In some embodiments, increasing glucose metabolism comprises increasing the production of adenosine triphosphate (ATP). In some embodiments, the production of ATP isAttorney Docket No. FRD-002WO increased by about 5% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%. In some embodiments, the production of ATP is increased by about 5% to 10%. In some embodiments, the production of ATP is increased by about 10% to 15%. In some embodiments, the production of ATP is increased by about 15% to 20%. In some embodiments, the production of ATP is increased by about 20% to 25%. In some embodiments, the production of ATP is increased by about 25% to 30%. In some embodiments, the production of ATP is increased by about 30% to 35%. In some embodiments, the production of ATP is increased by about 35% to 40%. In some embodiments, the production of ATP is increased by about 40% to 45%. In some embodiments, the production of ATP is increased by about 45% to 50%.

[0336] In some embodiments, the production of ATP is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%. In some embodiments, the production of ATP is increased by about 5%. In some embodiments, the production of ATP is increased by about 10%. In some embodiments, the production of ATP is increased by about 15%. In some embodiments, the production of ATP is increased by about 20%. In some embodiments, the production of ATP is increased by about 25%. In some embodiments, the production of ATP is increased by about 30%. In some embodiments, the production of ATP is increased by about 35%. In some embodiments, the production of ATP is increased by about 40%. In some embodiments, the production of ATP is increased by about 45%. In some embodiments, the production of ATP is increased by about 50%.

[0337] In certain embodiments, the method disclosed herein results in an increase in ATP production, restoration of cellular energy metabolism, compensation for glucose hypometabolism, improvement in metabolic efficiency, improvement in mitochondrial respiration, improvement in basal respiratory capacity, improvement in mitochondrial function, increase in oxygen consumption rate (OCR), improvement in neuronal viability, reduction in neuronal cell death, reduction in apoptosis, protection against amyloid-induced toxicity, promotion of neuronal survival, reduction in reactive oxygen species (ROS), reduction in oxidative stress, improvement in mitochondrial integrity, increased microglial uptake of amyloid beta, increased clearance of amyloid beta, acceleration of amyloid clearance kinetics, improvement in cognitive function, stabilization of cognitive decline, improvement in memory, improvement in alertness, improvement in language function, improvement in overall cognitive performance, improvement in cardiac output, improvement in cardiac function, improvement in ejection fraction, reduction in blood glucose levels, improvement in glycemic control, reductionAttomey Docket No. FRD-002WO in HbAlc, improvement in insulin sensitivity, reduction in insulin requirements, reduction in body weight, reduction in fat mass, reduction in liver fat, improvement in liver function, reduction in hepatic inflammation, increased time -in-range for glucose control, stabilization of metabolic parameters, increased energy levels, reduced fatigue, reduced sugar cravings, improved quality of life, sustained elevation of blood ketone levels, improved tolerability, and controlled or prolonged ketone release.

