Methods for regulating blood glucose levels using a dual ampk activator and mitochondrial uncoupler

Abstract

Provided herein are methods for regulating blood glucose levels in a subject in need thereof by effects manifested as increasing glucose effectiveness. The subject is insulin-eficient, and prior to treatment with the compounds herein, is taking or needs to take exogenous insulin. In some embodiments, the methods involve administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as described herein; monitoring the subject's blood glucose levels; and delaying need for use of exogenous insulin, or reducing and / or eventually eliminating the subject's need for exogenous insulin so long as the subject is being administered a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as described herein.

Description

METHODS FOR REGULATING BLOOD GLUCOSE LEVELS USING A DUAL AMPK ACTIVATOR AND MITOCHONDRIAL UNCOUPLER CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 514,696, filed July 20, 2023, which is incorporated herein by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (286502000840SEQLIST.xml; Size: 43,302 bytes; and Date of Creation: July 18, 2024) is herein incorporated by reference in its entirety. FIELD

[0003] The present disclosure relates generally to methods of regulating blood glucose levels using a dual AMPK activator and mitochondrial uncoupler, including for treating Type 1 diabetes (T1D) and other diseases, disorders or conditions in subjects who are insulin deficient and, prior to treatment using the compounds herein, are taking or need to take exogenous insulin (or an external source of insulin). BACKGROUND

[0004] Glucose disposal in humans is effectuated by both insulin-dependent and insulin- independent glucose uptake. In humans, the ability of glucose to stimulate its own uptake independently of insulin, which is known as “glucose effectiveness,” accounts for around 50% of glucose disposal. Under conditions of insulin deficiency, such as in individuals with Type-1 diabetes (T1D), which leads to hyperglycemia, increased glucose effectiveness may be advantageous. Anti-diabetic drugs currently on the market and in clinical development do not typically enhance glucose effectiveness in diabetic individuals.

[0005] ,Q^LQGLYLGXDOV^ZLWK^7^'^^ȕ-cells, which make insulin, are destroyed by the immune system. Without insulin, the body is unable to regulate glucose levels in the bloodstream, which leads to high blood sugar levels, also known in the art as hyperglycemia. Individuals with T1D rely on exogenous insulin to control blood-sugar levels. However, if these individuals take on more insulin than needed, their blood sugar can drop too low, resulting in hypoglycemia. There is thus a need in the art for more effective ways to controlblood sugar levels in patients who rely on exogenous insulin, including for example, therapies for T1D patients that increase glucose disposal by enhancing insulin-independent glucose effectiveness. BRIEF SUMMARY

[0006] In some aspects, provided herein is a method for regulating blood glucose levels in a subject in need thereof by effects manifested as increasing glucose effectiveness. In some embodiments, provided herein is a method for regulating blood glucose levels in a subject in need thereof by dual anti-hyperglycemic effects manifested as increasing glucose HIIHFWLYHQHVV^DQG^SUHVHUYLQJ^ȕ-cells. The subject is insulin-deficient, and prior to treatment using the compounds herein, is taking or needs to take exogenous insulin. In some embodiments, the method comprises: administering to the subject a compound of formula (I):or a pharmaceutically acceptable salt, solvate, or prodrug thereof; monitoring the subject’s blood glucose levels after administration of the compound; and reducing or eliminating the dose of exogenous insulin administered to the subject to maintain the subject’s blood glucose level within a normal range for the subject.

[0007] In some embodiments, the compound is repeatedly administered to the subject over a period of time. In some variations, when the compound is administered over the period of time, the dose of exogenous insulin administered to the subject is gradually reduced; and eventually the dose of exogenous insulin is eliminated so long as the compound of formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to the subject. In one variation, the exogenous dose of insulin is eliminated after about two weeks of repeated administration of the compound to the subject.

[0008] In one aspect, provided is a method for treating T1D in a subject in need thereof before insulin treatment has been started to delay need to use insulin, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another aspect, provided is a method for treating T1D in a subject in need thereof to reduce the need for insulin, comprising administering to the subjecta compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In another aspects, provided is a method for treating brittle diabetes in a subject in need thereof, in which the subject has too high and too low glucose despite the use of insulin, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0009] In certain aspects, also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a therapy, including any of the methods described herein. For instance, in some embodiments, provided is the use of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for regulating blood glucose levels in a subject in need thereof by effects manifested as increasing glucose effectiveness. In some variations, provided is the use of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for regulating blood glucose levels in a subject in need thereof by dual anti-hyperglycemic effects PDQLIHVWHG^DV^LQFUHDVLQJ^JOXFRVH^HIIHFWLYHQHVV^DQG^SUHVHUYLQJ^ȕ-cells.

[0010] In certain aspects, also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a medicament. In some embodiments, the medicament is for any of the methods described herein. For instance, in some embodiments, provided is the use of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for regulating blood glucose levels in a subject in need thereof by effects manifested as increasing glucose effectiveness. In some variations, provided is the use of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for regulating blood glucose levels in a subject in need thereof by dual anti-hyperglycemic effects manifested as increasing glucose effectiveness and SUHVHUYLQJ^ȕ-cells.

[0011] In one aspect, provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating T1D before insulin treatment has been started to delay need to use insulin. In another aspect, provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating T1D to reduce the need for insulin. In another aspects, provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrugthereof, for treating brittle diabetes, in which the subject has too high and too low glucose despite the use of insulin.

[0012] In some variations of the foregoing aspects, the subject is a human. DESCRIPTION OF THE FIGURES

[0013] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0014] FIG. 1 depicts the aversion of hyperglycemia by administering the compound of formula (I) to STZ mice. Fasted glucose (FIG. 1(a)) and insulin (FIG. 1(b)) levels with area under the curve (AUC) in control (n=7) and STZ mice untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 5 (n=6-8 / group). FIG.1(c): Total pancreatic insulin content in control and STZ mice untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 5 (n=7-8 / group). Islet cell area (FIG. 1(d)), Insulin positive (Ins+) (FIG. 1(e)), and Glucagon positive (Glu+) (FIG. 1(f)) cell fraction in control (n=3-5) and STZ mice untreated (n=3-5) or treated with 0.25 (n=3-5) and 0.5 (n=3-6) mg / g of the compound of formula (I), respectively, from day 5. Fasted glucose (FIG. 1(g)) and insulin (FIG. 1(h)) levels with area under the curve (AUC) in control (n=7) and STZ mice untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 15 (n=8-16 / group). (FIG. 1(i)) Total pancreatic insulin content in control (n=7) and STZ mice untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 15 (n=8-16 / group). Islet cell area (FIG. 1(j)), Ins+ (FIG. 1(k)) and Glu+ cell fraction (FIG. 1(l)) in control (n=3-5), STZ mice untreated (n=6-10) or treated with 0.25 (n=3-5) and 0.5 (n=6-10) mg / g of the compound of formula (I), respectively, from day 15. Please note that control mice in (FIGS.1(a)-1(f)) are the same as in corresponding panels in (FIGS. 1(g)-1(l)). Data are presented as mean ± SEM. Statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by Welch’s ANOVA followed by Games-Howell post hoc test (FIGS. 1(a)-1(d), 1(g)-1(j)) or one-way ANOVA followed by Tukey’s post hoc test (FIGS. 1(e)-1(f), 1(k)-1(l)) ) (*p<0.05, **p<0.01, ***p<0.001) and between control mice and STZ mice by Wilcoxon test (FIGS. 1(a)-1(d), 1(g)-1(j)) or by Student’s t-test (FIGS. 1(e)-1(f), 1(k)-1(l)) (#p<0.05, ##p<0.01, ###p<0.001).

[0015] FIG. 2 depicts the stimulation in skeletal muscle glucose uptake after administering the compound of formula (I) to STZ mice. FIG. 2(a): Timeline in days for STZ-treatment and FDG-PET scanning. (FIG. 2(b)) Representative PET / CT images of FDG uptake in an untreated mouse (upper panel), and a mouse treated with the compound of formula (I) (lower panel). (FIG. 2(c)) Estimated muscle and heart maximal glucose uptake (MRglu) at baseline (Scan 1), 9-10 days after the last STZ injection (Scan 2), and after 1 week of treatment (Scan 3) with 0.5mg / g of the compound of formula (I) (n=5) or no treatment (n=5). (FIG. 2(d)) Glycogen content in muscle and heart of control (n=6-18) and STZ mice untreated (n=14-36) or treated (n=13-27) with the compound of formula (I) from day 15. (FIG. 2(e)) Relative mRNA levels of Txnip, Slc2a1, Slc2a4, Hk2, Pkm, Ppargc1a, Pdk4, Pdha1, Shda, and Cox8b in muscle of control mice (n=5-7), untreated STZ mice (n=5-9) and STZ mice treated with the compound of formula (I) (n=6-8). (FIG. 2(f)) Relative mRNA levels of Txnip, Slc2a1, Slc2a4, Pdk4, Ucp2 and Ucp3 in heart of control mice (n=5), untreated STZ mice (n=9) and STZ mice treated with the compound of formula (I) (n=6-7). (FIG. 2(g)) Transmitral doppler in STZ treated mice at baseline (Scan 1), 15 days after STZ start (Scan 2,) and after 1 week treatment (Scan 3) with 0.5mg / g of the compound of formula (I) (n=9) or no treatment (n=9). Data are presented as mean ± SEM. Statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by Student’s t-test (FIG. 2(c): Muscle, FIG. 2(g)) or by Wilcox-test (FIG. 2(c): Heart, FIGS. 2(d)-2(f)) (*p<0.05, **p<0.01, ***p<0.001), and between control mice and STZ mice by Wilcoxon test (FIGS. 2(d)-2(f)) (#p<0.05,##p<0.01,###p<0.001), and between Scans in (FIG. 2(c), FIG. 2(g)) by 1-way repeated ANOVA followed by paired Student’s t- WHVW^^^S^^^^^^^

[0016] FIG. 3 depicts how the compound of formula (I) dose-dependently averts hyperglycemia in db / db mice. Fasted glucose (FIG. 3(a)) and insulin (FIG. 3(b)) levels with area under the curve (AUC) in BKS and db / db mice untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively (n=15-20 / group). HOMA-IR (FIG. 3(c)) and HOMA-ȕ^^FIG. 3(d)) (calculated from FIG. 3(a) and FIG. 3(b)) with area under the curve (AUC) in BKS and db / db mice untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I). (FIG. 3(e)) Glycogen content in muscle and heart of BKS (n=5-9) and db / db mice untreated (n=9-10) or treated with the compound of formula (I) (n=6-7). (FIG. 3(f)) Relative mRNA levels of Txnip, Slc2a1, Slc2a4, Hk2, Pkm, Ppargc1a, Pdk4, Pdha1, Sdha, Cox8b, Ucp2, and Ucp3 in muscle of BKS (n=6-13) and db / db mice untreated(n=15-22) or treated with 1.0 g / kg of the compound of formula (I) (n=8-15). (FIG. 3(g)) Relative mRNA levels of Txnip, Slc2a1, Slc2a4, Pdk4, Ucp2, and Ucp3 in heart of BKS (n=4-5), untreated db / db mice (n=8-9) and db / db mice treated with a compound of formula (I) (n=6-7). Data are presented as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch’s ANOVA followed by Games-Howell post hoc test (FIGS. 3(a)-3(d)), Student’s t- test (FIG. 3(e)) or Wilcoxon test (FIGS. 3(f), 3(g)) (*p<0.05, **p<0.01, ***p<0.001), and between BKS and db / db mice was determined by Wilcoxon test (#p<0.05,##p<0.01,###p<0.001) (FIGS. 3(a)-3(d), 3(f), 3(g)) or by Student’s t-test (FIG. 3(e)).

