Use of dihydroberberine or its derivatives in regulating GLP-1

Abstract

The present invention provides new compositions and methods for improving or modulating GLP-1 levels or stimulating GLP-1 secretion in a subject. The compositions can comprise dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid or analog or derivative thereof.

Description

Background Technology

[0001] Glucagon-like peptide-1 (GLP-1) is a gut-derived peptide hormone that plays a central role in coordinating postprandial glycemic homeostasis through its effects on insulin secretion, food intake, and intestinal motility. Exogenous GLP-1 acutely stimulates insulin secretion, inhibits glucagon secretion, and lowers plasma glucose concentrations in humans. Furthermore, GLP-1 inhibits gastric emptying and reduces appetite in patients. In rats, GLP-1 reverses age-dependent glucose decline in β-cell function and stimulates β-cell proliferation and regeneration. In one report, after six weeks of GLP-1 treatment, 20 patients with type 2 diabetes in a study experienced an average weight loss of 1.9 kg. Therefore, GLP-1 may be effective in glycemic control, weight management, insulin resistance, glucose tolerance management, and β-cell function.

[0002] The effects of dihydroberberine on GLP-1 have not been reported. In this invention, it was found that dihydroberberine (DHB) can regulate GLP-1 levels. Summary of the Invention

[0003] In a first aspect, the present invention provides a method for improving or modulating GLP-1 levels or stimulating GLP-1 secretion in a subject, comprising administering to the subject a composition comprising: an effective amount of dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid or analog or derivative thereof.

[0004] In some implementations, the method is used to improve metabolism, including weight loss, managing glucose or insulin tolerance, or improving blood lipids. Managing glucose or insulin tolerance includes stimulating insulin secretion, inhibiting glucagon secretion, and lowering fasting blood glucose levels.

[0005] In some implementations, dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analog or derivative thereof is administered in an effective amount.

[0006] In some implementations, the DHB-treated group showed an increase of at least 10% in GLP-1 compared to the untreated control group, preferably an increase of 15%, 20%, 30%, 50%, 70%, 80%, 90%, or 100%.

[0007] In some implementations, improving blood lipids means increasing the HDL / LDL ratio.

[0008] In some implementations, compared with the untreated control group, the DHB-treated group had a weight loss of about 5%, preferably 7% or 9%; the DHB-treated group had a fat content reduction of about 15%, preferably 19%, 30% or 35%; the DHB-supplemented group had an OGTT AUC reduction of about 5%, preferably 10%, 15% or 19%; and the DHB-administered group had an IPTT AUC reduction of about 15%, preferably 21%, 25%, 27% or 30%.

[0009] In some implementations, compared with the untreated control group, the DHB-treated group showed a 10% reduction in TG, preferably a 13%, 20%, or 26% reduction; a 5% reduction in TC, preferably a 9%, 15%, or 20% reduction; a 5% increase in HDL, preferably an 8%, 15%, or 19% increase; a 10% reduction in LDL, preferably a 15%, 18%, 25%, or 30% reduction; and, in particular, a 20% increase in the HDL / LDL ratio, preferably a 30%, 50%, or 70% increase.

[0010] In some implementations, the proportion of dihydroberberine (DHB) is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0011] In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives are administered in amounts of 1-2000 mg. In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives are administered in amounts of 1-1500, 10-1500 mg, 20-1000 mg, 10-800 mg, 20-600 mg, 30-300 mg, 40-200 mg, or 40-100 mg. In some embodiments, the daily dose is administered in divided doses or as a single dose. In some embodiments, administration is performed at least once daily or multiple times daily. In some embodiments, administration is performed for at least 7 days or more within a cycle.

[0012] In some embodiments, dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analogue or derivative thereof is administered in amounts from 0.1 μM to 1 M or from 0.01 to 50.0 wt% (w / w). In some embodiments, dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analogue or derivative thereof may be administered in amounts from 0.1 μM to 500 μM, 1 μM to 500 μM, 1 μM to 5 mM, 1 μM to 500 mM, 5 μM to 500 μM, 5 μM to 5 mM, 5 μM to 100 mM, 5 μM to 500 mM, 50 μM to 500 μM, or 50 μM to 5 mM. In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives may be applied in amounts of 0.05% to 45%, 0.05% to 40%, 0.05% to 30%, 0.05% to 25%, 0.1% to 40%, 0.1% to 30%, 0.1% to 25%, 0.1% to 15%, 0.5% to 30%, 0.5% to 20%, 0.5% to 10%, 1% to 35%, 1% to 25%, 1% to 10%, 2% to 25%, 2% to 10%, 5% to 9%, 1% to 7%, 2% to 7%, 0.05% to 7%, or 0.05% to 9 wt% (w / w).

