Inhibiting weight gain and the related muscle structural, functional and performance deterioration induced by imbalanced diet

Abstract

Provided herein are compositions comprising a thiazolium-based advanced glycation end product (AGE) breaker for use in methods to inhibit weight gain and associated muscle structural, functional, and performance deterioration induced by hyperglycemia. The thiazolium-based AGE breaker can be ALT-711.

Description

[0001] DESCRIPTION

[0002] TITLE

[0003] INHIBITING WEIGHT GAIN AND THE RELATED MUSCLE STRUCTURAL, FUNCTIONAL AND PERFORMANCE DETERIORATION INDUCED BY

[0004] IMBALANCED DIET

[0005] CROSS-REFERENCE TO RELATED APPLICATION

[0006] The present application claims the benefit of U.S. Provisional Application Serial No. 63 / 512,317, filed uly 7, 2023, which is hereby incorporated by reference herein in its entirety, including any figures, tables, or drawings.

[0007] BACKGROUND OF THE INVENTION

[0008] Diabetes is one of the most severe health issues that needs to be addressed in modern society. The rising prevalence is due to a sedentary lifestyle and an imbalanced diet, and the population with diabetes is estimated to increase by another 46% until 2045 to reach 783 million patients worldwide [1], For long-term diabetes, patients have reduced motion and a reduced quality of life, which forms a vicious circle to that worsens glucose mobilization. Skeletal muscle has been considered the primary defect site during hyperglycemia development, which showed insulin resistance before the glycemic change [2], Moreover, exercise is one of the most powerful hyperglycemia prevention strategies in common clinical practice. However, there are still no clinically available drugs targeting the skeletal muscle to inhibit or treat hyperglycemia.

[0009] Therefore, a novel therapeutic approach for targeting skeletal muscle to inhibit and / or treat hyperglycemia is needed.

[0010] BRIEF SUMMARY OF THE INVENTION

[0011] The present invention relates to compositions comprising a thiazolium-based advanced glycation end product (AGE) breaker for use in methods to inhibit weight gain and associated muscle structural, functional, and performance deterioration related hyperglycemia. The subject invention further pertains to methods of treating diabetes. In preferred embodiments, the diabetes is prediabetes or type 2 diabetes. In certain embodiments, the subject composition comprises a thiazolium-based AGE breaker, such as, for example, ALT-711. In certain embodiments, the thiazolium-based AGE breaker can inhibit weight gain; reduce hyperglycemia; reduce food intake; increase feed conversion ratio; inhibit the muscle deterioration effects of weight gain and hyperglycemia; inhibit and ameliorate the diet-related intramuscular AGE, fibronectin, and collagen accumulation; inhibit diet-related skeletal muscle stiffening; inhibit and improve diet-related skeletal muscle contraction and relaxation abnormality; inhibit and improve diet-related perturbation of skeletal muscle fatigue recovery rate; inhibit and improve the skeletal muscle force output under ex vivo stimulation; ameliorate the age-related intramuscular fibronectin and collagen accumulation; or any combination thereof.

[0012] BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 Diet plan of the control, prevention, and treatment groups. Repeated high-fat diet feeding plans were applied to the control, prevention, and treatment groups of animals.

[0014] FIGs. 2A-2D ALT-711 inhibits weight gain, reduces the extent of hyperglycemia, reduces food intake, and increases feed conversion ratio. Between the control and prevention groups, at the end of stage 1, animals showed (FIG. 2A) reduced weight gain, (FIG. 2B) reduced the severity of hyperglycemia, (FIG. 2C) reduced food intake, and (FIG. 2D) increased feed conversion ratio. Feed conversion ratio: food intake / weight gain in a set period. Statistical analysis is performed using the student’s T-test, *: p<0.05.

[0015] FIGs. 3A-3B ALT-711 prevents the deterioration of weight gain and hyperglycemia after receiving the second high-fat diet feeding episode. In the control group, the W16 timepoint showed further worsening of weight gain and hyperglycemia. However, both the prevention and treatment group showed a comparable level of weight (FIG. 3A) and glycemic level (FIG. 3B) with the control group in the W5 timepoint. Statistical analyses are performed using two-way ANOVA with p<0.05, J: compared with timepoint-matched control, +: compared with W5 timepoint in the control group.

[0016] FIGs. 4A-4F ALT-711 prevents and ameliorates the diet-related intramuscular AGE, fibronectin, and collagen accumulation. Compared between healthy and control groups, the W16 timepoint showed AGE, Fnl, and OH-Pro (collagen) accumulation. Here showed the representing image of AGE (FIG. 4 A), Fnl (FIG. 4C), and OH-Pro (FIG. 4E). And the expression level in the prevention and treatment groups was significantly lower than in the control group (FIG. 4B, FIG. 4D, FIG. 4F) Statistical analysis is performed using two-way ANOVA with p<0.05, &: compared with the timepoint-matched healthy group, J: compared with the timepoint-matched control group.

[0017] FIGs. 5A-5B ALT-711 prevents diet-related skeletal muscle stiffening. Compared between WO and W16 timepoint in the control group, the stiffness and ultimate strength were significantly increased. The results showed, in the prevention group, muscle stiffness (FIG. 5A) and ultimate strength (FIG. 5B) were comparable to the WO timepoint in the control group. Statistical analysis is performed using two-way ANOVA with p<0.05, #: compared with WO, J: compared with the timepoint-matched control group.

[0018] FIGs. 6A-6D ALT-711 prevents and improves diet-related skeletal muscle contraction and relaxation abnormality. According to the result, both the prevention and treatment groups showed improved max contraction rate compared to the age-matched control group (FIG. 6A); the treatment group showed the ameliorated time to max force downregulation compared to the age-matched control group (FIG. 6B); prevention and treatment group showed improved max relaxation time compared to the age-matched control group (FIG. 6C); treatment group showed improved half relaxation time compared to the age-matched control group (FIG. 6D). Statistical analysis is performed using two-way ANOVA with p<0.05, #: compared with WO, J: compared with the timepoint-matched control group.

[0019] FIGs. 7A-7B ALT-711 prevents and improves diet-related perturbation of skeletal muscle fatigue recovery rate. In the control group, 10 minutes fatigue recovery rate was significantly reduced. Our result showed that both the prevention and treatment group showed significant improvement in 5 minutes (FIG. 7A) and 10 minutes (FIG. 7B) of fatigue recovery rate. Statistical analyses are performed using two-way ANOVA with p<0.05, #: compared with W0, J: compared with the timepoint-matched control group.

[0020] FIGs. 8A-8B ALT-711 prevents and improves the skeletal muscle force output under ex vivo stimulation. The control group showed a significant reduction of twitch force in the W16 timepoint. However, the prevention and treatment groups were statistically comparable to the W0 timepoint in the control group (FIG. 8A). The prevention and treatment group showed significantly improved tetanic force output (FIG. 8B). Statistical analyses are performed using two-way ANOVA with p<0.05, #: compared with W0, J: compared with the timepoint-matched control group.

[0021] FIGs. 9A-9B ALT-711 prevents and improves the diet-related grip force weakening. The relative grip force was normalized to body weight. In the W11 timepoint, animal weights were comparable, and the control group showed force reduction compared to the W0 timepoint; however, the prevention and treatment group showed prevention and amelioration of diet- related force reduction (FIG. 9A). In the W16 timepoint, body weight was higher than the WO timepoint; however, the prevention and treatment group showed a reduction of grip force weakening (FIG. 9B). Statistical analyses are performed using two-way ANOVA with p<0.05, #: compared with WO, J: compared with the timepoint-matched control group.

[0022] FIG. 10 Diet plan of the aged and treatment groups. The treatment group was treated with the AGE breaker at 24-month-old for one month.