[0017] FIG. 4 depicts the induction of mitochondrial uncoupling by the compound of formula (I). Respirometry plots of intact differentiated C2C12 myotubes + / - 4 h treatment ZLWK^^^^^^^^^^^^^DQG^^^^^^0^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^VHTXHQWLDOO\^LQMHFWHG^ZLWK^ oligomycin, FCCP, and a cocktail of rotenone and antimycin showing Oxygen consumption Rate (OCR) (FIG. 4(a)) and extracellular acidification rate (ECAR) (FIG. 4(b)). FIG. 4(c): OCR vs ECAR plot from last baseline measurement (measurement 3 in panel FIG. 4(a) and FIG. 4(b)). FIG. 4(d): Mitochondrial function parameters calculated from OCR data in panel FIG. 4(a). Data are presented as mean ± SEM. n=5 / condition. Statistical significance in FIG. 4(d) between untreated and cells treated with the compound of formula (I) was determined by one-way ANOVA followed by Tukey's post hoc test (^p<0.05,^^p<0.01).

[0011] FIG. 5 GHSLFWV^WKH^SUHVHUYDWLRQ^RI^ȕ-FHOO^PDVV^DQG^H[SUHVVLRQ^RI^ȕ-cell markers in db / db mice following administration of the compound of formula (I). FIG. 5(a): Representative immunostaining of pancreases from 15w old BKS and db / db mice untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I) respectively, for Insulin (green) and Glucagon, Glut2, Ipf1 / Pdx1, Nkx6-1, Mafa, and Raldh3 (all red) (n=5 / group and antibody). FIG. 5(b): quantification of islet cell area. (FIG. 5(b)) in 6w old BKS and db / db mice and in 15w old BKS and db / db mice untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively, (n=4-6 / group). (FIG. 5(c)) Insulin (Ins+) and glucagon (Glu+) positive cell fraction in 15 w old BKS and db / db mice untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I) (n=5 for all groups). Total pancreatic insulin content (FIG. 5(d)) and pancreatic insulin / proinsulin ratio (FIG. 5(e)) in 15w old BKS (n= 9) and db / db mice untreated (n=7-10) or treated with 0.5 (n=9) and 1.0 mg / g of the compound of formula (I) (n=6-8). FIG. 5(f): Quantification of Glut2, Ipf1 / Pdx1, Nkx6-1,Mafa, and Raldh3 expression in islets of 15w old db / db mice untreated (n=5) or treated with 0.5 (n=5) and 1.0 (n=4-5) mg / g of the compound of formula (I). FIG. 5(g): Relative mRNA levels of Ins1 / 2, Slc2a2, Pdx1, Nkx6-1, Mafa, Ucn3, Trpm5, Txnip, Aldh1a3, Hspa5, Erp29, and Edem2 in islets of 15w old db / db mice untreated (n=11-13) or treated with 0.5 (n=14-15) and 1.0 (n=9-10) mg / g of the compound of formula (I). Data are presented as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch’s ANOVA followed by Games-Howell post hoc test (FIGS. 5(b)-5(f)) or Kruskal-Wallis test followed by Dunn’s post hoc test (FIG. 5(g)) (*p<0.05, **p<0.01, ***p<0.001), and between BKS and db / db mice was determined by Wilcoxon test (FIGS. 5(b)-5(e)) (#p<0.05,##p<0.01,###p<0.001).

[0012] FIG. 6 depicts the mitigation of hyperglycemia-induced islet gene expression changes in ex vivo cultured islets by the compound of formula (I). FIG. 6(a): MA plots showing differentially expressed genes between mouse islets cultured at 22mM (G22) vs ^^P0^^*^^^^JOXFRVH^DQG^^^P0^JOXFRVH^^^^^0^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^^*^^^&^,^^^ vs 11mM glucose. FIG. 6(b): Over-representation analysis (ORA) of Molecular signature Hallmark gene sets (MSIG) in mouse islets cultured at 22mM vs 11mM glucose and 22mM glucose ^^^^0^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^YV^^^P0^JOXFRVH^^FIG. 6(c): Log2 fold- change of normalized read counts for Txnip in mouse islets cultured at 11mM glucose, 22mM JOXFRVH^^DQG^^^P0^JOXFRVH^^^^^0^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^^Q^ ^^^IRU^DOO^JURXSV^^^ Data are presented as mean ± SEM. Statistical significance was determined by Wilcoxon test for 22mM vs 11mM glucose (##p^^^^^^^DQG^IRU^^^P0^JOXFRVH^^^^^0^RI^WKH^FRPSRXQG^RI^ formula (I) vs 22mM glucose (*p<0.05, **p<0.01). (FIG. 6(d)) Heatmaps of normalized read counts of DEGs from enriched categories from (FIG. 6(b)) and from KEGG: TCA_CYCLE. The number of genes is limited to the 20 most significant DEGs.

[0013] FIG. 7 depicts the mitigation of the effect of chronic hyperglycemia on GSIS, mTORC1, and AMPK signaling in INS-1E cells by the compound of formula (I). GSIS of INS-^(^FHOOV^FXOWXUHG^XQGHU^^^P0^RU^^^P0^JOXFRVH^IRU^^^G^^XQWUHDWHG^DQG^WUHDWHG^ZLWK^^^0^ of the compound of formula (I) for 4days (FIG. 7(a)) or 2 hours (FIG. 7(b)) (n= 4-5 / group). Protein expression ratios of Phosphorylated (P-) and total ACC, AMPK, RAPTOR, and S6 in INS-^(^FXOWXUHG^XQGHU^^^P0^RU^^^P0^JOXFRVH^IRU^^^G^^XQWUHDWHG^DQG^WUHDWHG^ZLWK^^^0^RI^ the compound of formula (I) for 4days (FIG. 7(c)) or 2 hours (FIG. 7(d)) (n= 4-5 / group). Data are presented as mean ± SEM. Statistical significance was determined by two-wayANOVA followed Tukey’s post hoc test between untreated and cells treated with the compound of formula (I) (*p<0.05, **p<0.01, ***p<0.001) and 11mM and 25mM glucose cultured cells (^p<0.05,^^p<0.01).

[0014] FIG. 8 depicts immunohistochemical and metabolic analyses of control and STZ mice. FIG. 8(a): Representative insulin (green) and glucagon (red) double immunostaining of pancreases from control and STZ mice untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I) from day 5 (n=5 for all groups). FIG. 8(b) Total pancreatic insulin content in STZ mice untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 5 (n=7-8 / group). Islet cell area (FIG. 8(c)) and Insulin (Ins+) (FIG. 8(d)) cell fraction in STZ mice untreated (n=3-5) or treated with 0.25 (n=3-5) and 0.5 (n=3-6) mg / g of the compound of formula (I), respectively, from day 5. FIG. 8(e): Non- fasted glucose levels with area under the curve (AUC) in control (n=6) and STZ mice untreated (n=9) or treated with 0.5 (n=9) mg / g of the compound of formula (I), respectively, from day 15. FIG. 8(f): Representative insulin and glucagon double immunostaining of pancreases from STZ mice untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 15 (n=5 for all groups). FIG. 8(g): Total pancreatic insulin content in STZ mice untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 15 (n=8-16 / group). Islet cell area (FIG. 8(h)) and Ins+ (FIG. 8(i)) cell fraction in STZ mice untreated (n=6-10) or treated with 0.25 (n=3-5) and 0.5 (n=6-10) mg / g of the compound of formula (I) from day 15. Data are presented as mean ± SEM. *P<0.05, **P<0.01, ***P<0.001, by Welch’s ANOVA followed by Games-Howell post hoc test (FIGS. 8(b), 8(c), 8(g), 8(h)) or one-way ANOVA followed by Tukey's post hoc test (FIGS. 8(d), 8(i)) or Student’s t-test (FIG. 8(f)).

[0015] FIG. 9 depicts standardized uptake values (SUVs) during FDG-PET scanning. SUV profiles of gastrocnemius muscle and heart during a 40-minute dynamic FDG-PET scan at baseline (Scan 1), 9-10 days after the last STZ injection (Scan 2), and after 1 week of treatment (Scan 3) with 0.5mg / g of the compound of formula (I) (n=5) or no treatment (n=5). Data are presented as mean ± SEM.

[0016] FIG. 10 depicts the quantification of protein levels by western blot analyses of p- T172 AMPK, p-S79 ACC, and TXNIP protein levels in extracts from vastus muscle in control (n= 5) and STZ mice untreated (n=9) or treated with 0.5 mg / g of the compound of formula (I) (n=9) from day 15.

[0017] FIG. 11 shows that treatment with the compound of formula (I) does not increase serum levels of lactate in STZ and db / db mice. Fasted glucose (FIG. 11(a)) and lactate (FIG. 11(b)) levels in STZ mice at day 15 (i.e. before treatment) and at day 22 after 1 week treatment with 0.5 mg / g of the compound of formula (I) (n=9 / group). Fasted glucose (FIG. 11(c)) and lactate (FIG. 11(d)) levels with area under the curve (AUC) in BKS and db / db mice untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively (n=7-9 / group). Data are presented as mean ± SEM. Statistical significance between timepoints in (FIG. 11(a)) was determined by Student’s t-test *P<0.05, and between untreated and the db / db mice treated with the compound of formula (I) was determined by Welch’s ANOVA followed by Games-Howell post hoc test (*P<0.05, **P<0.01, ***P<0.001), and between BKS and db / db mice was determined by Wilcoxon test in (FIG. 11(c), FIG. 11(d)) (##P<0.01).

[0018] FIG. 12 depicts PP+ and Som+ cell fraction and total pancreatic proinsulin content in BKS and db / db mice. FIG. 12(a): Pancreatic polypeptide (PP+) and somatostatin (Som+) positive cell fraction in 15 w old BKS and db / db mice untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I) (n=3 for each group). FIG. 12(b): Total pancreatic proinsulin content in 15w old BKS (n=8) and db / db mice untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively, (n=8-10 / group). Data are presented as mean ± SEM. *P<0.05, by Welch’s ANOVA followed by Games-Howell post hoc test, between untreated and of the compound of formula (I) treated db / db mice.#P<0.05, by Wilcoxon test, between BKS and db / db mice.