[0013] In some implementations, the subjects are mammals.

[0014] In some implementations, the subject is a human or an animal. In some implementations, the subject is a human.

[0015] In some embodiments, the composition is prepared as a food, beverage, supplement, biochemical composition, animal food, or nutritional composition.

[0016] In some implementations, administration is carried out via a variety of routes selected from oral, intravenous, intramuscular, intraperitoneal, topical, or sublingual administration.

[0017] In some embodiments, the composition is formulated as a solution, aqueous suspension, liquid suspension, parenteral solution, injection, microemulsion, (micro)capsule, drops, granules, liquid, powder, aerosol, tonic, syrup, tablet, pill, film, functional food, beverage, toothpaste, nutritional product, snack, chewing gum, stick, candy, and sublingual product.

[0018] In a second aspect, the present invention provides a composition comprising an effective amount of dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analog or derivative thereof, for improving or regulating GLP-1 levels or stimulating GLP-1 secretion in a subject.

[0019] In some embodiments, the composition is used to improve metabolism, including weight loss, managing glucose or insulin tolerance, or improving blood lipids, wherein managing glucose or insulin tolerance includes stimulating insulin secretion, inhibiting glucagon secretion, and lowering fasting blood glucose levels.

[0020] In some implementations, the proportion of dihydroberberine (DHB) is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0021] In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives are administered at daily doses of 1-2000 mg. In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives are administered at daily doses of 1-1500 mg, 10-1500 mg, 20-1000 mg, 10-800 mg, 20-600 mg, 30-300 mg, 40-200 mg, or 40-100 mg. In some embodiments, the daily dose is administered in divided doses or as a single dose. In some embodiments, administration is performed at least once daily or multiple times daily. In some embodiments, administration is performed for at least 7 days or more within a cycle.

[0022] In some embodiments, dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analogue or derivative thereof is administered in amounts from 0.1 μM to 1 M or from 0.01 to 50.0 wt% (w / w). In some embodiments, dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analogue or derivative thereof may be administered in amounts from 0.1 μM to 500 μM, 1 μM to 500 μM, 1 μM to 5 mM, 1 μM to 500 mM, 5 μM to 500 μM, 5 μM to 5 mM, 5 μM to 100 mM, 5 μM to 500 mM, 50 μM to 500 μM, or 50 μM to 5 mM. In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives may be applied in amounts of 0.05% to 45%, 0.05% to 40%, 0.05% to 30%, 0.05% to 25%, 0.1% to 40%, 0.1% to 30%, 0.1% to 25%, 0.1% to 15%, 0.5% to 30%, 0.5% to 20%, 0.5% to 10%, 1% to 35%, 1% to 25%, 1% to 10%, 2% to 25%, 2% to 10%, 5% to 9%, 1% to 7%, 2% to 7%, 0.05% to 7%, or 0.05% to 9 wt% (w / w).

[0023] In some implementations, the subjects are mammals.

[0024] In some implementations, the subject is a human or an animal. In some implementations, the subject is a human.

[0025] In some embodiments, the composition is prepared as a food, beverage, supplement, biochemical composition, animal food, or nutritional composition.

[0026] In some embodiments, the composition is formulated as a solution, aqueous suspension, liquid suspension, parenteral solution, injection, microemulsion, (micro)capsule, drops, granules, liquid, powder, aerosol, tonic, syrup, tablet, pill, film, functional food, beverage, toothpaste, nutritional product, snack, chewing gum, stick, candy, and sublingual product.

[0027] In a third aspect, the present invention provides the use of the composition in the preparation of a food, beverage, supplement, biochemical composition or nutritional composition for improving or regulating GLP-1 levels or stimulating GLP-1 secretion in a subject, wherein the composition comprises dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid or analog or derivative thereof.

[0028] In some embodiments, the composition is used to improve metabolism, including weight loss, managing glucose or insulin tolerance, or improving blood lipids, wherein managing glucose or insulin tolerance includes stimulating insulin secretion, inhibiting glucagon secretion, and lowering fasting blood glucose levels.