[0023] FIGs. 11A-11C ALT-711 ameliorates age-related hyperglycemia and reduces food intake. After treating the animals with the ALT-711 for one month. Aged animals showed (FIG. 11A) reduced IPGT-AUC, (FIG. 11B) reduced fasting blood glucose, and (FIG. 11C) reduced food intake. Statistical analyses are performed using t test with the p-value shown in the graphs.

[0024] FIG. 12 ALT-711 improves age-related grip strength reduction. The relative grip force was normalized to body weight. After treating the animals with the ALT-711 for one month. The grip strength was significantly increased compared to the age-match control animals. Statistical analyses are performed using t test with the p-value shown in the graphs.

[0025] FIGs. 13A-13D ALT-711 ameliorates the age-related intramuscular fibronectin and collagen accumulation. After treating the animals with the ALT-711 for one month. Treatment group showed reduced Fnl, and OH-Pro (collagen) accumulation. Here showed the representing image of OH-Pro (FIG. 13A) and Fnl (FIG. 13C). And the expression level in the prevention and treatment groups was significantly lower than in the aged group (FIG. 13B, FIG. 13D) Statistical analyses are performed using t test with the p-value shown in the graphs.

[0026] DETAILED DISCLOSURE OF THE INVENTION

[0027] Selected Definitions

[0028] As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising”. The transitional terms / phrases (and any grammatical variations thereof) “comprising”, “comprises”, “comprise”, “consisting essentially of’, “consists essentially of’, “consisting” and “consists” can be used interchangeably. The phrases “consisting essentially of’ or “consists essentially of’ indicate that the claim encompasses embodiments containing the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claim.

[0029] The term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured, z.e., the limitations of the measurement system. In the context of compositions containing amounts of ingredients where the term “about” is used, these compositions contain the stated amount of the ingredient with a variation (error range) of 0-10% around the value (X ± 10%). In other contexts, the term “about” is used provides a variation (error range) of 0-10% around a given value (X ± 10%). As is apparent, this variation represents a range that is up to 10% above or below a given value, for example, X ± 1%, X ± 2%, X ± 3%, X ± 4%, X ± 5%, X ± 6%, X ± 7%, X ± 8%, X ± 9%, or X ± 10%.

[0030] In the present disclosure, ranges are stated in shorthand to avoid having to set out at length and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range. For example, a range of 0.1-1.0 represents the terminal values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges encompassed within 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc. Values having at least two significant digits within a range are envisioned, for example, a range of 5-10 indicates all the values between 5.0 and 10.0 as well as between 5.00 and 10.00 including the terminal values. When ranges are used herein, combinations and subcombinations of ranges (e.g., subranges within the disclosed range) and specific embodiments therein are explicitly included.

[0031] “Treatment”, “treating”, “palliating” and “ameliorating” (and grammatical variants of these terms), as used herein, are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit. A therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease or symptom thereof such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the disease or symptom thereof.

[0032] As used herein, the terms “diabetes” or “diabetes mellitus” refers to a group of disorders characterized by excess glucose level in the blood (i.e., hyperglycemia). Diabetes can include chronic diabetes, such as, for example type 1 diabetes or type 2 diabetes. Diabetes can also include prediabetes and gestational diabetes. As used herein, the term “hyperglycemia” refers to a condition that is related to one or more of the following: high-fat diet, high-carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, immobilization, and aging.

[0033] As used herein, the term “hyperglycemia-related muscle structural deterioration” refers to a condition that is related to one or more of the following: high-fat diet, high-carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, immobilization, and aging.

[0034] As used herein, the term “hyperglycemia-related muscle or functional deterioration” refers to a condition that is related to one or more of the following: high-fat diet, high- carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, immobilization, and aging.

[0035] As used herein, the term “weight gain” refers to a condition that is related to one or more of the following: high-fat diet, high-carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, immobilization, and aging.

[0036] As used herein, the “weight gain-related muscle structural deterioration” refers to a condition that related to one or more of the following: high-fat diet, high-carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, immobilization, and aging.

[0037] As used herein, the “weight gain-related muscle functional deterioration” refers to a condition that related to one or more of the following: high-fat diet, high-carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, immobilization, and aging.

[0038] As used herein, “skeletal muscle performance deterioration” refers to a condition that is related to one or more of the following: high-fat diet, high-carbohydrate diet, Western diet, overnutrition, sedentary lifestyle, immobilization, and aging.

[0039] As used herein, the term “deterioration” refers to the development or progression of clinical and subclinical symptoms, disorders, or conditions.

[0040] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts that are non-toxic may be inorganic or organic acid addition salts and base addition salts.

[0041] “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. A “pharmaceutically acceptable vehicle” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used to facilitate administration of an agent and that is compatible therewith. Examples of vehicles include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0042] The term “effective amount” or “therapeutically effective amount” refers to that amount of an compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment. The therapeutically effective amount may vary depending on the intended application (in vitro or in vivo) or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response, e.g., enhancing the function of skeletal muscle. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0043] In some embodiments of the invention, the method comprises administration of multiple doses of the compositions of the subject invention. The method may comprise administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or more therapeutically effective doses of a composition of the subject invention as described herein. In some embodiments, doses are administered over the course of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 30 days, or more than 30 days. Moreover, treatment of a subject with a therapeutically effective amount of the compositions of the invention can include a single treatment or can include a series of treatments. It will also be appreciated that the effective dosage of a composition used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays or imaging techniques for detecting, for example, blood sugar concentration, which is well-known in the art. In some embodiments of the invention, the method comprises administration of the composition several time per day, including but not limiting to 2 times per day, 3 times per day, and 4 times per day.

[0044] As used herein, the term “subject” refers to an animal, needing or desiring delivery of the benefits provided by a therapeutic composition. The animal may be a primate or rodent. The animal may be, for example, humans, pigs, horses, goats, cats, mice, rats, dogs, apes, fish, chimpanzees, orangutans, guinea pigs, hamsters, cows, sheep, birds, chickens, as well as any other vertebrate or invertebrate. These benefits can include, but are not limited to, the treatment of a health condition, disease or disorder; prevention of a health condition, disease or disorder; immune health; enhancement of the function of enamel, an organ, tissue, or system in the body. The subject can be of any age or stage of development, including infant, toddler, adolescent, teenager, adult, or senior. The terms “subject” and “patient” can be used interchangeably.

[0045] By “reduces” is meant a negative alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.

[0046] By “increases” is meant as a positive alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.

[0047] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0048] Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.

[0049] Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. All references cited herein are hereby incorporated by reference.

[0050] Compositions

[0051] In certain embodiments, the compositions and methods according to the subject invention utilize a thiazolium -based AGE breaker with a core structure illustrated in Formula (I):

[0052] Formula (I) wherein Ri is a phenyl group or a phenylmethanol group;

[0053] R.2 is a methyl group or a hydrogen group; and R3 is a methyl group or a hydrogen group; methyl groups in R2 and.

[0054] In a preferred embodiment, Ri is a phenyl group and R2 and R3 are methyl groups.

[0055] In a preferred embodiment, Ri is a phenyl group and R2 and R3 are hydrogen groups.

[0056] In a preferred embodiment, Ri, is a phenylmethanol group, R2, is a methyl group, and R3 is a hydrogen group.

[0057] In certain embodiments, the thiazolium-based AGE breaker is ALT-711, according to formula (II):

[0058] In certain embodiments, the composition further comprises metformin, a sodiumglucose cotransporter-2 (SGLT-2) inhibitor, a glucagon-like peptide 1 (GLP-1) receptor agonist (RA), a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (RA), a dipeptidyl peptidase 4 (DPP-4) inhibitor, a thiazolidinedione, a sulfonylurea, insulin, or any combination thereof.

[0059] In certain embodiments, metformin can be administered at an amount of about 500 to about 2000 mg / day.