[0019] FIG. 13 depicts the effects of the compound of formula (I) on gene expression signatures in ex vivo cultured mouse and human islets. MA plots showing differentially expressed genes between mouse islets cultured at 22mM (G22) vs 11mM (G11) glucose (FIG. 13(a)^^^^^P0^JOXFRVH^^^^0^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^^*^^^&^,^^^YV^^^P0^ glucose (FIG. 13(b)^^DQG^^^P0^JOXFRVH^^^^^0^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^YV^^^P0^ glucose (FIG. 13(c)). MA plots showing differentially expressed genes between human islets cultured at 25mM (G25) vs 5.5mM (G5) glucose (FIG. 13(d)^^^^^P0^JOXFRVH^^^^^0^RI^WKH^ compound of formula (I) (G25+C(I)) vs 25mM glucose (FIG. 13(e)), and 25mM glucose + ^^0^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^YV^^^^P0^JOXFRVH^^FIG. 13(f)). FIG. 13(g): Overrepresentation analysis (ORA) of Molecular signature Hallmark gene sets in human LVOHWV^FXOWXUHG^DW^^^P0^YV^^^P0^JOXFRVH^DQG^^^P0^JOXFRVH^^^^^0^RI^WKH^FRPSRXQG^RI^formula (I) vs 22mM glucose. FIG. 14 depicts a representative immunoblot of INS-1E cells FXOWXUHG^XQGHU^^^P0^RU^^^P0^JOXFRVH^IRU^^^G^^XQWUHDWHG^DQG^WUHDWHG^ZLWK^^^0^RI^WKH^ compound of formula (I) for 4 days (4d) or 2 hours (2h).

[0020] FIG. 14 depicts a representative immunoblot of INS-1E cells cultured under ^^P0^RU^^^P0^JOXFRVH^IRU^^^G^^XQWUHDWHG^DQG^WUHDWHG^ZLWK^^^0^RI^WKH^FRPSRXQG^RI^IRUPXOD^ (I) for 4 days (4d) or 2 hours (2h).

[0021] FIG. 15 depicts a schematic model for the anti-diabetic effects of the compound of formula (I). As a dual AMPK activator and mitochondrial uncoupler compound (I) stimulates glucose uptake and utilization in muscle and averts the glucotoxicity effects of hyperglycePLD^RQ^ȕ-cell function, in part via reduction of mTORC1 signaling and thus Pdk expression. DETAILED DESCRIPTION

[0022] The following description sets forth exemplary compositions, methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.

[0023] Provided herein is a method for regulating blood glucose levels in a subject in need thereof. The method herein regulates blood glucose levels by dual anti-hyperglycemic effects PDQLIHVWHG^DV^LQFUHDVLQJ^JOXFRVH^HIIHFWLYHQHVV^DQG^SUHVHUYLQJ^ȕ-cells. In some variations, the subject is insulin-deficient and is taking or required to take exogenous insulin. In some variations of the foregoing, the subject is a human.

[0024] In some embodiments, the method comprises: administering to the subject a compound of formula (I):or a pharmaceutically acceptable salt, solvate, or prodrug thereof; monitoring the subject’s blood glucose levels after administration of the compound; and reducing or eliminating thedose of exogenous insulin administered to the subject to maintain the subject’s blood glucose level within a normal range for the subject.

[0025] In some embodiments, the normal blood glucose levels are as defined by the American Diabetes Association in the United States or equivalent organizations in other countries. In some variations, the normal range for the subject are as follows: x A1C: less than 7% x A1C may also be reported as eAG: less than 154 mg / dL x Before a meal (preprandial plasma glucose): 80–130 mg / dL x 1-2 hours after beginning of the meal (postprandial plasma glucose): Less than 180 mg / dL It should be understood that blood glucose levels may be measured using any suitable methods known in the art, including for example a glucometer or a continuous glucose monitor.

[0026] In other embodiments, the method further comprises: monitoring the subject’s urine for ketones, e.g., to check when blood glucose levels are higher than normal.

[0027] As described above, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, increases glucose effectiveness while preserving ȕ-cells. “Glucose effectiveness” refers to the process by which glucose itself enhances both its own uptake into cells from the circulatory system and its subsequent metabolism— independently of insulin. Administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, provided herein increases gOXFRVH^HIIHFWLYHQHVV^ZKLOH^SUHVHUYLQJ^ȕ-cell functionality under hyperglycemic conditions, even in the absence of exogenous insulin.

[0028] It was surprisingly observed that the compound provided herein behaves as an exercise mimetic in that it increases cardiac function and exercise capacity without promoting glycogen accumulation in heart tissue. The compound provided herein promotes mitochondrial uncoupling in myotubes. Mitochondrial uncoupling dissipates the potential- energy gradient across the inner mitochondrial membrane. The potential energy is convertedto heat energy rather than being used in oxidative phosphorylation (a process which converts ADP to ATP). Thus, administering the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, generates a metabolic demand for glucose that promotes glucose utilization rather than glycogen accumulation in cells.

[0029] It was also surprisingly observed that the compound provided herein acted on glucose control without insulin. Specifically, the compound improved glucose effectiveness independent of insulin, such as Type 1 diabetes (T1D) where beta cells are lost, or genetic conditions where insulin secretion is lost, or the subject has a genetic defect affecting tissues’ ability to respond to insulin (e.g., congenital hyperinsulinism).

[0030] Thus, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, may be used in various ways. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to a subject suffering from T1D before insulin treatment has been started to delay the need to use insulin. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to a subject suffering from TID to reduce the need for insulin. In certain embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to a subject suffering from T1DM with brittle diabetes, whereby the subject has too high and too low glucose despite the use of insulin. In yet other embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to a subject suffering from conditions where glucose control independent of insulin action is advantageous, e.g., genetic secretion defects, and genetic defects in tissue insulin signaling. Insulin Deficiency

[0031] ȕ-cells make insulin, which is needed for the body to regulate glucose levels in the bloodstream. If ȕ-cells are destroyed in a subject, e.g., due to cellular-mediated autoimmune GHVWUXFWLRQ^RI^WKH^ȕ-cells of the pancreas, the subject experiences high blood glucose levels, DOVR^UHIHUUHG^WR^LQ^WKH^DUW^DV^K\SHUJO\FHPLD^^^)RU^H[DPSOH^^LQ^LQGLYLGXDOV^ZLWK^7^'^^ȕ-cells are generally destroyed by the immune system^^DQG^WKH^ȕ-cells produce little or no insulin. Without enough insulin, glucose builds up in the bloodstream instead of going into the cells. This buildup of glucose in the blood is referred to as hyperglycemia.

[0032] Insulin deficiency may be absolute insulin deficiency or relative insulin deficiency. In one aspect, provided herein is a method for regulating blood glucose levels in a subject suffering from absolute insulin deficiency, which occurs when the body is unable to produce any amount of insulin because of autoimmune damage to the pancreatic beta cells or the complete removal of the pancreas. The pancreas is responsible for producing insulin, the hormone that manages the blood glucose levels in the body. With absolute insulin deficiency, since no insulin is present in the blood to regulate blood glucose levels, exogenous insulin (or an external source of insulin) is needed to perform the tasks that the insulin performs in the body, including controlling blood sugar levels, managing energy levels for the body, and accommodating the storage and distribution of glucose in the body’s cells.

[0033] In some embodiments, the individual suffers from T1D, chronic pancreatitis, pancreatectomy, cystic fibrosis, a monogenic diabetes disorder, or a post-infection following a severe acute respiratory syndrome (SARS) infection or another viral infection. In one embodiment, the individual suffers from T1D. In some embodiments, the subject suffers from maturity-onset diabetes of the young (MODY) or latent autoimmune diabetes in adults (LADA).

[0034] In another aspect, provided herein is a method for regulating blood glucose levels in an individual suffering from relative insulin deficiency, which typically occurs when the body develops insulin resistance and is unable to produce enough insulin to manage the blood glucose present in body.

[0035] In one aspect, provided herein is a method for regulating blood glucose levels in an individual suffering from acute insulin deficiency. In one embodiment, the individual suffers from diabetic ketoacidosis. In one embodiment, the individual suffers from brittle diabetes.

[0036] In some variations, the individual suffers from T1D where beta cells are lost. In other variations, the individual suffers from genetic conditions where insulin secretion is lost. In yet other variations, the individual suffers from a genetic defect affecting tissues’ ability to respond to insulin. In one variation, the individual suffers from congenital hyperinsulinism. Exogenous Insulin

[0037] In some variations, the subjects are humans. The subjects described in the method provided herein, prior to the initial administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, are taking or need to take exogenous insulin (or an external source of insulin). The subject may be taking or may need to take any suitable exogenous insulin therapies, including slow-acting insulin (also known as long-acting insulin) or fast-acting insulin (also known as rapid acting or short-acting insulin), or a combination thereof. Slow-acting insulin typically provides the body with the insulin it needs through the day and night. Examples may include, insulin glargine (Lantus), insulin determir (Levemir), and insulin degludec (Tesiba). Fast-acting insulin is typically taken before the subject eats or drinks something that has carbohydrates. Examples of fast-acting insulin include insulin aspart (Novorapid), insulin aspart (Fiasp), insulin lispro (Humalog), and insulin glulisine (Apidra). Such exogenous insulin may be administered to the subject using any suitable methods known in the art, including injections, insulin pumps, and insulin pens.

[0038] Surprisingly, after administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, over time, once the subject adapts to the effects of the compound, the need for exogenous insulin is reduced and ultimately eliminated over time, so long as the subject continues taking the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0039] In some embodiments of the method provided herein, the subject’s blood glucose level is monitored before and after administration of the compound. Because of the surprising dual anti-hyperglycemic effects of the compound, manifested as increasing glucose HIIHFWLYHQHVV^DQG^SUHVHUYLQJ^ȕ-cells, the subject’s insulin level gradually returns to normal levels without the need for exogenous insulin.

[0040] In some embodiments, the dose of exogenous insulin is eliminated, for example, after about two weeks of administering the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to the subject, so long as the subject continues administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the dose of exogenous insulin is first reduced and later eliminated.Treatment Compounds

[0041] In some embodiments of the foregoing, the treatment compound includes exemplary compounds as described in further detail below. The compound used in the methods provided herein may include salts, solvates, or prodrugs thereof.

[0042] In some embodiments, the compound is 4-chloro-N-[2-[(4-chlorophenyl)methyl]- 3-oxo-1,2,4-thiadiazol-5-yl]benzamide, or a salt, solvate or a prodrug thereof.