[0338] In certain embodiments, the method disclosed herein results in an increase in ATP production. In certain embodiments, the method disclosed herein results in restoration of cellular energy metabolism. In certain embodiments, the method disclosed herein results in compensation for glucose hypometabolism. In certain embodiments, the method disclosed herein results in improvement in metabolic efficiency. In certain embodiments, the method disclosed herein results in improvement in mitochondrial respiration. In certain embodiments, the method disclosed herein results in improvement in basal respiratory capacity. In certain embodiments, the method disclosed herein results in improvement in mitochondrial function. In certain embodiments, the method disclosed herein results in an increase in oxygen consumption rate (OCR). In certain embodiments, the method disclosed herein results in improvement in neuronal viability. In certain embodiments, the method disclosed herein results in reduction in neuronal cell death. In certain embodiments, the method disclosed herein results in reduction in apoptosis. In certain embodiments, the method disclosed herein results in protection against amyloid-induced toxicity. In certain embodiments, the method disclosed herein results in promotion of neuronal survival. In certain embodiments, the method disclosed herein results in reduction in reactive oxygen species (ROS). In certain embodiments, the method disclosed herein results in reduction in oxidative stress. In certain embodiments, the method disclosed herein results in improvement in mitochondrial integrity. In certain embodiments, the method disclosed herein results in increased microglial uptake of amyloid beta. In certain embodiments, the method disclosed herein results in increased clearance of amyloid beta. In certain embodiments, the method disclosed herein results in acceleration of amyloid clearance kinetics. In certain embodiments, the method disclosed herein results in improvement in cognitive function. In certain embodiments, the method disclosed herein results in stabilization of cognitive decline. In certain embodiments, the method disclosed herein results in improvement in memory. In certain embodiments, the method disclosed herein results in improvement in alertness. In certain embodiments, the method disclosed herein results in improvement in language function. In certain embodiments, the method disclosed herein results in improvement in overall cognitive performance. In certain embodiments, the method disclosed herein results in improvement in cardiac output. In certain embodiments, the method disclosed herein results inAttorney Docket No. FRD-002WO improvement in cardiac function. In certain embodiments, the method disclosed herein results in improvement in ejection fraction. In certain embodiments, the method disclosed herein results in reduction in blood glucose levels. In certain embodiments, the method disclosed herein results in improvement in glycemic control. In certain embodiments, the method disclosed herein results in reduction in HbAlc. In certain embodiments, the method disclosed herein results in improvement in insulin sensitivity. In certain embodiments, the method disclosed herein results in reduction in insulin requirements. In certain embodiments, the method disclosed herein results in reduction in body weight. In certain embodiments, the method disclosed herein results in reduction in fat mass. In certain embodiments, the method disclosed herein results in reduction in liver fat. In certain embodiments, the method disclosed herein results in improvement in liver function. In certain embodiments, the method disclosed herein results in reduction in hepatic inflammation. In certain embodiments, the method disclosed herein results in increased time-in-range for glucose control. In certain embodiments, the method disclosed herein results in stabilization of metabolic parameters. In certain embodiments, the method disclosed herein results in increased energy levels. In certain embodiments, the method disclosed herein results in reduced fatigue. In certain embodiments, the method disclosed herein results in reduced sugar cravings. In certain embodiments, the method disclosed herein results in improved quality of life. In certain embodiments, the method disclosed herein results in sustained elevation of blood ketone levels. In certain embodiments, the method disclosed herein results in improved tolerability. In certain embodiments, the method disclosed herein results in controlled or prolonged ketone release.

[0339] This previously unrecognized pattern of convergent enzymatic deficiencies at remarkably similar magnitudes (30-50% reductions) strongly supports a common metabolic pathophysiology and points to potential common therapeutic targets.Preserved Ketone Metabolism: The Critical Therapeutic Opportunity

[0340] The most significant and therapeutically relevant finding is that ketone metabolism remains intact or is enhanced across these conditions despite impaired glucose utilization:Alzheimer's Disease

[0341] Three independent PET studies using radiolabeled ketones confirmed that AD brains readily oxidize ketones at normal rates despite significant glucose hypometabolism.Parkinson's Disease

[0342] PD brain ketone utilization appears preserved, with preclinical models showing ketones effectively utilized and providing neuroprotection.Attorney Docket No. FRD-002WO Heart Failure

[0343] Failing hearts demonstrate ~2x higher ketone uptake and utilization than normal hearts, with upregulation of ketone-specific enzymes (BDH1, SCOT) and transporters.