[0060] In certain embodiments, the SGLT-2 inhibitor can be administered at an amount of about 5 to about 25 mg / day. In certain embodiments, the SGLT-2 inhibitor is Bexagliflozin, Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin, Ipragliflozin, Luseogliflozin, Remogliflozin, Sergliflozin, Sotagliflozin, Tofogliflozin, or any combination thereof. In certain embodiments, the GLP-1 receptor agonist and GIP receptor agonist can be administered at an amount of about 0.25 to about 1 mg / week. In certain embodiments, the GIP- 1 RA or the GLP-1 RA is Liraglutide, Semaglutide, Dulaglutide, Tirzepatide, Exenatide, Albiglutide, Lixisenatide, or any combination thereof.

[0061] In certain embodiments, the DPP-4 inhibitor can be administered at an amount of about 5to about 100 mg / day. In certain embodiments, the DPP -4 inhibitor is Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, or any combination thereof.

[0062] In certain embodiments, the thiazolidinedione can be administered at an amount of about 15 to about 45 mg / day. In certain embodiments, the thiazolidinedione is Rosiglitazone, Pioglitazone, or a combination thereof.

[0063] In certain embodiments, the sulfonylurea can be administered at an amount of about 1 to about 10 mg / day. In certain embodiments, the sulfonylurea is Acetohexamide, Carbutamide, Chlorpropamide, Glycyclamide, Metahexamide, Tolazamide, Tolbutamide, Glibenclamide, Glibornuride, Gliclazide, Glipizide, Gliquidone, Glisoxepide, Glyclopyramide, Glimepiride, or any combination thereof.

[0064] In certain embodiments, insulin can be administered at an amount of about 10 to about 100 unit / day. In certain embodiments, one international unit of insulin (1 IU) is defined as the "biological equivalent" of 34.7 pg pure crystalline insulin.

[0065] In some embodiments the subject invention provides pharmaceutically acceptable salts, solvates or hydrates thereof, of the compounds described herein. In certain embodiments, the subject composition can be dissolved in water, alcohol, or other polar solvents.

[0066] Pharmaceutically acceptable salts can be a salt with an inorganic acid, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid; an organic acid, such as trifluoroacetic acid (TFA), formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid; or a salt with a base, such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mono-, di-, trialkyl and aryl amines, and substituted ethanolamines.

[0067] Further, pharmaceutically acceptable salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-di sulfonic acid, 2-hydroxy ethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l -carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0068] Hydrate refers to a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0069] Solvate means a solvate formed from the association of one or more solvent molecules to a compound of the present invention. The term solvate" includes hydrates (e.g., mono hydrate, dihydrate, trihydrate, tetrahydrate, and the like).

[0070] Certain embodiments provide amorphous forms of salts of the compounds disclosed herein. Such amorphous forms are advantageous for oral, pulmonary, buccal, intravaginal, or suppository delivery. In preferred embodiments, the subject compounds are administered orally.

[0071] In one embodiment, the subject compositions are formulated as an orally-consumable product, such as, for example a food item, capsule, pill, or drinkable liquid. An orally deliverable pharmaceutical is any physiologically active substance delivered via initial absorption in the gastrointestinal tract or into the mucus membranes of the mouth. The topic compositions can also be formulated as a solution that can be administered via, for example, injection, which includes intravenously, intraperitoneally, intramuscularly, intrathecally, intracerebroventricularly or subcutaneously. In other embodiments, the subject compositions are formulated to be administered via the skin through a patch or directly onto the skin for local or systemic effects. The compositions can be administered sublingually, buccally, rectally, or vaginally. Furthermore, the compositions can be sprayed into the nose for absorption through the nasal membrane, nebulized, inhaled via the mouth or nose, or administered in the eye or ear.

[0072] Orally consumable products according to the invention are any preparations or compositions suitable for consumption, for nutrition, for oral hygiene, or for pleasure, and are products intended to be introduced into the human or animals oral cavity, to remain there for a certain period of time, and then either be swallowed (e.g., food ready for consumption or pills) or to be removed from the oral cavity again (e.g., chewing gums or products of oral hygiene or medical mouth washes). While an orally-deliverable pharmaceutical can be formulated into an orally consumable product, and an orally consumable product can comprise an orally deliverable pharmaceutical, the two terms are not meant to be used interchangeably herein.

[0073] Orally consumable products include all substances or products intended to be ingested by humans or animals in a processed, semi-processed, or unprocessed state. This also includes substances that are added to orally consumable products (particularly food and pharmaceutical products) during their production, treatment, or processing and intended to be introduced into the human or animals oral cavity.

[0074] Orally consumable products can also include substances intended to be swallowed by humans or animals and then digested in an unmodified, prepared, or processed state; the orally consumable products according to the invention therefore also include casings, coatings, or other encapsulations that are intended to be swallowed together with the product or for which swallowing is to be anticipated.

[0075] In one embodiment, the orally consumable product is a capsule, pill, syrup, emulsion, or liquid suspension containing a desired orally deliverable substance. In one embodiment, the orally consumable product can comprise an orally deliverable substance in powder form, which can be mixed with water or another liquid to produce a drinkable orally-consumable product.

[0076] In some embodiments, the orally-consumable product according to the invention can comprise one or more formulations intended for nutrition or pleasure. These particularly include baking products (e.g., bread, dry biscuits, cake, and other pastries), sweets (e.g., chocolates, chocolate bar products, other bar products, fruit gum, coated tablets, hard caramels, toffees and caramels, and chewing gum), alcoholic or non-alcoholic beverages (e.g., cocoa, coffee, green tea, black tea, black or green tea beverages enriched with extracts of green or black tea, Rooibos tea, other herbal teas, fruit-containing lemonades, isotonic beverages, soft drinks, nectars, fruit and vegetable juices, and fruit or vegetable juice preparations), instant beverages (e.g., instant cocoa beverages, instant tea beverages, and instant coffee beverages), meat products (e.g., ham, fresh or raw sausage preparations, and seasoned or marinated fresh meat or salted meat products), eggs or egg products (e.g., dried whole egg, egg white, and egg yolk), cereal products (e.g., breakfast cereals, muesli bars, and pre-cooked instant rice products), dairy products (e.g., whole fat or fat reduced or fat-free milk beverages, rice pudding, yoghurt, kefir, cream cheese, soft cheese, hard cheese, dried milk powder, whey, butter, buttermilk, and partly or wholly hydrolyzed products containing milk proteins), products from soy protein or other soy bean fractions (e.g., soy milk and products prepared thereof, beverages containing isolated or enzymatically treated soy protein, soy flour containing beverages, preparations containing soy lecithin, fermented products such as tofu or tempeh products prepared thereof and mixtures with fruit preparations and, optionally, flavoring substances), fruit preparations (e.g., jams, fruit ice cream, fruit sauces, and fruit fillings), vegetable preparations (e.g., ketchup, sauces, dried vegetables, deep-freeze vegetables, pre-cooked vegetables, and boiled vegetables), snack articles (e.g., baked or fried potato chips (crisps) or potato dough products and extrudates on the basis of maize or peanuts), products on the basis of fat and oil or emulsions thereof (e.g., mayonnaise, remoulade, and dressings), other ready-made meals and soups (e.g., dry soups, instant soups, and pre-cooked soups), seasonings (e.g., sprinkle-on seasonings), sweetener compositions (e.g., tablets, sachets, and other preparations for sweetening or whitening beverages or other food). The present compositions may also serve as semi-finished products for the production of other compositions intended for nutrition or pleasure.

[0077] The subject composition can further comprise one or more pharmaceutically acceptable carriers, and / or excipients, and can be formulated into preparations, for example, solid, semisolid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, aerosols, strips, wafers, films, pellets, caplets, troches, lozenges, dispersions, aqueous solution, non-aqueous solution, oil-in-water emulsion, or water-in-oil liquid emulsion.