[0043] In certain embodiments, the compound is an alkali metal salt of 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. “Alkali metals” are metals found, along with hydrogen, in group I of the periodic table. The alkali metals are lithium, sodium, potassium, rubidium, cesium, and francium. It will therefore be understood that an “alkali metal salt” is a chemical compound consisting of an assembly of cations of one or more alkali metals and associated anions. Accordingly, the term “an alkali metal salt of 4- chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide” refers to a compound comprising alkali metal cations (e.g., lithium, rubidium, cesium, sodium, and potassium) and anions of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5- yl]benzamide. For example, alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3- oxo-1,2,4-thiadiazol-5-yl]benzamide are as depicted below:. wherein X+represents the alkali metal (e.g. lithium, rubidium, cesium, sodium, or potassium) cation.

[0044] It will be understood that a “sodium salt” is a chemical compound consisting of an assembly of cations of sodium and associated anions. Accordingly, the term “a sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide” refers to a compound comprising sodium cations and anions of 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. For example:, wherein Na+represents the sodium cation.

[0045] The skilled person will recognize that, when dissolved in a suitable solvent (e.g., water), the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4- thiadiazol-5-yl]benzamide may dissociate into its anionic and cationic components.

[0046] Throughout this specification, structures may or may not be presented with chemical names. Where any question arises as to nomenclature, the structure prevails. Where it is possible for the compound to exist as a tautomer (e.g., in an alternative resonance form), the depicted structure represents one of the possible tautomeric forms, wherein the actual tautomeric form(s) observed may vary depending on environmental factors such as solvent, temperature, or pH. All tautomeric (and resonance) forms and mixtures thereof are included within the scope of the Invention. For example, the following tautomers are included within the scope of the invention:

[0047] For the avoidance of doubt, alkali metal salts of 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide are solid under ambient conditions, and thus the scope of the invention includes all amorphous, crystalline, and part crystalline forms thereof.

[0048] Alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4- thiadiazol-5-yl]benzamide may be prepared in accordance with techniques that are well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3- oxo-1,2,4-thiadiazol-5-yl]benzamide may be reacted with the appropriate alkali metalhydroxide, or an alternative alkali metal base compound. Salt switching techniques may also be used to convert one salt into another salt.

[0049] Sodium salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5- yl]benzamide may be prepared in accordance with techniques that are well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4- thiadiazol-5-yl]benzamide may be reacted with sodium hydroxide, or an alternative sodium base compound. Salt switching techniques may also be used to convert one salt into another salt.

[0050] Where the salt is prepared from 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo- 1,2,4-thiadiazol-5-yl]benzamide, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4- thiadiazol-5-yl]benzamide may be prepared in accordance with techniques that are well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3- oxo-1,2,4-thiadiazol-5-yl]benzamide may be made in accordance with the techniques described in international patent application WO 2011 / 004162.

[0051] Unless indicated otherwise, all technical and scientific terms used herein will have their common meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0052] In particular embodiments, the alkali metal salt of 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide is a sodium or potassium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. In one embodiment, the salt is a sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo- 1,2,4-thiadiazol-5-yl]benzamide.

[0053] In some embodiments, the compound used in the methods provided herein is a compound of formula (II):or a salt thereof, wherein R1is selected from the group consisting of -C(O)-C2H4-CO2H and - PO3H2, or a salt or solvate thereof. In some embodiments, this compound is able to metabolise in vivo to form 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5- yl] benzamide. In certain embodiments, this compound is a salt. For example, salts of this compound include:, wherein X+represents an alkali metal, alkaline earth metal or quaternary ammonium (e.g. lithium, magnesium, calcium, ammonium, tetramethylammonium and, particularly, sodium and potassium) cation, with appropriate stoichiometric adjustments being made in view of charges of the ions. In certain embodiments, X+represents an alkali metal (e.g. lithium, rubidium, cesium or, particularly, sodium or potassium) cation. Pharmaceutical Dosage Forms

[0054] The treatment compound is administered to a human subject in need thereof in the form of a pharmaceutical formulation, which is also referred to herein as a pharmaceutical dosage form.

[0055] In one embodiment, the treatment compound is the sole active pharmaceutical ingredient present in the dosage form. In a further embodiment, treatment compound is present in the dosage form alongside one or more other active pharmaceutical ingredients, or may be administered as part of a combination therapy with one or more other active pharmaceutical ingredients.

[0056] In particular embodiments, the treatment compound is provided in the form of particles having a particle size distribution defined by a D90 of less than about 10 μm (e.g. as measured using laser diffraction). In one embodiment, the particles containing the treatment compound may have a particle size distribution defined by a D90 of less than about 10 μm (e.g. from about 5 μm to about 10 μm) (e.g. as measured using laser diffraction). The particle size distribution may alternatively be defined by a D90 of less than about 8 μm (e.g. from about 5 μm to about 8 μm). In a further embodiment, the particles consisting of the treatment compound may have a particle size distribution defined by a D50 of less than about 6 μm (e.g. from about 0.5 μm to about 6 μm). In a yet further embodiment, the particle size distribution of the particles consisting of the treatment compound may further be a defined by a D10 of less than about 2 μm (e.g. from about 0.2 μm to about 2 μm). The particle size distribution parameters mentioned above may be applicable, individually or in combination. For example, in particular embodiments, the dosage form comprises particles containing the treatment compound, said particles having a particle size distribution defined by a D90 of less than about 10 μm and a D50 of less than about 6 μm. Still further, said particles may have a particle size distribution defined by a D90 of less than 9 μm; a D50 of less than 6 μm or less than 5 μm; and a D10 of less than 2 μm or less than 1.5 μm. The particle size distribution of particles containing the treatment compound may be measured by laser diffraction, using, for example a commercially available particle size analyzer. Dosage

[0057] The skilled person will understand that the pharmaceutical dosage forms described herein may act systemically, and may therefore be administered accordingly using suitable techniques known to those skilled in the art. The pharmaceutical dosage form as described herein will normally be administered orally, e.g., as an oral pharmaceutical dosage form. Thus, in some variations, provided is an oral pharmaceutical dosage form comprising from about 200 to about 1000 mg of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4- thiadiazol-5-yl]benzamide, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one variation, provided is an oral pharmaceutical dosage form comprising from about 200 to about 1000 mg of a sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4- thiadiazol-5-yl]benzamide.

[0058] In particular embodiments, the pharmaceutical dosage may comprise from about 200 mg to about 800 mg, from about 200 mg to about 600 mg, or from about 200 mg to about400 mg of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some variations, the pharmaceutical dosage form of the comprises from about 200 mg to about 400 mg of 4- chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, such as the sodium salt of 4- chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. Enteric Coating

[0059] Dosage forms intended for oral administration may further comprise an enteric coating in order to prevent or minimize dissolution or disintegration in the gastric environment. As such, oral preparations (e.g., capsules or tablets) coated by an enteric coating may provide targeted release of the treatment compound in the small intestine. For example, the enteric coating may be present on surface of the formulation (e.g., on the surface of a tablet or a capsule), or each of the particles containing the treatment compound may be coated with the enteric coating. Thus, in particular embodiments, the pharmaceutical dosage form used in the method of the invention further comprises an enteric coating.

[0060] In certain embodiments, the enteric coating is present on the pharmaceutical dosage form, and in some variations, said coating may be provided as an outer layer on the pharmaceutical dosage form.

[0061] Alternatively, particles containing the treatment compound may be individually coated with the enteric coating, and said coated particles may be prepared into the pharmaceutical dosage form. Thus, in particular embodiments, the pharmaceutical dosage form contains particles comprising the treatment compound and each particle is coated with the enteric coating.

[0062] The term “enteric coating” refers to a substance (e.g., a polymer) that is incorporated into an oral medication (e.g., applied onto the surface of a tablet, a capsule, particles or pellets) and that inhibits dissolution or disintegration of the medication in the gastric environment. Enteric coatings are typically stable at the highly acidic pH found in the stomach, but break down rapidly in the relatively basic pH of the small intestine. Therefore, enteric coatings prevent release of the active ingredient in the medication until it reaches the small intestine.

[0063] Any enteric coating known to the skilled person may be used in the present invention. Particular enteric coating materials that may be mentioned include those which comprise beeswax, shellac, an alkylcellulose polymer resin (e.g. ethylcellulose polymers, carboxymethylethylcellulose, or hydroxypropyl methylcellulose phthalate) or an acrylic polymer resin (e.g. acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate) copolymer, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers), cellulose acetate phthalate and polyvinyl acetate phthalate. Dosage Forms

[0064] In some variations, the treatment compound may be provided in the form of a tablet or particularly a capsule. For example, capsules such as soft gelatin capsules may be prepared containing the treatment compound alone, or together with a suitable vehicle, e.g. vegetable oil, fat, etc. Similarly, hard gelatin capsules may contain the treatment compound alone, or in combination with solid powdered ingredients such as a disaccharide (e.g. lactose or saccharose), an alcohol sugar (e.g. sorbitol or mannitol), a vegetable starch (e.g. potato starch or corn starch), a polysaccharide (e.g. amylopectin or cellulose derivatives), or gelling agent (e.g. gelatin).

[0065] The pharmaceutical dosage forms described herein may be prepared in accordance with standard and / or accepted pharmaceutical practice. The pharmaceutical dosage forms will generally be provided as a mixture comprising the treatment compound and one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may be selected with due regard to the intended route of administration in accordance with standard pharmaceutical practice. Such pharmaceutically acceptable excipients are preferably chemically inert to the active compound and are preferably have no detrimental side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations may be found in, for example, Remington The Science and Practice of Pharmacy,19th ed., Mack Printing Company, Easton, Pennsylvania (1995). A brief review of methods of drug delivery may also be found in, e.g., Langer, Science 249, 1527 (1990).Excipients

[0066] In some variations, the pharmaceutical compositions comprise the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and at least one pharmaceutically acceptable excipient. In particular, the at least one pharmaceutically acceptable excipient may be a lubricant, a binder, a filler, a surfactant, a diluent, an anti- adherent, a coating, a flavoring, a colorant, a glidant, a preservative, a sweetener, a disintegrant, an adsorbent, a buffering agent, an antioxidant, a chelating agent, a dissolution enhancer, a dissolution retardant, or a wetting agent.

[0067] Particular pharmaceutically acceptable excipients that may be mentioned include mannitol, PVP (polyvinylpyrrolidone) K30, lactose, saccharose, sorbitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredients, as well as disintegrating agents and lubricating agents such as sodium lauryl sulfate, Na-docusate, magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. In the preparation of a pharmaceutical dosage form of the treatment compound for oral administration, particles containing the treatment compound (preferably milled) may be mixed, either together or separately, with mannitol, PVP (polyvinylpyrrolidone) K30 and sodium lauryl sulfate.

[0068] In the preparation of a pharmaceutical dosage form, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, may be mixed, either together or separately, with one or more of the pharmaceutical excipients (including basic excipients) listed above.