[0029] In some implementations, the proportion of dihydroberberine (DHB) is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

[0030] In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives are administered at daily doses of 10-2000 mg. In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives are administered at daily doses of 1-1500 mg, 10-1500 mg, 20-1000 mg, 10-800 mg, 20-600 mg, 30-300 mg, 40-200 mg, or 40-100 mg. In some embodiments, the daily dose is administered in divided doses or as a single dose. In some embodiments, administration is performed at least once daily or multiple times daily. In some embodiments, administration is performed for at least 7 days or more within a cycle.

[0031] In some embodiments, dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analogue or derivative thereof is administered in amounts from 0.1 μM to 1 M or from 0.01 to 50.0 wt% (w / w). In some embodiments, dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analogue or derivative thereof may be administered in amounts from 0.1 μM to 500 μM, 1 μM to 500 μM, 1 μM to 5 mM, 1 μM to 500 mM, 5 μM to 500 μM, 5 μM to 5 mM, 5 μM to 100 mM, 5 μM to 500 mM, 50 μM to 500 μM, or 50 μM to 5 mM. In some embodiments, dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives may be applied in amounts of 0.05% to 45%, 0.05% to 40%, 0.05% to 30%, 0.05% to 25%, 0.1% to 40%, 0.1% to 30%, 0.1% to 25%, 0.1% to 15%, 0.5% to 30%, 0.5% to 20%, 0.5% to 10%, 1% to 35%, 1% to 25%, 1% to 10%, 2% to 25%, 2% to 10%, 5% to 9%, 1% to 7%, 2% to 7%, 0.05% to 7%, or 0.05% to 9 wt% (w / w).

[0032] In some implementations, the subjects are mammals.

[0033] In some implementations, the subject is a human or an animal. In some implementations, the subject is a human.

[0034] In some implementations, administration is carried out via a variety of routes selected from oral, intravenous, intramuscular, intraperitoneal, topical, or sublingual administration.

[0035] In some embodiments, the composition is formulated as a solution, aqueous suspension, liquid suspension, parenteral solution, injection, microemulsion, (micro)capsule, drops, granules, liquid, powder, aerosol, tonic, syrup, tablet, pill, film, functional food, beverage, toothpaste, nutritional product, snack, chewing gum, stick, candy, and sublingual product.

[0036] These and other features, aspects, and advantages of the invention will be better understood by referring to the following description and the appended claims. Attached Figure Description

[0037] Figure 1 This is the weight change curve for groups 1-4.

[0038] Figure 2 This represents the change in the proportion of fat content in mice in groups 1-4.

[0039] Figure 3 It is the area under the curve (AUC) of the oral glucose tolerance test (OGTT) in mice of groups 1-4.

[0040] Figure 4 It is the area under the curve (AUC) of the intraperitoneal insulin tolerance test (IPTT) for mice in groups 1-4.

[0041] Figure 5 This refers to the weight of the fat pads in groups 1-4.

[0042] Figure 6 This refers to the insulin levels in the serum of groups 1-4.

[0043] Figure 7 This refers to the TC levels in the serum of groups 1-4.

[0044] Figure 8 This refers to the TG levels in the serum of groups 1-4.

[0045] Figure 9 This refers to the LDL levels in the serum of groups 1-4.

[0046] Figure 10 This refers to the HDL levels in the serum of groups 1-4.

[0047] Figure 11 It refers to the GLP-1 level in the serum of groups 1-4. Detailed Implementation

[0048] As used herein, the term “or” is intended to include both “and” and “or”. In other words, the term “or” can also be replaced with “and / or”.

[0049] As used herein, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” are intended to include the plural forms as well.

[0050] As used herein, the terms “comprising” or “including” or variations thereof refer to items that are included in the context of the term in their non-restrictive sense, but do not exclude items not specifically mentioned. It also includes the more restrictive verbs 'consistently composed of' and 'comprises of'.

[0051] As used herein, the term "effective dose" refers to the amount required to achieve the effects taught herein. The specific effective dose level for any particular subject will depend on a variety of factors, including the condition being treated and its severity; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the timing, route of administration, and rate of excretion of dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives; the duration of treatment; and similar factors well known in the medical field. For example, it is well known to those skilled in the art that the initial dose of a compound is below the level required to achieve the desired effect, and the dose is gradually increased until the desired effect is achieved.