[0344] This differential preservation of ketone metabolism despite glucose hypometabolism represents a critical therapeutic opportunity that forms the core of the present invention.Therapeutic Efficacy Across Diverse Conditions

[0345] Robust clinical evidence demonstrates that addressing the common glucose hypometabolism through ketone therapy produces significant and consistent benefits across these diverse conditions:Controlled Clinical Evidence of EfficacyAlzheimer's Disease:

[0346] In one randomized controlled clinical study (n=152), APOE-e4-negative patients on ketogenic a compound of Formula (A)C-1202 improved by +4.7 points versus placebo on the ADAS-Cog at Day 45 (p=0.0005) and by +3.4 points at Day 90 (p=0.0148). Even in the overall intention-to-treat sample, a 1.9-point ADAS-Cog improvement (p=0.02) was observed. 5 of 7 clinical studies of ketogenic interventions in MC1 / AD showed significant cognitive or metabolic improvements.Parkinson's Disease:

[0347] In one randomized controlled clinical study (n=47), 8-week ketogenic diet produced 41% improvement in non-motor symptoms (MDS-UPDRS Part I) versus 11% with low-fat diet (p<0.001). Therapeutic ketosis led to improved P-hydroxybutyrate levels of ~2-3 mM, associated with symptom improvements.Heart Failure:

[0348] In clinical settings, administration of intravenous P-hydroxybutyrate to achieve blood concentrations of approximately 3 mM increased cardiac output by 2.0 L / min (-30% increase) without increasing myocardial oxygen consumption. SGLT2 inhibitors (which induce mild ketosis) demonstrated -25% reductions in HF hospitalization risk. Animal models: 4-week ketone ester improved ejection fraction by -15 percentage points.Dose-Response Relationship Across Conditions

[0349] A key finding supporting the unified mechanism is a consistent dose-response relationship between circulating ketone levels and clinical improvement across multiple diseaseAttorney Docket No. FRD-002WO states. For example, higher serum ketone levels are associated with greater cognitive improvement in subjects with Alzheimer’s disease. Similarly, in Parkinson’s disease, ketone levels in the range of approximately 2-3 mM are associated with greater improvement in clinical symptoms. In heart failure, blood P-hydroxy butyrate levels of approximately 3 mM are associated with increases in cardiac output on the order of approximately 30%. This consistent relationship between ketone levels and clinical improvement across diverse conditions strongly supports the mechanistic validity of the disclosed approach.Mechanistic DetailsMetabolic Bypass Mechanism

[0350] The invention leverages the critical insight that ketone bodies (P-hydroxybutyrate, acetoacetate) can bypass the glucose-specific metabolic blockade observed in these conditions:

[0351] In Alzheimer's and heart failure, pyruvate dehydrogenase (PDH) complex activity is reduced by 30-50%, creating a bottleneck for glucose-derived pyruvate to enter the TCA cycle. Ketone bodies are metabolized to acetyl-CoA via a distinct enzymatic pathway (|3-hydroxybutyrate dehydrogenase acetoacetate acetoacetyl-CoA acetyl-CoA) that entirely bypasses the PDH complex. In Parkinson's disease, Complex I deficiency (-30% reduced) limits NADH oxidation from glucose metabolism; ketone metabolism generates FADH2 that can enter the electron transport chain at Complex II, bypassing the Complex I deficiency. This metabolic bypass mechanism explains why ketone therapy is effective across these seemingly disparate conditions.Energy Yield and Efficiency Advantages

[0352] The invention further leverages previously unappreciated energetic advantages of ketone metabolism. Ketone bodies produce more ATP per oxygen molecule consumed compared to glucose (2.5 vs 2.25 ATP / O), providing energetic efficiency in oxygen-limited conditions. Ketone metabolism produces fewer reactive oxygen species than glucose or fatty acid oxidation, reducing oxidative stress that is common across these conditions. Ketones have direct signaling effects that activate mitochondrial biogenesis and antioxidant pathways (e.g., Nrf2), providing benefits beyond simple energy provision.Methods of Treatment

[0353] One aspect of the disclosure provides a method of treating a subject diagnosed with a glucose hypometabolic disorder, comprising:Attorney Docket No. FRD-002WO (a) measuring a glucose metabolism deficit (G_Diff) in one or more tissues of the subject using at least one diagnostic technique to obtain a quantitative indication of the subject’s impaired glucose utilization;(b) calculating a personalized exogenous ketone dosage (K) based on the measured G_Diff, wherein said calculation comprises applying at least one algorithm that correlates the measured G_Diff to the exogenous ketone intake required to at least partially compensate for the subject’s impaired glucose utilization; and(c) administering an exogenous ketone composition to the subject in accordance with the calculated personalized exogenous ketone dosage,wherein the administered exogenous ketone composition provides an alternative metabolic fuel to the affected tissues, thereby addressing the subject’s glucose hypometabolism.