[0078] The term “pharmaceutically acceptable” as used herein means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.

[0079] Carriers and / or excipients according the subject invention can include any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers), oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for, e.g., IV use, solubilizers (e.g., Polysorbate 65, Polysorbate 80), colloids, dispersion media, vehicles, fillers, chelating agents (e.g., EDTA or glutathione), amino acids (e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavorings, aromatizers, thickeners (e.g. carbomer, gelatin, or sodium alginate), coatings, preservatives (e.g., Thimerosal, benzyl alcohol, polyquaterium), antioxidants (e.g., ascorbic acid, sodium metabisulfite), tonicity controlling agents, absorption delaying agents, adjuvants, bulking agents (e.g., lactose, mannitol) and the like. The use of carriers and / or excipients in the field of drugs and supplements is well known. Except for any conventional media or agent that is incompatible with the target health-promoting substance or with the composition, carrier or excipient use in the subject compositions may be contemplated.

[0080] In one embodiment, the compositions of the subject invention can be made into aerosol formulations so that, for example, it can be nebulized or inhaled. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, powders, particles, solutions, suspensions or emulsions. Formulations for oral or nasal aerosol or inhalation administration may also be formulated with carriers, including, for example, saline, polyethylene glycol or glycols, DPPC, methylcellulose, or in mixture with powdered dispersing agents or fluorocarbons. Aerosol formulations can be placed into pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. Illustratively, delivery may be by use of a single-use delivery device, a mist nebulizer, a breath-activated powder inhaler, an aerosol metered-dose inhaler (MDI), or any other of the numerous nebulizer delivery devices available in the art. Additionally, mist tents or direct administration through endotracheal tubes may also be used.

[0081] In one embodiment, the compositions of the subject invention can be formulated for administration via injection, for example, as a solution or suspension. The solution or suspension can comprise suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3 -butanediol, water, Ringer's solution, or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, non-irritant, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. One illustrative example of a carrier for intravenous use includes a mixture of 10% USP ethanol, 40% USP propylene glycol or polyethylene glycol 600 and the balance USP Water for Injection (WFI). Other illustrative carriers for intravenous use include 10% USP ethanol and USP WFI; 0.01- 0.1% triethanolamine in USP WFI; or 0.01-0.2% dipalmitoyl diphosphatidylcholine in USP WFI; and 1-10% squalene or parenteral vegetable oil-in-water emulsion. Water or saline solutions and aqueous dextrose and glycerol solutions may be preferably employed as carriers, particularly for injectable solutions. Illustrative examples of carriers for subcutaneous or intramuscular use include phosphate buffered saline (PBS) solution, 5% dextrose in WFI and 0.01-0.1% triethanolamine in 5% dextrose or 0.9% sodium chloride in USP WFI, or a 1 to 2 or 1 to 4 mixture of 10% USP ethanol, 40% propylene glycol and the balance an acceptable isotonic solution such as 5% dextrose or 0.9% sodium chloride; or 0.01-0.2% dipalmitoyl diphosphatidylcholine in USP WFI and 1 to 10% squalene or parenteral vegetable oil-in-water emulsions.

[0082] In one embodiment, the compositions of the subject invention can be formulated for administration via topical application onto the skin, for example, as topical compositions, which include rinse, spray, or drop, lotion, gel, ointment, cream, foam, powder, solid, sponge, tape, vapor, paste, tincture, or using a transdermal patch. Suitable formulations of topical applications can comprise in addition to any of the pharmaceutically active carriers, for example, emollients such as carnauba wax, cetyl alcohol, cetyl ester wax, emulsifying wax, hydrous lanolin, lanolin, lanolin alcohols, microcrystalline wax, paraffin, petrolatum, polyethylene glycol, stearic acid, stearyl alcohol, white beeswax, or yellow beeswax. Additionally, the compositions may contain humectants such as glycerin, propylene glycol, polyethylene glycol, sorbitol solution, and 1,2,6 hexanetri ol or permeation enhancers such as ethanol, isopropyl alcohol, or oleic acid.

[0083] The subject invention also concerns kits comprising in one or more containers of at least 1, 2, 3, or more compounds of the subject invention. A kit of the invention can also comprise one or more compounds, biological molecules, or drugs. In one embodiment, a kit of the invention comprises a compound of the subject invention. In certain embodiments, the subject invention further pertains to a kit comprising the compounds of the subject invention, compositions comprising the subject compounds and, optionally, other compounds, including, for example, insulin effective in treating symptoms of diabetes. In preferred embodiments, the diabetes is prediabetes or type 2 diabetes.

[0084] The invention further provides kits, including compounds of the subject invention and pharmaceutical formulations, packaged into suitable packaging material, optionally in combination with instructions for using the kit components, e.g., instructions for performing a method of the invention. In one embodiment, a kit includes an amount of compounds of the subject invention and instructions for administering the compounds of the subject invention to a subject in need of treatment on a label or packaging insert. In further embodiments, a kit includes an article of manufacture, for delivering the compounds of the subject invention into a subject locally, regionally or systemically, for example.

[0085] As used herein, the term “packaging material” refers to a physical structure housing the components of the kit. The packaging material can maintain the components sterilely and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampules, etc.). The label or packaging insert can include appropriate written instructions, for example, practicing a method of the invention, e.g., treating diabetes, an assay for identifying a subject having hyperglycemia, etc. Thus, in additional embodiments, a kit includes a label or packaging insert including instructions for practicing a method of the invention in solution, in vitro, in vivo, or ex vivo. In preferred embodiments, the diabetes is prediabetes or type 2 diabetes.

[0086] Instructions can therefore include instructions for practicing any of the methods of the invention described herein. For example, pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration to a subject. Instructions may additionally include appropriate administration route, dosage information, indications of a satisfactory clinical endpoint or any adverse symptoms that may occur, storage information, expiration date, or any information required by regulatory agencies such as the Food and Drug Administration or European Medicines Agency for use in a human subject.

[0087] The instructions may be on “printed matter,” e.g., on paper or cardboard within the kit, on a label affixed to the kit or packaging material, or attached to a vial or tube containing a component of the kit. Instructions may comprise voice or video tape and additionally be included on a computer readable medium, such as a disk (floppy diskette or hard disk), optical CD such as CD- or DVD-ROM / RAM, magnetic tape, electrical storage media such as RAM and ROM and hybrids of these such as magnetic / optical storage media.

[0088] Kits can additionally include a buffering agent, a preservative, or an agent for stabilizing the compounds of the subject invention. The kit can also include control components for assaying for the presence of blood sugar, e.g., a control sample or a standard. Each component of the kit can be enclosed within an individual container or in a mixture and all of the various containers can be within single or multiple packages.

[0089] Methods of Using the Subject Compositions The present invention relates to methods and compositions for the treatment of hyperglycemia in a subject, hyperglycemia-related muscle structural or functional deterioration in a mammal, weight gain in a mammal, weight gain-related muscle structural or functional deterioration in a mammal, or for skeletal muscle performance deterioration in a subject by administration of an effective dose of an thiazolium-based advanced glycation end product (AGE) breaker. Such methods and compositions are advantageously easy to administer and to increase patient compliance.

[0090] In certain embodiments, thiazolium-based AGE breaker can be administered to a subject. Any means of administration that can be used, including, for example, orally, intravenously, intraperitoneally, intramuscularly, intrathecally, or subcutaneously are envisioned in the subject methods.

[0091] In certain embodiments, the orally administered thiazolium-based AGE breaker is absorbed through oral mucosa. In certain embodiments, the oral mucosa is selected from one or more of the following: sublingual mucosa, buccal mucosa, and labial mucosa. In certain embodiments, the orally administered thiazolium-based AGE breaker is absorbed through the intestine. In certain embodiments, the present invention provides a method of administering the subject compositions in an orodispersible dose.