[0052] Those skilled in the art recognize that even if the condition is not completely eradicated or prevented, but its symptoms and / or effects are partially improved or relieved in the subjects, the amount can still be considered "effective".

[0053] As used herein, the term "physiologically acceptable" means pharmaceutically, physiologically, dietaryly, and / or nutritionally acceptable, and refers to combinations of compositions or reagents, materials or compositions and / or dosage forms thereof that are suitable for contact with human and animal tissues, compatible with other components of the composition, without excessive toxicity, irritation, allergic reactions or other problems or complications, and commensurate with a reasonable benefit / risk ratio, within the bounds of reasonable medical judgment.

[0054] As used herein, the terms “mammal” and “subject” are used interchangeably to refer to any animal to which the methods and compositions of this disclosure may be applied or administered. Animals may suffer from illness or other diseases, but they do not need to be sick to benefit from the methods and compositions of this disclosure. Therefore, any animal may utilize the disclosed combinations, compositions, or kits or become a recipient of the disclosed methods. “Mammal” includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, primates such as monkeys, chimpanzees, and apes, and especially humans. Although human subjects are preferred, the methods and compositions of this invention can be applied in veterinary medicine.

[0055] The range of doses of dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives and / or compositions comprising the same can be wide, depending on the desired effect and indication. Depending on the patient's needs, the dose may be a single dose administered over a period of one or more days, or two or more doses. In some embodiments, the compound is administered for a period of time, such as a week or longer, or for months or years.

[0056] As used herein, the term "application" refers to the process of delivering the disclosed composition or active ingredient to a subject. The compositions of the present invention can be administered in a variety of ways, including orally, intragastrically and parenterally (e.g., intravenously and intra-arterially, and other suitable parenterial routes), topically, etc.

[0057] Dyslipidemia, or high blood lipids, are associated with an increased risk of cardiovascular disease. High-density lipoprotein (HDL) is clinically important because there is an inverse correlation between plasma HDL concentration and the risk of atherosclerotic disease. Most of the cholesterol stored in atherosclerotic plaques originates from LDL; therefore, elevated low-density lipoprotein (LDL) concentrations are closely associated with atherosclerosis. The HDL / LDL ratio is a clinical risk indicator for atherosclerosis, particularly coronary atherosclerosis. This invention can improve dyslipidemia by increasing GLP-1 levels, thereby increasing the HDL / LDL ratio.

[0058] As used herein, "parenteral solution" refers to a solution that can be administered to any part of the body other than the mouth and digestive tract. It is not delivered through the intestines. For example, parenteral solutions can be delivered intravenously.

[0059] As used in this article, "tonics" refers to medicinal substances that give people a feeling of vitality or health.

[0060] As used in this article, "syrup" refers to a viscous liquid derived from sugar-rich plants such as sugarcane, corn, and maple.

[0061] There are various techniques for administering the composition in the art, including but not limited to oral, rectal, topical, aerosol, injection, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intracardiac, intraperitoneal, intranasal, and intraocular injection.

[0062] The term "intraperitoneal" as used here refers to administration within or through the peritoneum. The peritoneum is a thin, transparent membrane that lines the walls of the abdominal cavity (peritoneum) and contains / encloses abdominal organs such as the stomach and intestines.

[0063] As used in this article, "sublingual" refers to something located or applied under the tongue.

[0064] "Functionalized food compositions" include food compositions that have potential positive effects on health beyond just basic nutrition.

[0065] Various embodiments of the present invention provide methods for administering dihydroberberine (DHB) or its physiologically acceptable salts, polymers, esters, acids, or analogs or derivatives to a subject to effectively improve or regulate GLP-1 levels or stimulate GLP-1 secretion in the subject. For example, this method is used for weight loss (dietary reduction), managing glucose tolerance, or lowering fasting blood glucose levels. For example, about 10 mg to about 1000 mg of dihydroberberine can be administered to a person. DHB can be administered in various forms, such as solutions, aqueous suspensions, liquid suspensions, parenteral solutions, injections, microemulsions, (micro)capsules, drops, granules, liquids, powders, aerosols, tonics, syrups, tablets, pills, films, functional foods, beverages, toothpaste, nutritional supplements, snacks, chewing gum, bars, candies, and sublingual products.