[0354] In certain embodiments, the at least one diagnostic technique is selected from positron emission tomography (PET), magnetic resonance spectroscopy (MRS), metabolic assays, and wearable biosensors.

[0355] In certain embodiments, the calculation in step (b) comprises computing the personalized exogenous ketone dosage (K) using Formula (I):K = G_Diff x (4 / 4.7) x F x p(I)wherein,G_Diff is the measured glucose deficit in grams or equivalent energy units;(4 / 4.7) is a factor accounting for relative energy yields of glucose versus ketones; F is an efficiency factor (F 1) reflecting systemic overhead or disease-specific factors; and p is a partition factor (0 < p1) representing tissue-specific ketone uptake capacity.

[0356] It will be appreciated that Formula (I) is one exemplary approach to determining the ketone dosage K based on G_Diff. In other embodiments, the personalized ketone dosage can be calculated using different algorithms or computational techniques. For instance, a machinelearning model (trained on data from numerous patients) may predict an optimal ketone dose by taking the measured G_Diff as well as additional patient-specific parameters into account (such as the patient’s age, liver function, current diet, or oxygen saturation). In another embodiment, a simple lookup table or an iterative titration protocol is used: the system might start at a baselineAttorney Docket No. FRD-002WO ketone dose and adjust upward or downward in controlled increments until the patient’s metabolic markers reach target ranges. The computational module performing the dose calculation can be implemented locally (e.g., on a wearable device or pump controller) or remotely (e.g., a cloud server that receives the diagnostic data and returns a dosing recommendation). In all cases, the core principle is that the dose is quantitatively based on the measured glucose deficit, regardless of the specific mathematical model used. This ensures that even if different formulae or algorithms are employed, they fall within the scope of using G_Diff to inform therapy.

[0357] In certain embodiments, the glucose hypometabolic disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, heart failure, stroke, spinal cord injury, type 2 diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), polycystic ovary syndrome (PCOS), epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer, cancer cachexia, peripheral vascular disease, mitochondrial disorders, chronic fatigue syndrome, metabolic syndrome, bipolar disorder, major depressive disorder, anxiety disorders, schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), and any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

[0358] In certain embodiments, the glucose hypometabolic disorder is Alzheimer’s disease. In certain embodiments, the glucose hypometabolic disorder is Parkinson's disease. In certain embodiments, the glucose hypometabolic disorder is Huntington’s disease. In certain embodiments, the glucose hypometabolic disorder is heart failure. In certain embodiments, the glucose hypometabolic disorder is stroke. In certain embodiments, the glucose hypometabolic disorder is spinal cord injury. In certain embodiments, the glucose hypometabolic disorder is type 2 diabetes. In certain embodiments, the glucose hypometabolic disorder is obesity. In certain embodiments, the glucose hypometabolic disorder is non-alcoholic fatty liver disease (NAFLD). In certain embodiments, the glucose hypometabolic disorder is non-alcoholic steatohepatitis (NASH). In certain embodiments, the glucose hypometabolic disorder is polycystic ovary syndrome (PCOS). In certain embodiments, the glucose hypometabolic disorder is epilepsy. In certain embodiments, the glucose hypometabolic disorder is traumatic brain injury. In certain embodiments, the glucose hypometabolic disorder is amyotrophic lateral sclerosis. In certain embodiments, the glucose hypometabolic disorder is cancer. In certain embodiments, the glucose hypometabolic disorder is cancer cachexia. In certain embodiments, the glucose hypometabolic disorder is peripheral vascular disease. In certain embodiments, the glucose hypometabolic disorder is a mitochondrial disorder. In certain embodiments, the glucoseAttomey Docket No. FRD-002WO hypometabolic disorder is chronic fatigue syndrome. In certain embodiments, the glucose hypometabolic disorder is metabolic syndrome. In certain embodiments, the glucose hypometabolic disorder is bipolar disorder. In certain embodiments, the glucose hypometabolic disorder is major depressive disorder. In certain embodiments, the glucose hypometabolic disorder is an anxiety disorder. In certain embodiments, the glucose hypometabolic disorder is schizophrenia. In certain embodiments, the glucose hypometabolic disorder is autism spectrum disorder. In certain embodiments, the glucose hypometabolic disorder is attention deficit hyperactivity disorder (ADHD). In certain embodiments, the glucose hypometabolic disorder is any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization.