[0092] In certain embodiments, the method further comprises administering the dose of the thiazolium-based AGE breaker is within the range from about 0.1 mg to 50 mg per kg body weight of the subject. In certain embodiments, the dose of the thiazolium-based AGE breaker is about 20 mg per kg body weight.

[0093] In certain embodiments, the method further comprises administering the dose of a thiazolium-based AGE breaker is administered at least every about 7 days, at least daily, or at least twice daily. In certain embodiments, the dose of the thiazolium-based AGE breaker is administered daily.

[0094] In certain embodiments, the method further comprises administering the dose of a thiazolium-based AGE breaker in a form selected from strips, wafers, films, pellets, caplets, tablets, troches, lozenges, dispersions, powder, granules, aqueous solution, non-aqueous solution, oil-in-water emulsion, or water-in-oil liquid emulsion.

[0095] In certain embodiments, the method additionally comprises administering a lifestyle modification, such as, for example, a dietary modification, time-restricted eating, caloric restriction, endurance training, weight training, or any combination thereof. In certain embodiments, the method additionally comprises administering hypoglycemic drugs in one or more of the following: metformin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, a glucagon-like peptide 1 (GLP-1) receptor agonist, a glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, a dipeptidyl peptidase 4 (DPP -4) inhibitor, a thiazolidinedione, a sulfonylurea, insulin, or any combination thereof.

[0096] In certain embodiments, metformin can reduce gut glucose absorption, increase muscle glucose uptake, liver glucose production. In certain embodiments, SGLT-2 inhibitors can reduce glucose reuptake. In certain embodiments, GIP receptor agonist can affect the incretin system. In certain embodiments, GLP-1 receptor agonist can affect the incretin system. In certain embodiments, DPP-4 inhibitors can affect the incretin system. In certain embodiments, thiazolidinediones can inhibit Pparg signaling. In certain embodiments, sulfonylureas can promote insulin secretion.

[0097] In certain embodiments, the method further comprises inhibiting muscle structural deterioration in a skeletal muscle mechanical property, intramuscular extracellular matrix (ECM), intramuscular AGE, or any combination thereof.

[0098] In certain embodiments, the muscle structural deterioration is measured by histology, immuno assays, ultrasound, photoacoustic effect, fluorescent, or combination thereof.

[0099] In certain embodiments, the muscle structural deterioration is determined by at least a 5% change in the diseased subjects compared to the average of the healthy subjects of its skeletal muscle mechanical property, intramuscular extracellular matrix (ECM), intramuscular AGE, or any combination thereof.

[0100] In certain embodiments, the method further inhibiting skeletal muscle functional deterioration by measuring muscle contraction and muscle relaxation ability.

[0101] In certain embodiments, the muscle contraction and muscle relaxation deterioration is determined by at least a 5% change in the diseased subjects compared to the average of the healthy subjects of its time to max contraction force, max contraction rate, half relaxation time, and max relaxation rate, or any combination thereof.

[0102] In certain embodiments, the method further inhibiting skeletal muscle performance deterioration, which can be determined using an ex vivo muscle performance test, clinical muscle performance test, or combination thereof.

[0103] In certain embodiments, skeletal muscle ex vivo performance deterioration is determined by at least a 5% change in the diseased subjects compared to the average of the healthy subject of its 5 minutes fatigue recovery, 10 minutes fatigue recovery, specific twitch force, specific tetanic force, or any combination thereof.

[0104] In certain embodiments, skeletal muscle clinical muscle performance deterioration is determined by at least a 1 standard deviation lower in the specific gender and age group in the diseased subjects compared to the average of the healthy subjects of its timed-get-up-and-go test, chair stand test, gait speed test, grip strength test, isokinetic muscle performance test, one- repetition maximum test, maximum isometric strength tests, muscle power tests, or any combination thereof.

[0105] In certain embodiments, the method further comprises inhibiting hyperglycemia, which can be measured using fast blood glucose, 2 hours post oral glucose tolerance test (OGTT) blood glucose, 2 hours post intraperitoneal glucose tolerance test (IPGTT) blood glucose, OGTT area under the curve (AUC), IPGTT AUC, HbAlc, or any combination thereof.

[0106] In certain embodiments, hyperglycemia is determined by at least a 10% change in the diseased subjects compared to the average of the healthy subjects of its fast blood glucose, 2 hours post OGTT blood glucose, 2 hours post IPGTT blood glucose, OGTT AUC, IPGTT AUC, or any combination thereof.

[0107] In certain embodiments, hyperglycemia is determined by fast blood glucose > lOOmg / dL, 2 hours post OGTT blood glucose > 140 mg / dL, HbAlc > 5.7%, or any combination thereof.

[0108] In certain embodiments, the method further comprises inhibiting weight gain by, for example, decreasing or stabilizing body weight, decreasing food intake, increasing feed conversion ratio, or any combination there.

[0109] In certain embodiments, weight gain is determined by at least a 5% change on average in the diseased subjects compared to the average of the healthy subjects of its body weight or determined by the BMI > 25.

[0110] In certain embodiments, the present invention provides an orally administered composition for the treatment for hyperglycemia in a mammal, for hyperglycemia-related muscle structural or functional deterioration in a mammal, for weight gain in a mammal, for weight gain-related muscle structural or functional deterioration in a mammal, or for skeletal muscle performance deterioration in a mammal comprising administering a (i) thiazolium- based AGE breaker within the range of from about 0.1 mg to 50 mg per kg body weight; or a (ii) thiazolium-based AGE breaker at a concentration of about 20 mg per kg body weight. In certain embodiments, the composition further comprises one or more of the following: dietary modification, time-restricted eating, caloric restriction, endurance training, and weight training.

[0111] In certain embodiments, the subject compounds can be administered to a subject before the subject is diagnosed with diabetes (e.g., prediabetes) or to treat a subject diagnosed with diabetes. In preferred embodiments, the diabetes is prediabetes or type 2 diabetes. In certain embodiments, the compounds of the subject invention can be administered in combination with hypoglycemic drugs, such as, for example, insulin. In certain embodiments, the dosage of insulin can be about 10 to 100 units per day. In certain embodiments, the compounds of the subject invention or compositions thereof can be administered concurrently with a hypoglycemic drug, before an administration of a hypoglycemic drug, or after an administration of a hypoglycemic drug to the subject. In certain embodiments, the administration of a hypoglycemic drug occurs less than or about 15 minutes before or after the administration of the composition. In preferred embodiments, the compounds of the subject invention or compositions thereof can be administered concurrently with a hypoglycemic drug.

[0112] Therapeutic or prophylactic application of the subject compounds and compositions containing the compounds thereof, can be accomplished by any suitable therapeutic or prophylactic method and technique presently or prospectively known to those skilled in the art. The compounds can be administered by any suitable route known in the art including, for example, oral, intramuscular, intraspinal, intracranial, nasal, rectal, parenteral, subcutaneous, or intravascular e.g., intravenous) routes of administration. In preferred embodiments, the compound or composition thereof can be administered orally. Administration of the compounds of the invention can be continuous or at distinct intervals as can be readily determined by a person skilled in the art.

[0113] In some embodiments, an amount of the compounds can be administered 1 time per day or 2 times per day for 1, 2, 3, 4, 5, 6, 7, or more days. Treatment can continue as needed, e.g., for several weeks, for several months, for several years.