[0069] Mixtures of the treatment compound and one or more pharmaceutically acceptable excipients may be processed into pellets or granules, or compressed into tablets. Thus, pharmaceutical dosage form of the method of the inventions may be a tablet, mini-tablets, blocks, pellets, particles, granules, or a powder for oral administration.

[0070] Pharmaceutical formulations that may be mentioned include those in which the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is present in a total amount that is at least 1% (or at least 10%, at least 30% or at least 50%) by weight of the formulation. That is, the weight ratio of the treatment compound to the totality of the components (i.e., the treatment compound and all pharmaceutical excipients, e.g. adjuvants, diluents and carriers) of the pharmaceutical formulation is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50).

[0071] A “therapeutically effective amount”, an “effective amount” or a “dosage” as used herein refers to an amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, that is sufficient to produce a desired effect, which can be a therapeutic and / or beneficial effect. The effective amount or dosage will vary with the age or general condition of the individual or subject (e.g., a human), the severity of the condition being treated, the particular agents administered, the duration of the treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and like factors within the knowledge and expertise of those skilled in the art. As appropriate, a “therapeutically effective amount”, “effective amount,” or “dosage” in any individual case can be determined by one of skill in the art by reference to the pertinent texts and literature and / or by using routine experimentation. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

[0072] The skilled person will understand that suitable formulations may be administered (for example, by way of one or more preparations as described herein) at varying doses, with suitable doses being readily determined by one of skill in the art. The total dosage of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, that is to be administered to a subject in need thereof may range from about 0.01 to about 2000 mg / kg of body weight per day (mg / kg / day), about 0.1 to about 500 mg / kg / day, or about 1 to about 100 mg / kg / day.

[0073] When administered orally, treatment with such formulations (including capsules containing such formulations) may comprise administration of a unit dose formulation containing from about 0.01 mg to about 3000 mg of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for example from about 0.1 mg to about 2000 mg, or from about 1 mg to about 1000 mg (e.g. from about 10 mg to about 500 mg), of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, treatment comprises administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof (including capsules containing said formulation), using a single daily dose. Alternatively, the total daily dosage of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, may be administered in divided doses two, three or four times daily (e.g. twice daily with reference to the doses described herein, such as a dose of 100 mg, 250 mg,500 mg, or 1000 mg twice daily). The skilled physician will recognize that the dosage will vary from subject to subject.

[0074] In particular embodiments, the daily dose of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, administered to a subject is in the range of from about 1 mg to about 3000 mg. In particular embodiments, the daily dose of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, administered to a subject is in the range of from about 1 mg to about 1000 mg.

[0075] The term “about,” as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, refers to variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It is contemplated that, at each instance, such terms may be replaced with the notation “±10%”, or the like (or by indicating a variance of a specific amount calculated based on the relevant value). It is also contemplated that, at each instance, such terms may be deleted.

[0076] It will be understood that the dosage amounts and pharmacokinetic parameters described below relate to treating patients with particular diseases, specifically, T1D, as set forth herein.

[0077] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a patient in need of at a dose of from about 100 mg to about 1,000 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily at dose of from about 200 mg to about 1,000 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily at dose of from about 400 mg to about 800 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily at dose of from about 100 mg to about 300 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily at dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg or about 500 mg.

[0078] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally oncedaily to a patient in need of, wherein the administration results in a steady state blood plasma FRQFHQWUDWLRQ^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^J^P / ^WR^DERXW^^^^^^J^P / ^^^ In some embodiments, compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state blood plasma concentration of the FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^J^P / ^WR^DERXW ^^^^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^ compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state blood plasma concentration of the compound of formula (I) of from DERXW^^^^^J^P / ^WR^DERXW^^^^^^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^FRPSRXQG^RI^IRUPXOD^^,^^RU^D^ pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state blood SODVPD^FRQFHQWUDWLRQ^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^J^P / ^WR^DERXW^^^^^ ^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^FRPSRXQG^RI^IRUPXOD^^,^^RU^D^SKDUPDFHXWLFDOO\^DFFHSWDEOH^ salt, solvate, or prodrug thereof is administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state blood plasma concentration of the FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^^J^P / ^WR^DERXW^^^^^^J / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof s administered daily to the subject (e.g., human) and results in a steady state EORRG^SODVPD^FRQFHQWUDWLRQ^RI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^^^

[0079] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a patient in need of, wherein the administration results in a steady state AUC0-24of WKH^FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^^^K^^J^P / ^WR^DERXW^^^^^^^K^^J^P / ^^^,Q^VRPH^ embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state AUC0-24of the compound of formula (I) RI^IURP^DERXW^^^^^^^K^^J^P / ^WR^DERXW^^^^^^^K^^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^WKH^ compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state AUC0-24of the compound of formula (I) of from about ^^^^^^K^^J^P / ^WR^DERXW^^^^^^^K^^J^P / ^^^,Q^VRPH embodiments, the compound of formula(I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state AUC0-24of WKH^FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^^^K^^J^P / ^WR^DERXW^ ^^^^^^K^^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^WKH^FRPSRXQG^RI^IRUPXOD^^,^^RU^D^SKDUPDFHXWLFDOO\^ acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state AUC0-24of the FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^^^K^^J^P / ^WR^DERXW^^^^^^^K^^J^P / ^^^,Q^VRPH^ embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state AUC0-24of the compound of formula (I) RI^IURP^DERXW^^^^^^^K^^J^P / ^WR^DERXW^^^^^^^K^^J^P / ^^,Q^VRPH^HPERGLPHQWV^^WKH^FRPSRXQG^ of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a steady state AUC0-24of the compound of formula (I) of from about 3.000 K^^J^P / ^WR^DERXW^^^^^^^K^^J^P / ^

[0080] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily a patient in need of, wherein the administration results in a Cmaxof the compound of IRUPXOD^^,^^RI^IURP^DERXW^^^^^J^P / ^WR^DERXW^^^^^^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^WKH^ compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a CmaxRI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^WKH^FRPSRXQG^RI^IRUPXOD^^,^^RU^D^SKDUPDFHXWLFDOO\^ acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a Cmaxof the compound of IRUPXOD^^,^^RI^IURP^DERXW^^^^^^J^P / ^WR^DERXW^^^^^^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^WKH^ compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a CmaxRI^WKH^FRPSRXQG^RI^IRUPXOD^^,^^RI^IURP^DERXW^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^^^,Q^VRPH^HPERGLPHQWV^^WKH^FRPSRXQG^RI^IRUPXOD^^,^^RU^D^SKDUPDFHXWLFDOO\^ acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject or a patient in need of, wherein the administration results in a Cmaxof the compound of formula (I) of from about 1200 ^J^P / ^WR^DERXW^^^^^^J^P / ^^

[0081] In some variations of the foregoing, the subject or patient in need thereof is a human. For the avoidance of doubt, the dose administered to a subject (e.g., human), in the context of the present invention should be sufficient to effect a therapeutic response in the subject over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the subject to be treated, and the stage / severity of the disease.

[0082] In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage which will be most suitable for a subject. The above- mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. Uses of the Compound

[0083] In certain aspects, provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a therapy, including any of the methods described herein. For instance, in some embodiments, provided is the use of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in regulating blood glucose levels in a subject in need thereof by effects manifested as increasing glucose effectiveness. In some variations, provided is the use of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in regulating blood glucose levels in a subject in need thereof by dual anti-hyperglycemic effects PDQLIHVWHG^DV^LQFUHDVLQJ^JOXFRVH^HIIHFWLYHQHVV^DQG^SUHVHUYLQJ^ȕ-cells. In one embodiment, the therapy comprises: administering to the subject the compound; monitoring the subject’s blood glucose levels after administration of the compound; and reducing or eliminating the dose of exogenous insulin administered to the subject to maintain the subject’s blood glucose level within a normal range for the subject.

[0084] In certain aspects, also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a medicament. In some embodiments, the medicament is for any of the methods describedherein. For instance, in some embodiments, provided is the use of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for regulating blood glucose levels in a subject in need thereof by effects manifested as increasing glucose effectiveness. In some variations, provided is the use of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for regulating blood glucose levels in a subject in need thereof by dual anti-hyperglycemic effects manifested as increasing glucose effectiveness and SUHVHUYLQJ^ȕ-cells.

[0085] In one embodiment, the medicament comprising the compound is administered to the subject; the subject’s blood glucose levels are monitored after administration of the compound; and the dose of exogenous insulin administered to the subject is reduced or eliminated to maintain the subject’s blood glucose level within a normal range for the subject. EXAMPLES

[0086] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.

[0087] Herein, and unless otherwise indicated, “Cmpd-(I)” or “Compound of formula (I)” referred to in the experiments detailed in the following Examples, and is 4-chloro-N-[2-[(4- chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0088] Mice. Mice were housed in a certified animal facility, with 12 h light / dark cycle and ad libitum access to the respective diets. Leptin receptor-deficient male BKS.Cg-Dock7m + / + Leprdb / J (db / db) and C57BLKS / J (BKS) mice were obtained. F1 mice were obtained from breeding male C57BL / 6J mice with female CBA / CaCrl. Nine weeks old male F1 mice were treated with multiple low dose streptozotocin (50 mg / kg*day for 5 consecutive days; freshly prepared in 0.1 mM sodium citrate, pH 4.5) to induce diabetes. Mice were ad libitum fed D10001 diet or D10001 formulated with the compound of formula (I) at 0.25 mg / g, 0.5 mg / g and 1 mg / g of the compound of formula (I) (CAS # 1261289-04-6). Cohorts of BKS, db / db and F1 mice were housed in groups of 4-5 mice / cage. Mice with apparent health problems such as >10% reduction in body weight or fighting were excluded with no differences between groups. In the different cohorts, mice were randomly allocated to the cages, based on weight and fasting blood glucose and allocated cage-wise, or if possibleindividually, to different treatments in order to minimize influence of starting weight and glucose homeostasis. For in vitro analyses such as western blot, qPCR, histology and immunohistology work, samples from 5-9 mice / diet were randomly selected. All in vivo analyses were performed between 9 am to 3 pm.