[0359] In certain embodiments, the method further comprises classifying the subject’s disease severity into one or more metabolic stages (Stage 0 through 4) based on the measured G_Diff, and increasing the exogenous ketone dosage for each advancing metabolic stage to at least partially offset the subject’s progressively reduced glucose utilization.

[0360] In certain embodiments, measuring the glucose metabolism deficit (G_Diff) comprises performing a fluorodeoxyglucose PET (FDG-PET) scan to quantify local or global glucose uptake in the subject’s tissue, and comparing the measured local or global glucose uptake to a reference level to determine a magnitude of G_Diff, wherein the calculated personalized exogenous ketone dosage (K) in step (b) is directly proportional to the measured impaired glucose utilization.

[0361] In certain embodiments, the method further comprises concurrently administering at least one standard-of-care therapy for the glucose hypometabolic disorder, wherein the exogenous ketone composition provides an unexpectedly synergistic improvement in clinical or functional outcomes relative to the standard-of-care therapy alone. In some embodiments, the standard-of-care therapy is a standard-of-care-therapy for Alzheimer’s disease. In some embodiments, the standard-of-care therapy is a standard-of-care-therapy for Parkinson’s disease. In some embodiments, the standard-of-care therapy is a standard-of-care-therapy for heart failure.

[0362] In certain embodiments, the exogenous ketone therapy is administered in combination with at least one standard-of-care treatment for the subject’s condition. For example, a subject with Alzheimer’s disease may continue on an acetylcholinesterase inhibitor or other approved Alzheimer’s medication while receiving the ketone therapy; a subject with Parkinson’s disease may concurrently receive dopaminergic therapy (e.g., L-DOPA or a dopamine agonist); and a heart failure patient may remain on standard heart failure medications such as beta blockers orAttorney Docket No. FRD-002WO ACE inhibitors. The ketone supplementation in these cases provides a synergistic or additive improvement in clinical outcomes relative to standard therapy alone, by addressing the metabolic deficit underlying the disease. In essence, the platform can augment existing therapies rather than replace them, integrating metabolic treatment into the patient’s overall care regimen.

[0363] In certain embodiments, the exogenous ketone composition comprises delivering an amount sufficient to raise the subject’s blood beta-hydroxybutyrate (PHB) concentration to at least about 0.5 millimolar (rnM), wherein a therapeutic level of ketosis is induced thereby alleviating the measured glucose metabolism deficit (G_Diff).

[0364] In certain embodiments, the exogenous ketone composition is administered via any suitable route, including but not limited to oral, enteral (e.g., through a feeding tube), parenteral (such as intravenous infusion), or other routes tailored for efficient delivery. For example, the ketone formulation can be given sublingually or buccally (e.g., as a dissolvable film, lozenge, or spray) to allow rapid absorption through the oral mucosa. In other embodiments, a transdermal patch or implant provides slow, sustained release of a ketone precursor, ensuring prolonged therapeutic ketosis without repeated dosing. Yet another delivery mode involves intranasal or inhalable formulations - for instance, an aerosolized ketone preparation that can be inhaled for direct uptake via the lungs. These alternative delivery routes, in addition to standard oral or injectable routes, broaden the clinical usability of the therapy and can be selected based on the patient's needs (rapid vs. sustained release, outpatient vs. inpatient setting, etc.).