[0114] In certain embodiments, the inhibition of muscle mechanical property deterioration was determined by using a passive stretching method to compare the skeletal muscle between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 10% improvement of the predetermined average deterioration indicates an inhibition of muscle mechanical property deterioration. In certain embodiments, the subject compositions and method can inhibit skeletal muscle mechanical property deterioration by inhibiting skeletal muscle stiffening. In certain embodiments, inhibiting skeletal muscle mechanical property deterioration comprises the amelioration of skeletal muscle stiffening. In certain embodiments, inhibiting skeletal muscle mechanical property deterioration comprises the inhibition of skeletal muscle ultimate strength upregulation. In certain embodiments, inhibiting skeletal muscle mechanical property deterioration comprises the amelioration of the upregulated skeletal muscle ultimate strength. In certain embodiments, inhibiting skeletal muscle mechanical property deterioration comprises the inhibition of skeletal muscle viscoelasticity upregulation. In certain embodiments, inhibiting skeletal muscle mechanical property deterioration comprises the amelioration of the upregulated skeletal muscle viscoelasticity. In certain embodiments, inhibiting skeletal muscle mechanical property deterioration comprises the inhibition of skeletal muscle stress-relaxation rate upregulation. In certain embodiments, inhibiting skeletal muscle mechanical property deterioration comprises the amelioration of upregulated skeletal muscle stress-relaxation rate.

[0115] In certain embodiments, inhibiting intramuscular ECM deterioration was determined by using an immune staining to compare the skeletal muscle between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 10% improvement of the predetermined average deterioration indicates an inhibition of intramuscular EM deterioration. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the inhibition of intramuscular collagens accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the amelioration of intramuscular collagens accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the inhibition of intramuscular fibronectins accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the amelioration of intramuscular fibronectins accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the inhibition of intramuscular elastin accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the amelioration of intramuscular elastin accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the inhibition of intramuscular decorin accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the amelioration of intramuscular decorin accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the inhibition of intramuscular hyaluronic acids accumulation. In certain embodiments, inhibiting intramuscular ECM deterioration comprises the amelioration of intramuscular hyaluronic acids accumulation.

[0116] In certain embodiments, inhibiting intramuscular AGE deterioration was determined by using an immune staining to compare the skeletal muscle between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 10% improvement of the predetermined average deterioration indicates an inhibition of intramuscular AGE deterioration.

[0117] In certain embodiments, inhibiting intramuscular AGE deterioration comprises the inhibition of intramuscular dialdehyde AGE precursors accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the amelioration of intramuscular dialdehyde AGE precursors accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the inhibition of intramuscular non-crosslinking-non-fluorescent AGEs accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the amelioration of intramuscular non-crosslinking-non-fluorescent AGEs accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the inhibition of intramuscular non-crosslinking-fluorescent AGEs accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the amelioration of intramuscular non-crosslinking-fluorescent AGEs accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the inhibition of intramuscular crosslinking-non-fluorescent AGEs accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the amelioration of intramuscular crosslinking- non-fluorescent AGEs accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the inhibition of intramuscular crosslinking-fluorescent AGEs accumulation. In certain embodiments, inhibiting intramuscular AGE deterioration comprises the amelioration of intramuscular crosslinking-fluorescent AGEs accumulation.

[0118] In certain embodiments, inhibiting muscle contraction deterioration was determined by providing a sequence of electric stimulation to record the respond of the skeletal muscle to compare the skeletal muscle between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 10% improvement of the predetermined average deterioration indicates an inhibition of muscle contraction deterioration.

[0119] In certain embodiments, inhibiting muscle contraction deterioration comprises the inhibition of downregulation of time to max force. In certain embodiments, inhibiting muscle contraction deterioration comprises the amelioration of downregulated time to max force. In certain embodiments, inhibiting muscle contraction deterioration comprises the inhibition of upregulation of the max contraction rate. In certain embodiments, inhibiting muscle contraction deterioration comprises the amelioration of upregulated max contraction rate.

[0120] In certain embodiments, inhibiting muscle relaxation deterioration was determined by providing a sequence of electric stimulation to record the respond of the skeletal muscle to compare the skeletal muscle between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 10% improvement of the predetermined average deterioration indicates an inhibition of muscle relaxation deterioration.

[0121] In certain embodiments, inhibiting muscle relaxation deterioration comprises the inhibition of upregulation of half relaxation time. In certain embodiments, inhibiting muscle relaxation deterioration comprises the amelioration of upregulated half relaxation time. In certain embodiments, inhibiting muscle relaxation deterioration comprises the inhibition of downregulation of the max relaxation rate. In certain embodiments, inhibiting muscle relaxation deterioration comprises the amelioration of downregulated max relaxation rate.

[0122] In certain embodiments, inhibiting ex vivo muscle performance deterioration was determined by providing a sequence of electric stimulation to record the respond of the skeletal muscle to compare the skeletal muscle between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 10% improvement of the predetermined average deterioration indicates an inhibition of ex vivo muscle performance deterioration

[0123] In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the inhibition of downregulated twitch force. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the amelioration of downregulated twitch force. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the inhibition of downregulated specific twitch force. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the amelioration of downregulated specific twitch force. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the inhibition of downregulated tetanic force. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the amelioration of downregulated tetanic force. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the inhibition of downregulated specific twitch force. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the amelioration of downregulated specific twitch force. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the inhibition of downregulated fatigue resistance. In certain embodiments, inhibiting ex vivo muscle performance deterioration comprises the amelioration of downregulated fatigue resistance.

[0124] In certain embodiments, inhibiting clinical muscle performance deterioration was determined by providing a sequence of electric stimulation to record the respond of the skeletal muscle to compare the skeletal muscle between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 10% improvement of the predetermined average deterioration indicates an inhibition of clinical muscle performance deterioration.

[0125] In certain embodiments, inhibiting clinical muscle performance deterioration comprises the inhibition of reduced performance in a timed-get-up-and-go test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the amelioration of reduced performance in a timed-get-up-and-go test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the inhibition of reduced performance in the chair stand test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the amelioration of reduced performance in the chair stand test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the inhibition of reduced performance in the gait speed test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the amelioration of reduced performance in the gait speed test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the inhibition of reduced performance in the grip strength test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the amelioration of reduced performance in the grip strength test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the inhibition of reduced performance in the isokinetic muscle performance test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the amelioration of reduced performance in the isokinetic muscle performance test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the inhibition of reduced performance in the one-repetition maximum test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the amelioration of reduced performance in the one-repetition maximum test. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the inhibition of reduced performance in the maximum isometric strength tests. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the amelioration of reduced performance in the maximum isometric strength tests. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the inhibition of reduced performance in the muscle power tests. In certain embodiments, inhibiting clinical muscle performance deterioration comprises the amelioration of reduced performance in the muscle power tests.

[0126] In certain embodiments, inhibiting hyperglycemia was determined by blood glucose measurement to compare the value of fast blood glucose, 2 hours post OGTT blood glucose, 2 hours post IPGTT blood glucose, OGTT AUC, IPGTT AUC, or HbAlc between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 10% reduction of the value of fast blood glucose, 2 hours post OGTT blood glucose, 2 hours post IPGTT blood glucose, OGTT AUC, IPGTT AUC, or HbAlc indicates an inhibition of hyperglycemia.

[0127] In certain embodiments, inhibiting hyperglycemia comprises the inhibition of increased fast blood glucose. In certain embodiments, inhibiting hyperglycemia comprises the amelioration of increased fast blood glucose. In certain embodiments, inhibiting hyperglycemia comprises the inhibition of increased 2 hours post OGTT blood glucose. In certain embodiments, inhibiting hyperglycemia comprises the amelioration of increased 2 hours post OGTT blood glucose. In certain embodiments, inhibiting hyperglycemia comprises the inhibition of increased 2 hours post IPGTT blood glucose. In certain embodiments, inhibiting hyperglycemia comprises the amelioration of increased 2 hours post IPGTT blood glucose. In certain embodiments, inhibiting hyperglycemia comprises the inhibition of increased OGTT AUC. In certain embodiments, inhibiting hyperglycemia comprises the amelioration of increased OGTT AUC. In certain embodiments, inhibiting hyperglycemia comprises the inhibition of increased IPGTT AUC. In certain embodiments, inhibiting hyperglycemia comprises the amelioration of increased IPGTT AUC. In certain embodiments, inhibiting hyperglycemia comprises the inhibition of increased HbAlc. In certain embodiments, inhibiting hyperglycemia comprises the amelioration of increased HbAlc.