[0066] In some embodiments, the composition may contain one or more additives, such as flavoring agents (e.g., natural and / or artificial), vitamins, minerals, binders, and / or any other suitable additives. Additives may alter taste, color, and / or texture. Additives may increase palatability and / or promote inclusion in a delivery carrier (e.g., tablets, food, beverage products such as mixed drinks, etc.). In some embodiments, dihydroberberine may be processed to increase bioavailability, solubility, palatability, and / or combination with other compounds.

[0067] Any headings or subheadings used in this document are for organizational purposes and should not be used to limit the scope of the embodiments disclosed herein.

[0068] The following embodiments are provided to provide a complete disclosure and description of how to make and use the invention to those skilled in the art, and are not intended to limit the scope of what the inventors consider to be their invention, nor are they intended to represent all or only the experiments conducted. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be taken into account.

[0069] All publications and patent applications cited in this specification are incorporated herein by reference, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Example

[0070] At the start of the experiment, mice were randomly divided into four groups: a control group (Group 1, n=8), an HFD group (Group 2, n=8), an HFD+DHB group (Group 3, n=8), and an NC+DHB group (Group 4, n=8). The DHB supplementation dose was 1.5 mg / kg. Group 1 served as the control group and was fed a normal diet; Group 2 was a high-fat diet for 8 weeks; Group 3 also continued on a high-fat diet and received daily intragastric administration of samples for 8 weeks; Group 4 was fed a normal diet and received daily intragastric administration of samples for 8 weeks. Body fat and weight were recorded weekly for each group. On the last day of week 8, an oral glucose tolerance test (OGTT) / insulin intraperitoneal tolerance test (IPTT) was performed, after which the mice were sacrificed, and serum was collected and stored at -80°C.

[0071] Blood glucose measurement: Oral glucose tolerance test (OGTT): In week 16 of the experiment, after a 15-hour fast, glucose (2 g / kg) was administered intravenously, and blood glucose was measured at 0, 15, 30, 60, 90, and 120 minutes. Intraperitoneal insulin tolerance test (IPTT): In week 16 of the experiment, after a 15-hour fast, insulin (1 U / kg) was injected intraperitoneally, and blood glucose was measured at 0, 15, 30, 60, 90, and 120 minutes.

[0072] Body composition analysis: During the experiment, fat mass and lean body mass were measured weekly using an MRI body composition analyzer.

[0073] Serum assays by ELISA: Whole blood was collected by removing the eyeball at week 8 of the experiment. Serum was obtained after centrifugation (10,000 rpm for 15 minutes) and stored at -80°C for later use. The concentrations of insulin (INS), cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and GLP-1 in the serum were measured using an ELISA kit.

[0074] Weight of fat pads: At week 17, mice were sacrificed, and the fat pads (subcutaneous, epididymal, and perirenal) were dissected, photographed, and weighed.

[0075] Weight changes: From the start of the experiment, weigh yourself once a week at a fixed time.

[0076] Figure 1 This is the weight change curve for groups 1-4. Figure 1In the study, after 8 weeks of DHB administration, the HFD+DHB group (33.36 g) showed a 9.84% weight loss compared to the HFD group (37 g), and the NC+DHB group (31.33 g) showed a 7.75% weight loss at week 8 compared to the NC group (33.96 g). Therefore, the weight loss curves indicate that DHB helps suppress high-fat induced obesity. Compared to the untreated control group, the DHB-treated groups experienced approximately a 5% weight loss, with optimal reductions of 7% and 9%. Figure 2 This represents the change in the proportion of body fat in mice from groups 1 to 4. High body fat percentage strongly suggests possible obesity or endocrine system abnormalities. Figure 2 As shown, mice in groups 3 and 4 were more effective in suppressing obesity. The fat content of the HFD+DHB group (group 3) was reduced by about 19% compared with the HFD group (group 2), while the fat content of the NC+DHB group (group 4) was reduced by about 35% compared with the control mice (group 1). Figure 3 It is the area under the curve (AUC) of the oral glucose tolerance test (OGTT) in mice of groups 1-4. Figure 4 It is the area under the curve (AUC) of the intraperitoneal insulin tolerance test (IPTT) for mice in groups 1-4.

[0077] exist Figure 3 In the HFD+DHB group (group 3), the AUC of OGTT was reduced by approximately 19% compared to the HFD group (group 2), and in the NC+DHB group (group 4), the AUC of OGTT was reduced by approximately 10% compared to the control group (group 1). Figure 4 It can be seen that the AUC of IPTT in the HFD+DHB group (Group 3) was reduced by approximately 27% compared with the HFD group (Group 2), and the AUC of IPTT in the NC+DHB group (Group 4) was reduced by approximately 21% compared with the control mice (Group 1). Compared with mice that did not receive DHB supplementation, DHB supplementation can improve blood glucose and insulin tolerance.