[0365] The exogenous ketone composition itself can take on various forms. In different embodiments, the composition comprises one or more of the following (alone or in combination): [3-hydroxybutyrate (PHB) in a salt form (with a physiologically acceptable cation) or attached to a carrier molecule; acetoacetate (AcAc) in salt or ester form; ketone esters (for example, glycerol tri-P-hydroxybutyrate, 1,3 -butanediol mono- or di-ester of PHB, or other polyol-based ketone esters as described elsewhere herein); ketone amides or ethers; mediumchain triglycerides (MCTs) that are metabolized into ketone bodies; and various ketone analogs or precursors that yield ketone bodies upon metabolism (such as 1,3-butanediol itself, or certain ketogenic amino acids). Any pharmaceutically acceptable derivative of these compounds (e.g., salts, esters, or co-crystals) is included. In some embodiments, the chosen ketone composition is one of the specifically disclosed compounds of Formula (A) (for instance, a polyol bearing multiple P-hydroxybutyrate groups) formulated with a suitable excipient. In all cases, the administered exogenous ketone composition is provided in an amount effective to achieve a therapeutically useful level of ketosis (for example, raising blood PHB to around or above 0.5Attorney Docket No. FRD-002WO mM), thereby at least partially compensating for the subject’s measured glucose metabolism deficit.

[0366] In certain embodiments, the exogenous ketone composition is administered orally, enterally, parenterally, or intravenously, and the exogenous ketone composition is selected from the group consisting of: beta-hydroxybutyrate (PHB) salts, beta-hydroxybutyrate (PHB) bound to any carrier molecule, acetoacetate (AcAc) salts, acetoacetate (AcAc) bound to any carrier molecule, 1,3-butanediol, glycerol tributyrate or other glycerol-butyric acid esters, mediumchain triglycerides (MCTs) capable of conversion to ketone bodies, ketone amides, ketone ethers, ketone analogs, and any pharmaceutically acceptable derivatives or combinations thereof, and wherein the administered exogenous ketone composition provides a therapeutically effective level of ketones that at least partially compensates for the subject’s measured glucose metabolism deficit. In some embodiments, the exogenous ketone composition is an exogenous ketone composition described herein (e.g., in the Compounds and Compositions section).

[0367] In certain embodiments, the exogenous ketone composition is a compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of-O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S-, -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- ,-S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.. In certain embodiments, the exogenous ketone composition is a compound in Table 1. In certain embodiments, the exogenous ketone composition is a compound selected from the groupAttorney Docket No. FRD-002WO

[0368] Another aspect of the disclosure provides a method of treating a subject diagnosed with a glucose hypometabolic disorder, comprising:Attomey Docket No. FRD-002WO (a) administering to the subject an exogenous ketone composition in an amount sufficient to achieve and maintain a sustained blood ketone level of at least about 0.5 mM P-hydroxybutyrate ( HB) for a therapeutically effective duration; and(b) periodically measuring or estimating the subject’s ketone levels by one or more suitable techniques,wherein said sustained blood ketone level alleviates or improves one or more clinical symptoms of the glucose hypometabolic disorder, independent of explicitly measuring any glucose metabolism deficit in the subject.

[0369] In certain embodiments, the glucose hypometabolic disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any condition in which the subject’s tissue exhibits a quantifiable reduction in glucose utilization. In certain embodiments, the glucose hypometabolic disorder is Alzheimer’s disease. In certain embodiments, the glucose hypometabolic disorder is Parkinson’s disease. In certain embodiments, the glucose hypometabolic disorder is heart failure.