[0128] In certain embodiments, inhibiting weight gain was determined by body weight measurement to compare body weight between the subjects treated with the invention and the diseased subjects. In certain embodiments, an at least 5% reduction of the BMI indicates an inhibition of weight gain.

[0129] In certain embodiments, inhibiting weight gain comprises the inhibition of increased body weight. In certain embodiments, inhibiting weight gain comprises the amelioration of increased body weight. In certain embodiments, inhibiting weight gain comprises the inhibition of increased food intake. In certain embodiments, inhibiting weight gain comprises the amelioration of increased food intake. In certain embodiments, inhibiting weight gain comprises the inhibition of a reduced feed conversion ratio. In certain embodiments, inhibiting weight gain comprises the amelioration of a reduced feed conversion ratio.

[0130] MATERIALS AND METHODS

[0131] Animals:

[0132] Male C57BL / 6J mice at 12 weeks old were obtained from the Laboratory Animal Services Centre in The Chinese University of Hong Kong. The animals were housed in a room under controlled temperature and humidity, with a 12-hour light cycle with ad libitum access to food and water. And the animals were randomly allocated to receive control diet (14.8% calories from fat, 3002906, LabDiet) or high-fat diet (60% calories from fat, DI 2492, Research Diet) by following the diet plan.

[0133] IPGT test:

[0134] Animals will have 16 hours of food deprivation. Sterilized 20 wt% glucose solution was injected intraperitoneally at 1% of the body weight. The blood glucose level was measured by a commercial blood glucose meter at 0 minutes (before injection, fast glucose level) and 15, 30, 60, and 120 minutes after injection. Blood glucose values were plotted with time and measure the total area under the curve (AUC).

[0135] Forelimb grip strength test:

[0136] The animals were allowed to grasp the grip strength machine's handlebar, and then the animals were gently pulled back horizontally by holding its tail. The maximum tension was recorded when the animal released the bar and used it as the grip strength and the value was normalized by the body weight. ex vivo muscle function test:

[0137] Muscle active contraction ability and the passive mechanical properties were measured by the Isolated Muscle Test System (1200A, Aurora Scientific, Inc.) and analyzed by the Dynamic Muscle Control and Analysis Software (DMC v5.4; DMA v3.2; Aurora Scientific, Inc.) The animals were sacrificed, and the extensor digitorum longus (EDL) muscle was isolated to conduct a 6-step passive stretching protocol to measure the muscle's passive mechanical properties. And the gastrocnemius (GA) muscle was isolated to conduct the active contraction ability. The raw data was normalized by the cross-section area before further analysis. EDL passive mechanical property was measured using a 6-step stretching protocol to elongate the muscle in the increment of 10% of optimal length at a 2 cm / s rate with a 1.5- second stabilization period between stretches until reaching 160% of optimal length. GA active contraction ability was measuring the response to multiple 150 Hz stimuli to calculate the max contraction time, time to max force, max relaxation time, 1 / 2 relaxation time, specific twitch force, specific tetanic force, 5 minutes fatigue recovery rate, and 10 minutes fatigue recovery rate, contraction and relaxation parameters.

[0138] Immunostaining:

[0139] Freshly isolated GA muscles were snap freeze in liquid nitrogen pre-cool-isopentane and then stored at -80 °C for further processing. Frozen muscles were embedded in an embedding medium and sectioned at 7 m and then stored at -80 °C for further staining. Frozen section samples were blocked with 2% horse serum for 1 hour at room temperature and followed with the hydroxyproline, AGE, or Fnl antibody incubation for 1 hour at room temperature. After washing with PBS, samples were incubated with secondary antibodies at room temperature for 1 hour and incubated with DAPI for another 5 minutes. Image processing was done by using ImageJ software.

[0140] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0141] Following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

[0142] EXAMPLE 1— PREVENTION OF THE DIET-RELATED MUSCLE STRUCTURAL DETERIORATION WITH THIAZOLIUM-B ASED AGE BREAKER.

[0143] An aqueous ALT-711 solution was prepared in phosphate-buffered saline at the concentration of 20 mg per Kg body weight.

[0144] As described in FIG. 1, the animal model is fed by an intermittent high-fat diet feeding plan. The ALT-711 solution with the said concentration was provided to the animals daily in stage 1 through oral gavage in order to study the effect of ALT-711 on the diet-related muscle structural deterioration, hyperglycemia-related muscle structural deterioration, weight gain- related muscle structural deterioration.

[0145] Muscle structural change was measured on W5 and W16 timepoints using histology staining and passive mechanical property.

[0146] EXAMPLE 2— AMELIORATION OF THE DIET-RELATED MUSCLE FUNCTIONAL DETERIORATION WITH THIAZOLIUM-B ASED AGE BREAKER.

[0147] An aqueous ALT-711 solution was prepared in phosphate-buffered saline at the concentration of 20 mg per Kg body weight.

[0148] As described in FIG. 1, the animal model is fed by an intermittent high-fat diet feeding plan.

[0149] The ALT-711 solution with the said concentration was provided to the animals daily in stage 2 through oral gavage in order to study the effect of ALT-711 on the diet-related muscle functional deterioration, hyperglycemia-related muscle functional deterioration, and weight gain-related muscle functional deterioration.

[0150] Muscle functional change was measured on W5 and W16 timepoints using muscle contraction and relaxation parameters.

[0151] EXAMPLE 3— IMPROVE OF THE DIET-RELATED MUSCLE PERFORMANCE DETERIORATION WITH THIAZOLIUM-B ASED AGE BREAKER.

[0152] An aqueous ALT-711 solution was prepared in phosphate-buffered saline at the concentration of 20 mg per Kg body weight.

[0153] As described in FIG. 1, the animal model is fed by an intermittent high-fat diet feeding plan.

[0154] The ALT-711 solution with the said concentration was provided to the animals daily in stage 1 or stage 2 through oral gavage in order to study the effect of ALT-711 on diet-related muscle performance deterioration, hyperglycemia-related muscle performance deterioration, and weight gain-related muscle performance deterioration.

[0155] Muscle performance was measured on W5, Wi l, and W16 timepoints using grip strength, force output, and fatigue recovery rate. EXAMPLE 4— REDUCE THE EXTENT OF DIET-RELATED WEIGHT GAIN, AND HYPERGLYCEMIA WITH THIAZOLIUM-BASED AGE BREAKER.

[0156] An aqueous ALT-711 solution was prepared in phosphate-buffered saline at the concentration of 20 mg per Kg body weight.

[0157] As described in FIG. 1, the animal model is fed by an intermittent high-fat diet feeding plan.

[0158] The ALT-711 solution with the said concentration was provided to the animals daily in stage 1 or stage 2 through oral gavage in order to study the effect of ALT-711 on ameliorating diet-related hyperglycemia, diet-related weight gain.

[0159] The extent of hyperglycemia and weight gain were measured on W5, Wi l, and W16 timepoints. The food intake and the feed conversion ratio were measured on the W5 timepoint.

[0160] EXAMPLE 5— AMELIORATION OF THE AGE-RELATED MUSCLE STRUCTURAL DETERIORATION WITH THIAZOLIUM-BASED AGE BREAKER.