[0078] from Figure 1-4 The results showed that DHB supplementation had beneficial effects on metabolic health compared to no DHB supplementation. Specifically, compared to the untreated control group (HFD group), the DHB-treated group experienced a weight loss of approximately 5%, preferably 7% or 9%; a reduction in body fat percentage of approximately 15%, preferably 19%, 30%, or 35%; a decrease in the AUC of the OGTT in the DHB-supplemented group of approximately 5%, preferably 10%, 15%, or 19%; and a decrease in the AUC of the IPTT in the DHB-administered group of approximately 15%, preferably 21%, 25%, 27%, or 30%.

[0079] Figure 5 This refers to the weight of the fat pads in groups 1-4. Figure 5In mice, DHB supplementation significantly increased the weight of the perirenal fat pad compared to mice that did not receive DHB supplementation. Figure 6-11 These are serum lipid metabolism indicators across all groups, including insulin (INS), total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and GLP-1 levels. Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue. HDL has long been considered "good cholesterol," beneficial overall, especially for cardiovascular health. TG is a very important component of blood lipids, and elevated levels can lead to heart disease. "Bad cholesterol," LDL, has a significant impact on atherosclerosis. Therefore, LDL is also known as an atherogenic factor. When LDL, especially oxidized low-density lipoprotein (OX-LDL), is excessive, the cholesterol it carries accumulates on the arterial walls, easily leading to atherosclerosis over time. The importance of GLP-1 has been discussed above.

[0080] From the perspective of serum indicators ( Figure 6-11The TG results showed that serum TG in the HFD+DHB group was reduced by 26.1% compared to the HFD group, and serum TG in the NC+DHB group was reduced by 13.2% compared to the NC group. Regarding TC, serum TC in the HFD+DHB group was reduced by 20.6% compared to the HFD group, and serum TC in the NC+DHB group was reduced by 9.8% compared to the NC group. The HDL results showed that serum HDL in the HFD+DHB group was increased by 19% compared to the HFD group, and serum HDL in the NC+DHB group was increased by 8.8% compared to the NC group. Regarding LDL, the HFD+DHB group showed a reduction of 32.3% compared to the HFD group, and the NC+DHB group showed a reduction of 18.3% compared to the NC group. Furthermore, regarding the HDL / LDL ratio, the HFD+DHB group showed a 76% increase compared to the HFD group, and the NC+DHB group showed a 33% increase compared to the NC group. Therefore, DHB has a beneficial effect on INS, GLP-1, LDL, and HDL. Compared to the untreated control group, the DHB-treated group showed a 10% reduction in TG, with preferred reductions of 13%, 20%, and 26%; a 5% reduction in TC, with preferred reductions of 9%, 15%, and 20%; a 5% increase in HDL, with preferred increases of 8%, 15%, and 19%; and a 10% reduction in LDL, with preferred reductions of 15%, 18%, 25%, and 30%. In particular, the HDL / LDL ratio increased by 20%, with preferred increases of 30%, 50%, and 70%; and GLP-1 increased by 10%, with preferred increases of 15%, 20%, 30%, 50%, 70%, 80%, 90%, and 100%. Compared to mice that did not receive DHB supplementation, DHB supplementation significantly increased HDL and GLP-1, and decreased INS, TC, TG, and LDL, indicating that DHB has a role in improving obesity and metabolism. This effect will persist as long as the experimental protocol continues.

[0081] While specific embodiments and examples of the invention have been described herein, those skilled in the art will understand that any modifications and variations can be made without departing from the principles of the invention. The above embodiments and descriptions do not limit the scope of the invention. Any combination of embodiments of the invention, as well as any obvious extensions or analogies thereof, are within the scope of the invention. Furthermore, the invention covers any arrangement intended to achieve the same purpose, and all such variations and modifications falling within the scope of the appended claims.

Claims

1. A method for improving or regulating GLP-1 levels or stimulating GLP-1 secretion in subjects, characterized in that, The method includes administering a composition to the subject, the composition comprising: an effective amount of dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analog or derivative thereof.