[0370] In certain embodiments, the exogenous ketone composition comprises a sustained-release or slow-release formulation, thereby maintaining the blood ketone level at or above about 0.5 mM for at least about 4 hours following a single administration.

[0371] In certain embodiments, the periodic measurement or estimation of the subject’s ketone levels is performed using any invasive or non-invasive technique, including but not limited to finger-stick blood testing, continuous or intermittent ketone monitoring devices, breath ketone analysis, transdermal sensors, saliva testing, or urine ketone measurements.

[0372] In certain embodiments, the method further comprises adjusting a dosage or frequency of administration of the exogenous ketone composition based on said measured or estimated ketone levels, thereby maintaining a therapeutic blood ketone concentration between about 0.5 mM and about 5.0 mM.

[0373] In certain embodiments, the method further comprises administering, concurrently or sequentially, at least one adjunctive metabolic therapy selected from lactate, pyruvate, mediumchain triglycerides (MCTs), insulin-sensitizing agents, or hyperbaric oxygen therapy, wherein said adjunctive therapy enhances or complements the therapeutic efficacy of sustained ketosis.

[0374] In certain embodiments, the ketone therapy is combined with the administration of one or more additional metabolic fuels or modulators to further support cellular energy production. For instance, lactate or pyruvate can be administered alongside the exogenous ketones, eitherAttorney Docket No. FRD-002WO intravenously or via another route, providing an alternative fuel that certain tissues can utilize directly. In other embodiments, an insulin-sensitizing agent (such as metformin or a PPAR agonist) is co-administered to improve the efficiency of the subject’s residual glucose utilization and enhance uptake of ketones by tissues. These adjunctive treatments, when used in conjunction with the ketone supplementation, help to alleviate the energy crisis by attacking the problem from multiple angles - e.g., improving glucose handling with insulin sensitizers or supplying additional fuel substrates like lactate. The combination of ketones with such cotherapies is intended to be within the scope of the present platform, as it addresses the same underlying glucose hypometabolism with a multi-faceted approach.

[0375] In certain embodiments, the exogenous ketone composition is administered via any suitable route, including but not limited to oral, enteral (e.g., through a feeding tube), parenteral (such as intravenous infusion), or other routes tailored for efficient delivery. For example, the ketone formulation can be given sublingually or buccally (e.g., as a dissolvable film, lozenge, or spray) to allow rapid absorption through the oral mucosa. In other embodiments, a transdermal patch or implant provides slow, sustained release of a ketone precursor, ensuring prolonged therapeutic ketosis without repeated dosing. Yet another delivery mode involves intranasal or inhalable formulations - for instance, an aerosolized ketone preparation that can be inhaled for direct uptake via the lungs. These alternative delivery routes, in addition to standard oral or injectable ro...

Claims

Attorney Docket No. FRD-002WO CLAIMSWhat is claimed is:

1. A compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, whereinR1is a polyol, amino acid, or a derivative thereof;X is a covalent linker selected from the group consisting of -O-C(O)-, -C(O)-O-, -C(O)-NH-, -NH-C(O)-, -C(O)-S- -S-C(O)-, -O-C(O)-O- , -O-C(O)-NH- or -NH-C(O)-O- , -O-P(O2)-O- , -O-SO2-O- , -C=N- -C=N-NH- , -O- , -NH- , -S- , and -S-S- ;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

2. The compound of claim 1, wherein R1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, taurine, glycerol, allulose, aspartic acid, and carnosine.