[0161] An aqueous ALT-711 solution was prepared in phosphate-buffered saline at the concentration of 20 mg per Kg body weight.

[0162] As described in FIG. 10, the animal model is 24-month-old.

[0163] The ALT-711 solution with the said concentration was provided to the animals daily for one month through oral gavage in order to study the effect of ALT-711 on the age-related muscle structural deterioration.

[0164] Muscle structural change was measured on 25-month-old timepoints using histology staining.

[0165] EXAMPLE 6— AMELIORATION OF THE AGE-RELATED MUSCLE PERFORMANCE DETERIORATION WITH THIAZOLIUM-BASED AGE BREAKER.

[0166] An aqueous ALT-711 solution was prepared in phosphate-buffered saline at the concentration of 20 mg per Kg body weight.

[0167] As described in FIG. 10, the animal model is 24-month-old.

[0168] The ALT-711 solution with the said concentration was provided to the animals daily for one month through oral gavage in order to study the effect of ALT-711 on the age-related muscle performance deterioration.

[0169] Muscle performance was measured on 25-month-old timepoints using grip strength, EXAMPLE 7— AMELIORATION OF AGE-RELATED HYPERGLYCEMIA WITH THIAZOLIUM-BASED AGE BREAKER.

[0170] An aqueous ALT-711 solution was prepared in phosphate-buffered saline at the concentration of 20 mg per Kg body weight.

[0171] As described in FIG. 10, the animal model is 24-month-old.

[0172] The ALT-711 solution with the said concentration was provided to the animals daily for one month through oral gavage in order to study the effect of ALT-711 on ameliorating age- related hyperglycemia.

[0173] The extent of hyperglycemia and weight gain was measured on 25-month-old timepoints. The food intake was measured on 25-month-old timepoints.

[0174] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and / or all other elements or limitations (individually or in any combination) or any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated with the scope of the invention without limitation thereto.

[0175] REFERENCES

[0176] E Magliano, D.J., E.J. Boyko, and I.DE.D.A.t.e.s. committee, IDF Diabetes Atlas, in Idf diabetes atlas. 2021, International Diabetes Federation © International Diabetes Federation, 2021.: Brussels. . DeFronzo, R. A. and D. Tripathy, Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care, 2009. 32 Suppl 2(Suppl 2): p. SI 57-63.

Claims

CLAIMSWe claim:

1. A composition comprising a thiazolium-based advanced glycation end product (AGE) breaker.

2. The composition of claim 1, wherein the thiazolium-based AGE breaker is formula (I):Formula Iwherein Ri is a phenyl group or a phenylmethanol group;R2 is a methyl group or a hydrogen group; andR3 is a methyl group or a hydrogen group.

3. The composition of claim 2, whereinRi is a phenyl group, R2 is a methyl group, and R3 is a methyl group;Ri is a phenyl group, R2 is a hydrogen group, and R3 is a hydrogen group; orRi is a phenylmethanol group, R2 is a methyl group, and R3 is a hydrogen group.

4. The composition of claim 2, wherein the thiazolium-based AGE breaker is ALT-711, according to Formula (II):Formula (II)5. The composition of claim 1, wherein a concentration of the thiazolium -based AGE breaker is about 0.1 mg to 50 mg per Kg body weight.

6. The composition of claim 1, further comprising at least one carrier or excipient.

7. The composition of claim 6, wherein the carrier or excipient is a phosphate- buffered saline.

8. The composition of claim 1, further comprising metformin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, a glucagon-like peptide 1 (GLP-1) receptor agonist, a GLP-1 analog, a gastric inhibitory polypeptide (GIP), a dipeptidyl peptidase 4 (DPP-4) inhibitor, a thiazolidinedione, a sulfonylurea, insulin, or any combination thereof.

9. A method of treating muscle structural or functional deterioration in a subject, the method comprising administering a composition comprising an effective dose of thiazolium-based AGE breaker.

10. The method of claim 9, wherein the thiazolium-based AGE breaker is formula (I):Formula Iwherein Ri is a phenyl group or a phenylmethanol group;R2 is a methyl group or a hydrogen group; andR3 is a methyl group or a hydrogen group.

11. The method of claim 10, whereinRi is a phenyl group, R2 is a methyl group, and R3 is a methyl group;Ri is a phenyl group, R2 is a hydrogen group, and R3 is a hydrogen group; orRi is a phenylmethanol group, R2 is a methyl group, and R3 is a hydrogen group.

12. The method of claim 10, wherein the thiazolium-based AGE breaker is ALT-, according to Formula (II):

13. The method of claim 9, wherein a concentration of the thiazolium -based AGE breaker is about 0.1 mg to 50 mg per Kg body weight.

14. The method of claim 9, wherein the composition further comprises at least one carrier or excipient.

15. Themethod of claim 14, wherein the carrier or excipient is a phosphate-buffered saline.

16. The method of claim 9, wherein the composition further comprises metformin, a SGLT-2 inhibitor, a GLP-1 receptor agonist, a GLP-1 analog, a GIP, a DPP-4 inhibitor, a thiazolidinedione, a sulfonylurea, insulin, or any combination thereof.

17. The method of claim 9, wherein the muscle structural or functional deterioration is related to hyperglycemia or weight gain in the subject.

18. The method of claim 9, wherein the muscle structural or functional deterioration is skeletal muscle structural or functional deterioration.

19. The method of claim 9, wherein the composition is administered at least every 7 days.

20. The method of claim 19, wherein the composition is administered at least once daily.

21. The method of claim 9, wherein the subject is a primate or rodent.

22. The method of claim 9, further comprising reducing caloric intake in the subj ect, time-restricted eating in the subject, endurance training by the subject, weight training by the subject, increasing feed convention ratio in the subject, or any combination thereof.

23. The method of claim 9, further comprising administering metformin, a SGLT-2 inhibitor, a GLP-1 receptor agonist, a GLP-1 analog, a GIP, a DPP -4 inhibitor, a thiazolidinedione, a sulfonylurea, insulin, or any combination thereof.

24. The method of claim 9, wherein treating muscle structural or functional deterioration in a subject comprises inhibiting skeletal muscle stiffening, inhibiting skeletal muscle ultimate strength upregulation, inhibiting skeletal muscle viscoelasticity upregulation, inhibiting skeletal muscle stress-relaxation rate upregulation, inhibiting intramuscular collagens accumulation, inhibiting intramuscular fibronectins accumulation, inhibiting intramuscular elastins accumulation, inhibiting intramuscular decorins accumulation, inhibiting intramuscular hyaluronic acids accumulation, inhibiting intramuscular dialdehyde AGE precursors accumulation, non-crosslinking-non-fluorescent AGEs accumulation, inhibiting intramuscular non-crosslinking-fluorescent AGEs accumulation, inhibiting intramuscular crosslinking-non-fluorescent AGEs accumulation, inhibiting intramuscular crosslinking-fluorescent AGEs accumulation, or any combination thereof.

25. The method of claim 17, wherein treating hyperglycemia-induced or weight gain- induced skeletal muscle performance deterioration comprises inhibiting downregulation of time to max force, inhibiting upregulation of max contraction rate, inhibiting upregulation of half relaxation time, inhibiting downregulation of max relaxation rate, inhibiting downregulation of twitch force, inhibiting downregulation of specific twitch force, inhibiting downregulation of tetanic force, inhibiting downregulation of specific twitch force, inhibiting downregulation of fatigue resistance, inhibiting reduced performance in timed-get-up-and-go test, inhibiting reduced performance in chair stand test, inhibiting reduced performance in gait speed test, inhibiting reduced performance in grip strength test, inhibiting reduced performance in isokinetic muscle performance test, inhibiting reduced performance in one repetition maximum test, inhibiting reduced performance in maximum isometric strength tests, inhibiting reduced performance in muscle power tests, or any combination thereof.