2. The method according to claim 1, characterized in that, The method is used to improve metabolism, including weight loss, managing glucose or insulin tolerance, or improving blood lipids, wherein managing glucose or insulin tolerance includes stimulating insulin secretion, inhibiting glucagon secretion, and lowering fasting blood glucose levels.

3. The method according to claim 1 or 2, characterized in that, Compared with the untreated control group, the DHB-treated group showed an increase of at least 10% in GLP-1.

4. The method according to claim 1 or 2, characterized in that, The improvement in blood lipids is achieved by increasing the HDL / LDL ratio.

5. The method according to any one of claims 1 to 4, characterized in that, The proportion of dihydroberberine (DHB) is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

6. The method according to any one of claims 1 to 5, characterized in that, The dihydroberberine (DHB) or its physiologically acceptable salt, polymer, ester, acid, or analogue or derivative is administered in an amount of 1-2000 mg.

7. The method according to any one of claims 1 to 6, characterized in that, The dihydroberberine (DHB) or its physiologically acceptable salt, polymer, ester, acid, or analogue or derivative is administered in amounts from 0.1 μM to 1 M or from 0.01 to 50.0 wt% (w / w).

8. The method according to any one of claims 1 to 7, characterized in that, The subjects were mammals.

9. The method according to any one of claims 1 to 8, characterized in that, The subjects are either humans or animals.

10. The method according to any one of claims 1 to 9, characterized in that, The composition is prepared as a food, beverage, supplement, biochemical composition, animal food, or nutritional composition.

11. The method according to any one of claims 1 to 10, characterized in that, The administration is carried out via a variety of routes selected from oral, intravenous, intramuscular, intraperitoneal, topical, or sublingual administration.

12. The method according to any one of claims 1 to 11, characterized in that, The composition is formulated as a solution, aqueous suspension, liquid suspension, parenteral solution, injection, microemulsion, (micro)capsule, drops, granules, liquid, powder, aerosol, tonic, syrup, tablet, pill, film, functional food, beverage, toothpaste, nutritional product, snack, chewing gum, stick, candy and sublingual product.

13. A composition comprising an effective amount of dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analogue or derivative thereof, characterized in that, The composition is used to improve or regulate GLP-1 levels or stimulate GLP-1 secretion in subjects.

14. The composition according to claim 13, characterized in that, The composition is used to improve metabolism, including weight loss, managing glucose or insulin tolerance, or improving blood lipids, wherein managing glucose or insulin tolerance includes stimulating insulin secretion, inhibiting glucagon secretion, and lowering fasting blood glucose levels.

15. The composition according to claim 13 or 14, characterized in that, The proportion of dihydroberberine (DHB) is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

16. The composition according to any one of claims 13 to 15, characterized in that, The dihydroberberine (DHB) or its physiologically acceptable salt, polymer, ester, acid, or analogue or derivative is administered at a daily dose of 1-2000 mg.

17. The use of the composition in the preparation of a food, beverage, supplement, biochemical composition, or nutritional composition for improving or regulating GLP-1 levels or stimulating GLP-1 secretion in a subject, characterized in that, The composition comprises dihydroberberine (DHB) or a physiologically acceptable salt, polymer, ester, acid, or analog or derivative thereof.

18. The use according to claim 17, characterized in that, The composition is used to improve metabolism, including weight loss, managing glucose or insulin tolerance, or improving blood lipids, wherein managing glucose or insulin tolerance includes stimulating insulin secretion, inhibiting glucagon secretion, and lowering fasting blood glucose levels.

19. The use according to claim 17 or 18, characterized in that, The subjects were mammals.

20. The use according to any one of claims 17 to 19, characterized in that, The proportion of dihydroberberine (DHB) is at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%.

21. The use according to any one of claims 17 to 20, characterized in that, The dihydroberberine (DHB) or its physiologically acceptable salt, polymer, ester, acid or analog or derivative thereof is administered at a daily dose of 1-2000 mg or at an amount of 0.1 μM to 1 M or 0.01 to 50.0 wt% (w / w).

22. The use according to any one of claims 17 to 21, characterized in that, The composition is formulated as a solution, aqueous suspension, liquid suspension, parenteral solution, injection, microemulsion, (micro)capsule, drops, granules, liquid, powder, aerosol, tonic, syrup, tablet, pill, film, functional food, beverage, toothpaste, nutritional product, snack, chewing gum, stick, candy and sublingual product.

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