[0089] PET analyses of in vivo glucose uptake. All in vivo experiments were successfully repeated 2-3 times. In vitro analyses of tissues were successfully repeated 2-3 times with different cohorts. Mice were starved for three hours before each scan. Before the scan, mice were sedated with <2% isoflurane in oxygen (800 mL / min) and cannulated via the tail vein using a 27G needle and a tailor-made catheter. A dynamic (frames 8x30s, 8x60s, 6x180s, 2x300s) 40-minute PET acquisition commenced with the injection of 50-7^^ / ^RI^ 13.9+2.3 MBq [18F]-Fluorodeoxyglucose (FDG) dissolved in saline. The maximal metabolic rate of glucose, MRglu was calculated using Patlak analysis of PET data combined with measured glucose concentrations. PET / CT imaging started with a 50 kV, 0.088 mAs, helical CT acquisition reconstructed to images with 0.375x0.375x0.377mm3voxel size. PET images were reconstructed to a voxel size (0.4x0.4x0.4), with 4 iterations and 4 subsets using the Tera-Tomo 3D iterative reconstruction, with attenuation, scatter, and randoms-correction. Image analysis and Patlak pharmaco-kinetic calculation was performed with imlook4d software. During the scans, mice were supervised on a temperature-controlled bed, and blood glucose was measured at 10, 20, and 40 minutes after injection using tail vein blood. A region-of-interest (ROI) consisting of both the left and right gluteus medius / rectus femoris muscles was defined in coronal views as 10-pixel-diameter and 10-slice cylinders. The myocardial ROI was defined by thresholding a manually delineated search volume in the last PET frame at 40% of the highest voxel. The vena cava ROI was defined as the voxels above 60% of the maximum voxel in the first frame with uptake. An image-derived input function was approximated using the time activity curve from the vena cava ROI. Patlak analysis was performed employing above image-derived input function, determining the irreversible uptake rate Kiby linear regression between 16-40 minutes. Patlak Kivalues were calculated on ROI level for quantification, and on voxel level for illustrations. The saturated glucose consumption was estimated as:with the Michaelis-Menten Km= 130 mg / dL, and using the average measured blood glucose level Cglufrom the three samples taken over the scan.

[0090] Echocardiography. For echocardiography mice were sedated using 1.5-2% isoflurane, in 0.8L·min-1O2(g), and placed on a temperature-controlled table. Chest hair was removed using hair removal cream. Respiration and ECG were monitored during the scan, and anaesthesia adjusted to avoid depression of respiration. Total scan time did not exceed 15 minutes. Stroke volume, cardiac output and wall thicknesses were measured in the parasternal long-axis view using Bmode and M-mode images. Diastolic left ventricle inflow used transmitral doppler in the apical four-chamber view. Off-line analysis was done in a blinded manner.

[0091] Mitochondrial respiration analyses. C2C12 myoblasts were in growth media, 10% fetal bovine serum and 20U / ml Penicillin-Streptomycin. To obtain myotubes, C2C12 myoblasts were seeded in poly-L-Lysin coated XF96 plates at 7500 cells / cm2, cultivated in growth media for 3 days to 80% confluence, thereafter switched to differentiation media (DM; growth media with FBS replaced by 2% horse serum for 6 days with media changes every 2 days. Respiration assays were performed using an extracellular flux analyzer according to the manufacturer’s “Mito-stress” protocol and mitochondrial parameters. Briefly, differentiated myotubes were pre-treated by switching to growth media with 1% horse serum together with the compound of formula (I) (sodium salt formulation) for 4h. Myotubes were then equilibrated for 1h in Seahorse assay medium (1mM Na-Pyruvate, 10mM Glucose, 2mM L-Glutamine) adjusted to pH7.4 and supplemented with the compound of formula (I) as during pretreatment. Measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was collected for baseline, followed by sequential DGGLWLRQ^RI^^^0^ROLJRP\FLQ^^^^0^)&&3^^DQG^^^^^0^URWHQRQH^^^^^^^0^DQWLP\FLQ^$^^ Mitochondrial function parameters were calculated according to the manufacturer’s recommendations.

[0092] Western Blot analysis. Vastus muscles were isolated from non-fasted mice and crushed in a mortar using a pestle and liquid nitrogen. Vastus muscles and INS-1E cell samples were homogenized in ice cold protein lysis buffer (100mM Tris pH 6.8, 2% SDS), with protease inhibitor cocktail and phosphatase inhibitor cocktail and sonicated. The vastus supernatant was collected after 10 min at 14,000 rpm. Protein concentration was measured using the BCA kit after which samples were diluted in Laemmli buffer and denaturized. 20^J^RI^YDVWXV^DQG^^^^J^RI^,16-1E cell protein samples were separated on 4–15 % CriterionTM TGX Stain-FreeTM Protein Gels and blotted to low fluorescent PVDF or Nitrocellulose membrane respectively. Primary and secondary antibodies are listed Table 2. Values were normalized to stain-free total protein signal or to a beta-actin. Table 2

[0093] qRT PCR. Total RNA from isolated islets was prepared using RNeasy Micro Kit. Total RNA from gastrocnemius muscles and left cardiac ventricles was prepared using RNeasy Fibrous Tissue Mini kit after first crushing the tissue in liquid nitrogen using a pestle. First strand cDNA synthesis was done using SuperScript III according to the manufacturer’sinstructions. Primers used for qRT-PCR are listed in Table 3. Expression of Tbp was used for normalization of samples from islets, gastrocnemius muscle and left cardiac ventricle. Normalization by Tbp was validated by Rpl32 in left cardiac ventricle samples and gastrocnemius muscles. Table 3

[0094] Islet isolation and culture. Mouse islets were isolated essentially and cultured for 48h in media (RPMI 1640 medium, 1% fetal bovine serum, 10 mM HEPES, 1 mM sodium S\UXYDWH^^^^^0^^-mercaptoethanol, 50U / ml Pen:Strep) supplemented with 11mM glucose or 22mM glucose + / - ^^0^RI^WKH^FRPSRXnd of formula (I). Human islets from nondiabetic donors were cultured for 48 h in media (CMRL medium, 10 % fetal bovine serum, 20 U / ml Pen:Strep and 1X GlutaMax) supplemented with 5.5mM glucose or 25mM glucose + / - ^^0^ of the compound of formula (I).

[0095] RNA-seq. RNA-seq was performed. RNA-seq libraries were prepared from 150ng total RNA using the Illumina TruSeq stranded mRNA Library Kit followed by 100 bp paired- end sequencing on a NovaSeq 6000 Illumina Sequencer. RNA-seq reads were processed. Fastq files with 100-nt paired-end sequenced reads were quality-checked, aligned to the mouse or human genome (GRCm39 or GRCh38). Fragment - gene hits were counted. Subsequent analysis was performed in R using packages DESeq2 and clusterProfiler. Normalization and differential expression analysis were performed using DESeq2 with batch correction (referring to islet preparation batch and human donor respectively), independent filtering (alpha = 0.05) and False Discovery Rate (FDR) < 0.05. Genes with baseMean expression > filterThreshold were considered to be expressed and to constitute the gene background for subsequent ORA and GSEA analysis using clusterProfiler with a pvalueCutoff = 0.05 and a qvalueCutoff =0.2 for overrepresented gene categories.

[0096] Insulin secretion assay. GSIS was performed in UB-buffer (125mM NaCl, 6mM KCl, 1.3mM CaCl2, 1.2mM MgCl2, 25mM Hepes(pH7.3), 2mM glucose, 0.1% BSA) at 37°C in normal atmosphere. Briefly, INS-1E cells were washed and equilibrated for 1h in UB buffer, transferred to UB buffer containing either 2 or 20mM glucose for 30min, and insulin levels in the supernatant was determined by ELISA. Insulin secretion was normalized to protein content.

[0097] Cell lines. INS-1E and C2C12 were commercially available and therefore not authenticated following purchase. The cells were free of mycoplasma as determined by PCR.

[0098] Statistical analyses. The experimental design was considered to consist of a non- diabetic control group (BKS or Control (i.e. vehicle injected F1 mice), a diabetic control (db / db mice or STZ mice, i.e. STZ injected F1 mice) and compound-of-formula-(I)-treated group(s) (db / db mice or STZ mice kept on a diet formulated with the compound of formula (I)). First, the validity of the diabetic models was tested by comparing the control and diabetic groups. Second, the effect of the compound-of-formula-(I) diet was evaluated by comparing the compound-of-formula-(I)-treated group(s) to the diabetic group. The parametric nature and heteroscedasticity of the data were evaluated by Shapiro-Wilk test and Leven’s test and used to select the appropriate statistical test. For two-group comparisons, heteroscedastic t-test or Wilcoxon-test were used together with holm correction for multiple testing. For multiple groups, ANOVA analysis, were used followed by the appropriate post hoc analysis (see figure legends). P<0.05 was considered as statistically significant. Dataanalysis, statistical analysis and visualization were performed in R using the tidyverse, rstatix, and ggpubr packages. Example 1: The compound of formula (I) prevents the development of diabetes in STZ mice.

[0099] To assess whether the compound of formula (I) could ameliorate diabetes in an insulin deficient context, beta-cell function was ablated in mice through streptozotocin (STZ) injections. STZ mice were treated with a diet formulated with the compound of formula (I) at 0.25 or 0.5 mg / g, denoted Cmpd-(I)-(0.25) and Cmpd-(I)-(0.5), from day 5 or 15. In untreated STZ mice insulin levels rapidly decreased with a concomitant increase in glucose levels (FIGS. 1(a), 1(b)). In contrast, treatment with the compound of formula (I) from day 5 normalized glucose levels (FIG. 1(a)) without increasing plasma insulin levels (FIG. 1(b)). Pancreatic insulin content was 10-20-fold lower in mice treated with the compound of formula (I) compared with non-diabetic control mice (FIGS. 1(c), 8(b)). In both untreated STZ mice and STZ mice treated with the compound of formula (I) islet cell area and Ins+ cell fraction were decreased whereas Glu+ islet cell fraction was increased (FIGS. 1(d)-1(f), 8(a), 8(c), 8(d)). The compound of formula (I) rapidly reduced glucose levels in STZ mice also when treatment was initiated first at day 15, i.e. when the mice had developed overt diabetes, without enhancing plasma insulin levels (FIGS. 1(g), 1(h), 8(e)). Pancreatic insulin content was again lower, ~20-fold, in mice treated with the compound of formula (I) compared with that of control mice (FIGS. 1(i), 8(g)). Similarly, islet cell area and Ins+ islet cell fraction was reduced and Glu+ islet cell fraction increased in untreated mice and STZ mice treated with the compound of formula (I) (FIGS. 1(j)-1(l), 8(f), 8(h), 8(i)). Together these findings show that the compound of formula (I) potently and in an insulin independent manner reverts diabetes in an insulin deficient mouse model of diabetes.

[0100] Overall, this example unexpectedly showed that starting treatment with the compound of formula (I) after administration of STZ did not prevent the destruction of beta cells (insulin levels were reduced over time as shown in FIG. 1(b)) but prevented the onset of diabetes (glucose levels remained normal as shown in FIG. 1(a)). Additionally, when mice were already diabetic in response to STZ-destruction of their beta cells, treatment with the compound of formula (I) led to improved glucose control (FIG. 1(g)) without a rescue of insulin levels (FIG. 1(h)). Thus, the compound of formula (I) unexpectedly improvedglucose effectiveness independent of insulin. Further, administration of the compound of formula (I) was not observed to cause hypoglycemia, as shown in FIGS. 1(a) and 1(g). Example 2: The compound of formula (I) ameliorates hyperglycemia in STZ mice by stimulating muscle glucose uptake.