3. The compound of claim 1, wherein R1is trehalose, myo-inositol, or D-ribose.

4. The compound of claim 1, wherein X is -O-.

5. The compound of claim 1, wherein X is -NH-.

6. The compound of claim 1, wherein R2is P-hydroxybutyryl.

7. The compound of claim 1 , wherein R2is acetoacetyl.

8. The compound of claim 1, wherein n is an integer from 1 to 20.

9. The compound of claim 1 , wherein n is equal to the number of hydroxy groups in R1.

10. The compound of claim 1, wherein the compound is compound of Formula (A):Attorney Docket No. FRD-002WOor a pharmaceutically acceptable salt or solvate thereof, whereinR1is selected from the group consisting of trehalose, myo-inositol, D-ribose, inulin, creatine, glycine, carnitine, and taurine;X is -O- or -NH-;R2is a ketone body moiety selected from P-hydroxybutyryl, acetoacetyl, or a derivative thereof; andn is an integer from 1 to 50, wherein n represents the total number of ketone body moieties attached to R1, and wherein n can be less than or equal to the total number of available attachment sites on R1.

11. The compound of claim 1, wherein the compound is selected from the group consistingAttorney Docket No. FRD-002WOAttorney Docket No. FRD-002WO12. A pharmaceutical composition comprising a compound according to any one of claims 1-11 and a pharmaceutically acceptable carrier, excipient, or diluent.

13. The pharmaceutical composition of claim 11, comprising at least two unique compounds according to claim 1.

14. The pharmaceutical composition of claim 13, wherein at least one compound comprises R2as P-hydroxybutyryl and at least one compound comprises R2as acetoacetyl.

15. The pharmaceutical composition of claim 14, wherein the at least two unique compounds are attached to the same R1carrier molecule.

16. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is formulated for oral, enteral, parenteral, or intravenous administration.

17. A method of treating a glucose hypometabolic disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-11 or a pharmaceutical composition according to any one of claims 12-16.

18. The method of claim 17, wherein the glucose hypometabolic disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, heart failure, type 2 diabetes, epilepsy, traumatic brain injury, amyotrophic lateral sclerosis, cancer cachexia, metabolic syndrome, and any condition in which the subject's tissue exhibits a quantifiable reduction in glucose utilization.

19. The method of claim 17, wherein the therapeutically effective amount is determined based on a measured glucose metabolism deficit (G_Diff) in one or more tissues of the subject.Attorney Docket No. FRD-002WO 20. The method of claim 19, wherein the amount is calculated using the formula:K = G_Diff x (4 / 4.7) x F x p(I)whereinK is the recommended ketone dosage,G_Diff is the measured glucose deficit,(4 / 4.7) accounts for the relative energy yields of glucose versus ketones,F is an efficiency factor, andp is a partition factor representing tissue-specific ketone uptake capacity.

21. The method of claim 17, further comprising administering at least one standard-of-care therapy for the glucose hypometabolic disorder.

22. The method of claim 17, wherein the administered compound provides an amount sufficient to raise the subject's blood beta-hydroxybutyrate (BHB) concentration to at least about 0.5 millimolar (mM).

23. A method of making a compound according to claim 1, comprising:(a) providing a polyol;(b) providing a ketone body or protected ketone body, wherein the ketone body is 0-hydroxybutyrate, acetoacetate, or a combination thereof;(c) activating the ketone body or protected ketone body for coupling;(d) reacting the activated ketone body or protected ketone body with the polyol to form ester or amide linkages, wherein the reaction conditions are controlled to achieve either partial or complete substitution of available attachment sites; and(e) optionally deprotecting any protected groups to yield the final compound.

24. The method of claim 23, further comprising:(a) initially reacting the polyol with a first ketone body to achieve partial substitution; and(b) subsequently reacting the partially substituted intermediate with a second, different ketone body to create a mixed conjugate containing both [3-hydroxybutyrate and acetoacetate moieties on the same carrier molecule.

25. A kit comprising:(a) a compound according to any one of claims 1-11 or a pharmaceutical composition according to any one of claims 12-16;Attorney Docket No. FRD-002WO (b) instructions for measuring or estimating a glucose metabolism deficit (G_Diff) in a subject; and(c) a reference chart or algorithmic guide that translates the measured G_Diff into a recommended personalized dosage.

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