[0101] The potent reduction of glucose levels in STZ mice treated with the compound of formula (I) provide evidence that the compound of formula (I) promotes insulin independent glucose uptake in vivo. Sequential dynamic [18F]-Fluorodeoxyglucose PET analyses showed that the maximal metabolic rate of glucose, MRglu, in skeletal muscle was greatly enhanced in STZ mice following 1 week of treatment with the compound of formula (I) (scan 3), compared both with that before treatment (scan 2) and with that of untreated STZ mice at day 22 (scan 3) (FIGS. 2(a)-2(c), 9). Moreover, MRgluwas reduced in hearts of diabetic STZ mice at day 14-15, i.e. at scan 2, but normalized to baseline levels after one week of treatment with the compound of formula (I) (FIG. 2(c)). Skeletal muscle and cardiac glycogen content were analyzed to address the metabolic fate of glucose in STZ mice treated with the compound of formula (I). Muscle and cardiac glycogen content was increased in muscle and heart of untreated STZ mice compared to that of control mice but reduced in STZ mice treated with the compound of formula (I) compared with untreated STZ mice (FIG. 2(d)). Thus, under hyperglycemic conditions, treatment with the compound of formula (I) stimulates insulin independent glucose uptake and glucose utilization but not glycogen storage. Example 3: The compound of formula (I) promote gene expression profile favoring glucose oxidation in the muscle and heart of STZ mice.

[0102] Skeletal muscle TXNIP expression levels are negatively correlated with glucose uptake. Concurrent with enhanced skeletal muscle glucose uptake, Txnip mRNA and protein levels were reduced in skeletal muscle of STZ mice treated with the compound of formula (I) compared with untreated STZ mice (FIG. 2(e), 10). Moreover, skeletal muscle expression of Slc2a4, encoding Glut4, was reduced in STZ mice compared with controls but normalized in STZ mice treated with the compound of formula (I) and that of Slc2a1, encoding Glut1, tended to be increased (p=0.059) in STZ mice treated with the compound of formula (I) (FIG. 2(e)). Similarly, the increased expressions of Pyruvate Dehydrogenase Kinase 4, Pdk4, a negative regulator of pyruvate dehydrogenase (PDH) and thus oxidative glucosemetabolism, and Uncoupling protein 3 (Ucp3), which favor lipids as fuel substrate, in STZ mice were reduced in mice treated with the compound of formula (I) (FIG. 2(e)), suggesting that the compound of formula (I) counteracts metabolic inflexibility in skeletal muscle of STZ diabetic mice. Txnip expression was increased also in hearts of STZ mice but comparatively reduced in STZ mice treated with the compound of formula (I) (FIG. 2(f)). Moreover, cardiac expressions of Slc2a1 and Slc2a4 were decreased in untreated STZ mice but tended (p=0.088 for both) to be increased in mice treated with the compound of formula (I) (FIG. 2(f)). The expressions of Pdk4, Ucp2, and Ucp3 were increased in heart of untreated STZ mice but attenuated (p= 0.055 for Ucp2) in STZ mice treated with the compound of formula (I) (FIG. 2(f)). Thus, the compound of formula (I) promoted gene expression changes favoring glucose uptake, oxidative glucose metabolism, and ATP generation in skeletal muscle and heart of STZ mice (FIGS. 2(e), 2(f)). Hyperglycemia has been shown to rapidly increase cardiac expression of Pdk4 and Ucp3, and to provoke metabolic inflexibility and cardiac dysfunction in mice

[0034] . Untreated STZ mice showed gradually decreased E peak velocity and increased isovolumetric relaxation time (IVRT), indicating impaired diastolic function, whereas 1 week treatment with the compound of formula (I) reduced IVRT and increased peak E velocity and thus E / A ratio (FIG. 2(g), Table 4). The improved filling of the left ventricle in mice treated with the compound of formula (I) also resulted in increased stroke volume and cardiac output (Table 4). Altogether these findings show that in diabetic STZ mice, the compound of formula (I) ameliorated hyperglycemia by stimulating insulin independent glucose uptake and utilization, mitigated glycogen accumulation, and reverted diabetic cardiomyopathy.Table 4

[0103] Table 4 shows echocardiographic measurements of left ventricular dimensions in para-sternal long axis (PLAX) B-mode or M-mode. HR, heart rate; SV, stroke volume; CO, cardiac output; EDV, end-diastolic volume; ESV, end-systolic volume; AWd / s, anterior wall thickness in diastole / systole; LVIDd, / s left ventricular inner diameter in diastole / systole; PWd / s, posterior wall thickness in diastole / systole; EF, ejection fraction; FS, fractional shortening; E / A, ratio of E and A peak wave velocity; Decel time, deceleration time of E wave from peak to projected baseline; IVRT, isovolumetric relaxation time. Statistics used One-way repeated ANOVA with Tukey’s post-hoc test. *P<0.05 between RD and the compound of formula (I) at same timepoint.#P^^^^^^FRPSDUHG^WR^EDVHOLQH^^^P<0.05 compared to scan 2. Data are mean±SD.Example 4: The compound of formula (I) ameliorates hyperglycemia and promotes gene expression profiles favoring glucose oxidation in muscle of db / db mice.

[0104] To explore the potential of the compound of formula (I) to ameliorate hyperglycemia in the context of severe insulin resistance, db / db mice were treated with a diet formulated with the compound of formula (I) at a concentration of 0.5 or 1.0 mg / g of the compound of formula (I), denoted Cmpd-(I)-(0.5) and Cmpd-(I)-(1.0), for 9w. BKS mice were used as controls. At 6w of age, compensatory hyperinsulinemia was evident in db / db mice (FIGS. 3(a), 3(b)). Untreated db / db mice failed to compensate for the ensuing insulin resistance and blood glucose levels rapidly increased as a result of declining insulin levels (FIGS. 3(a), 3(b)). The compound of formula (I) dose-dependently increased insulin levels compared both with starting values and with untreated db / db mice and thus attenuated an increase in blood glucose levels (FIGS. 3(a), 3(b)). These findings provide evidence that the compound of formula (I) preserved a compensatory beta-cell insulin secretory response and homeostasis model assessment of beta-cell function (HOMA-beta) calculations showed that the decline in beta-cell function was attenuated in db / db mice treated with the compound of formula (I) (FIG. 3(c)). The compound-of-formula-(I)-mediated attenuation of hyperglycemia in db / db mice was paralleled by reduced glycogen accumulation in skeletal muscle and heart (FIGS. 3(d)), suggesting that the compound of formula (I) stimulated glucose utilization also in diabetic db / db mice. The decreased expression of Txnip, Pdk4 and Ucp3 together with the increased expression of Slc2a4, Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha (Ppargc1a), a positive regulator of mitochondrial biogenesis and respiration, and Cox8b, a driver of oxidative phosphorylation, in skeletal muscle of db / db mice treated with the compound of formula (I) compared with untreated db / db mice supports this notion (FIG. 3(f)). The increased cardiac expression of Slc2a1 and the attenuated expressions of Txnip, Pdk4, and Ucp3 in treated compared with untreated db / db mice (FIG. 3(g)) is also consistent with that observed in STZ mice treated with the compound of formula (I). Notably, the compound of formula (I) did not increase serum lactate levels in STZ mice treated with the compound of formula (I) and db / db mice (FIG. 11). Taken together, these findings provide evidence that, in both STZ and db / db diabetic mice, the compound of formula (I) averts gene signatures associated with metabolic inflexibility that in turn is associated with diabetes and diabetic cardiomyopathy.Example 5: The compound of formula (I) stimulates mitochondrial uncoupling in myotubes.

[0105] The increase in glucose utilization and reduced glycogen content observed in skeletal muscle and heart of STZ and db / db mice treated with the compound of formula (I) suggests that the compound of formula (I) increases energy expenditure by generating a metabolic demand either via futile cycling and / or mitochondrial uncoupling. Studies of mitochondrial and glycolytic function in intact, differentiated C2C12 myotubes were performed to elucidate a potential uncoupling potential for the compound of formula (I). The compound of formula (I) dose-dependently increased oxygen consumption rate (OCR), a measure of oxidative phosphorylation, in C2C12 myotubes, and the ratio of basal OCR to basal ECAR (extracellular acidification rate) (FIGS. 4(a)-4(c)), indicating that the compound of formula (I) increased the cellular preference for oxidative metabolism. The compound of formula (I) also showed a diminished reduction in OCR in response to oligomycin, which blocks the ATP synthase, and thus increased proton leak (FIGS. 4(a), 4(d)). However, consistent with our previously published findings, the compound of formula (I) did not significantly reduce cellular ATP levels (FIG. 4(d)). Altogether these results show that the compound of formula (I) increased cellular respiration by functioning as mitochondrial uncoupler, providing evidence that the compound of formula (I), by stimulating TCA flux and oxidative metabolism, induces a metabolic demand that enhances energy expenditure. Example 6: The compound of formula (I) preserves beta-cell function and mass in db / db mice.

[0106] Consistent with the described initial compensatory increase in beta-cell mass in db / db mice, islet cell area was increased at 6w of age in db / db compared with BKS mice (FIGS. 5(a), 5(b)). By 15w of age islet cell area was relatively reduced (p=0.09) compared with that at 6w of age in untreated db / db mice but dose-dependently preserved in the mice treated with the compound of formula (I) mice (FIGS. 5(a), 5(b)). The percentage of Ins+ cells was increased in mice treated with the compound of formula (I) compared with untreated db / db mice whereas the percentage cells positive for other pancreatic endocrine hormones tended to be reduced in db / db mice treated with the compound of formula (I) (FIGS. 5(c), 12(a)). Accordingly, pancreatic insulin and proinsulin content and the pancreatic insulin:proinsulin ratio, a measure of the efficiency of proinsulin processing, was increased in db / db mice treated with the compound of formula (I) compared to untreated db / db mice(FIGS. 5(d), 5(e), 12(b)). Together these data provide evidence that the compound of formula (I) averts beta-cell loss and preserves beta-cell function in db / db mice. Protein expression of glucose transporter Glut2, encoded by Slc2a2, was partially restored in islets of the db / db mice treated with the compound of formula (I) (FIGS. 5(a), 5(f)). The expressions of the transcription factors Nkx6.1 and MafA, markers of a mature beta-cell identity, were increased and Ipf1 / Pdx1 tended to be increased in islets of db / db mice treated with the compound of formula (I) (FIGS. 5(a), 5(f)). The expression of Raldh3, encoded by Aldehyde dehydrogenase 1a3 (Aldh1a3), which is upregulated in diabetic islets, was not altered (FIGS. 5(a), 5(f)). mRNA expression analyses of isolated islets showed that the expression of Urocortin 3 (Ucn3), a marker of mature beta-cells and regulator of insulin secretion, and Nkx6.1 was increased in islets from db / db mice treated with the compound of formula (I) (FIG. 5(g)). Treatment with the compound of formula (I) did not change the expression of Aldh1a3 whereas the expression of Txnip, which negatively affects insulin transcription and provokes oxidative stress in beta-cells, was reduced in islets of db / db mice treated with Cmpd-(I)-(1.0) compared with untreated db / db mice (FIG. 5(g)). Similarly, the expressions of the ER stress associated genes Endoplasmic Reticulum Protein 29 (Erp29) and ER degradation enhancing alpha-mannosidase-like 2 (Edem2) were reduced in islets of db / db mice treated with the compound of formula (I) (FIG. 5(g)). These data suggest that reduced expression of Txnip and ER stress genes, together with increased expression of genes regulating beta-cell identity and insulin secretion, contribute to the compound-of-formula-(I)- mediated maintenance of compensatory beta-cell function, GSIS, and beta-cell mass in insulin resistant db / db mice. The maintained compensatory insulin secretion in db / db mice treated with the compound of formula (I) likely explain the unchanged expression of Aldh1a3, suggesting that increased Aldh1a3 expression is a marker for metabolically challenged beta-cells. Example 7: The compound of formula (I) alleviates islet gene expression changes provided by acute hyperglycemia.

[0107] To investigate the ability of the compound of formula (I) to directly modulate the response of pancreatic islets to glucotoxic conditions we performed RNAseq analysis of mouse and human islets cultured ex vivo at low (11 mM) and high (22 mM) glucose + / - ^^^0^ of the compound of formula (I). Mouse islets responded to high glucose by upregulating 1924 and downregulating 1568 differentially expressed genes (DEGs) (FIGS. 6(a), 13(a)-13(c)).At high glucose, the compound of formula (I) reduced the number of DEGs to 143 upregulated and 208 downregulated (FIGS. 6(a), 13(a)-13(c)). As expected, exposure of mouse islets to high glucose resulted in a significant increase in Txnip expression which was attenuated by the compound of formula (I) (FIG. 6(b)). Overrepresentation analysis (ORA) of Molecular signature Hallmark, KEGG and Wiki-pathways gene sets revealed that the gene sets associated with enhanced beta-cell activity such as “Protein Secretion”, “Unfolded protein response” and “Pancreas beta-cells”, were overrepresented among DEGs upregulated by high glucose but averted by the compound of formula (I) at high glucose (FIG. 6(c)). The metabolic pathways “Fatty acid metabolism”, “Glycolysis” and “Hypoxia”, were also overrepresented together with “KEGG: TCA cycle” (P=0.073) among DEGs regulated by high glucose and counterregulated by the compound of formula (I). Hierarchal clustering of the top 20 most significant DEGs of these pathways, regardless of direction, showed opposing regulation by high glucose and addition of the compound of formula (I) (FIG. 6(d)). These results demonstrate the ability of the compound of formula (I) to directly preserve key metabolic gene expression patterns in beta-cells under glucotoxic conditions. Gene expression differences in human islets were dominated by donor effects, and even after batch correction, few DEGs were detected (FIGS. 13(d)-13(f)). Nonetheless, gene set enrichment analysis (GSEA) show that high glucose induced genes within the “Pancreatic beta-cells” gene set, which was counter regulated by the compound of formula (I), and that alike that observed for mouse islets, the compound of formula (I) induced upregulation of genes within “Hypoxia” and “Glycolysis” gene sets (FIG. 13(g)). Example 8: The compound of formula (I) prevents the negative effects of hyperglycemia on GSIS in INS-1E cells.

[0108] Chronic hyperglycemia activates mTORC1 signaling and suppresses AMPK signaling in beta-cells in vitro, resulting in reduced glucose metabolism and impaired glucose stimulated insulin secretion (GSIS). Consistently, our RNA seq analysis identified mTORC1 signaling to be upregulated in islets exposed to high (22 mM) glucose, which was prevented by exposure to the compound of formula (I) (FIG. 6(c)). To explore the effects of the compound of formula (I) on GSIS under conditions of chronic hyperglycemia, INS-1E cells were cultured at 25 mM glucose for 4 days (d), which impaired GSIS whereas concomitant exposure to the compound of formula (I) during the entire 4 d culture period averted these negative effects (FIG. 7(a)). Short term (2 hours) exposure of INS-1E cells to the compoundof formula (I) at the end of the 4 d culture period also partly reversed the negative effects of hyperglycemia on GSIS (FIG. 7(b)). Thus, the compound of formula (I) both prevented and reverted the negative effects of hyperglycemia on GSIS. Analyses of downstream targets of mTORC1, i.e. ribosomal protein 6 (pS6), and AMPK, i.e. Acetyl-CoA carboxylase (ACC) and Raptor, showed that both long- and short-term exposure of INS1-E cells to the compound of formula (I) at high glucose reduced pS6-Ser240 / 244 levels but increased pACC-Ser79 and pRaptor-Ser792 levels (FIGS. 7(c), 7(d), 14). Together, these findings provide evidence that the compound of formula (I) preserves beta-cell function under hyperglycemic conditions by antagonizing mTORC1 and preserving AMPK signaling.

Claims

CLAIMS What is claimed is:

1. A method for regulating blood glucose levels in a subject in need thereof by effects manifested as increasing glucose effectiveness, wherein the subject is insulin-deficient and is taking or needs to take exogenous insulin, the method comprising: administering to the subject a compound having the structure:(I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof; monitoring the subject’s blood glucose levels after administration of the compound; delaying need for use of exogenous insulin, or reducing or eliminating the dose of exogenous insulin administered to the subject to maintain the subject’s blood glucose level within a normal range for the subject.

2. The method of claim 1, wherein the normal range is: (i) less than 7% AIC; (ii) less than 154 mg / dL A1C (which may also be reported as eAG); (iii) before a meal, 80-130 mg / dL preprandial plasma glucose; or (iv) 1-2 hours after beginning of the meal, less than 180 mg / dL postprandial plasma glucose, or any combination of (i)-(iv).

3. The method of claim 1 or 2, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is repeatedly administered to the subject over a period of time.

4. The method of claim 3, wherein the dose of exogenous insulin administered is gradually reduced over the period of time during which the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered.

5. The method of claim 4, wherein the dose of exogenous insulin is eliminated after about two weeks of repeated administration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to the subject.

6. The method of claim 5, wherein the dose of exogenous insulin remains eliminated so long as the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to the subject.

7. The method of any one of claims 1 to 4, wherein the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered to the subject before exogenous insulin is administered to the subject to delay need to use exogenous insulin.

8. A method for treating Type 1 Diabetes (T1D) in a subject in need thereof, wherein the subject experience too high and too low glucose despite the use of exogenous insulin, comprising: administering to the subject a compound having the structure:(I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

9. The method of any one of the preceding claims, wherein the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered once daily.

10. The method of any one of the preceding claims, wherein the compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is administered orally.

11. The method of any one of the preceding claims, wherein an alkali metal salt of the compound is administered.

12. The method of any one of the preceding claims, wherein a sodium salt of the compound is administered.

13. The method of any one of claims 1 to 12, wherein the subject suffers from absolute insulin deficiency.

14. The method of claim 13, wherein the subject suffers from Type 1 Diabetes (T1D), chronic pancreatitis, pancreatectomy, cystic fibrosis, a monogenic diabetes disorder, or a post-infection following a severe acute respiratory syndrome (SARS) infection or other viral infections.

15. The method of claim 14, wherein the subject suffers from maturity-onset diabetes of the young (MODY) or latent autoimmune diabetes in adults (LADA).

16. The method of any one of claims 1 to 12, wherein the subject suffers from acute insulin deficiency.

17. The method of any one of claims 1 to 12, wherein the subject suffers from diabetic ketoacidosis.

18. The method of any one of claims 1 to 12, wherein the subject suffers from brittle diabetes.

19. The method of any one of claims 1 to 12, wherein the subject suffers from T1D, wherein the subject’s beta cells are lost.

20. The method of any one of claims 1 to 12, wherein the subject suffers from genetic conditions where insulin secretion is lost.

21. The method of any one of claims 1 to 12, wherein the subject suffers from a genetic defect in tissues’ ability to respond to insulin.

22. The method of any one of claims 1 to 12, wherein the subject suffers from congenital hyperinsulinism.

23. The method of any one of the preceding claims, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered in a pharmaceutical composition.

24. The method of claim 23, wherein the pharmaceutical composition is a tablet or capsule.

25. The method of any one of the preceding claims, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the patient at a dose of from about 100 mg to about 1,000 mg.

26. The method of claim 25, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the patient at a dose of from about 200 mg to about 600 mg.

27. The method of claim 25, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the patient at a dose of from about 400 mg to about 800 mg.

28. The method of claim 25, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the patient at a dose of about 400 mg.

29. The method of any one of claims 1 to 28, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the subject and results in a steady state blood plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, RI^IURP^DERXW^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^ 30. The method of any one of claims 1 to 28, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the subject and results in a steady state blood plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, RI^IURP^DERXW^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^ 31. The method of claim 30, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the subject and results in a steady state blood plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, RI^IURP^DERXW^^^^^^J^P / ^WR^DERXW^^^^^^J^P / ^32. The method of claim 30, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the subject and results in a steady state blood plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, RI^IURP^DERXW^^^^^^J^P / ^WR^DERXW^^^^^^J^P / ^ 33. The method of any one of claims 1 to 32, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily to the subject and results in a steady state AUC0-24of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, RI^IURP^DERXW^^^^^^^K^^J^P / ^ WR^DERXW^^^^^^^K^^J^P / ^ 34. The method of claim 33, wherein the steady state AUC0-24of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is from about ^^^^^^K^^J^P / ^WR^ DERXW^^^^^^^K^^J^P / ^ 35. The method of claim 33, wherein the steady state AUC0-24of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is from about ^^^^^^K^^J^P / ^WR^ DERXW^^^^^^^K^^J^P / ^ 36. The method of claim 33, wherein the steady state AUC0-24of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is from about ^^^^^^K^^J^P / ^WR^ DERXW^^^^^^^K^^J^P / ^ 37. The method of claim 33, wherein the steady state AUC0-24of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is from about ^^^^^^K^^J^P / ^ WR^DERXW^^^^^^^K^^J^P / ^ 38. The method of any one of claims 33 to 37, wherein the Cmaxof the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, LV^IURP^DERXW^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^ 39. The method of any one of claims 33 to 37, wherein the Cmaxof the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, LV^IURP^DERXW^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^40. The method of any one of claims 33 to 37, wherein the Cmaxof the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, LV^IURP^DERXW^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^ 41. The method of any one of claims 33 to 37, wherein the Cmaxof the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, LV^IURP^DERXW^^^^^^J^P / ^WR^ DERXW^^^^^^J^P / ^ 42. The method of any one of the preceding claims, wherein the subject is a human.

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