Medicament for preventing or treating metabolic diseases and use thereof

Abstract

The present application relates to a medicine for preventing or treating metabolic diseases and application, and relates to the technical field of biological medicine, and application of N-acetyl valine in preparation of products for treating or preventing metabolic diseases, the present application proposes a new type of metabolic regulation medicine, functional food or nutritional supplement based on N-acetyl valine, which is applied to the prevention and treatment of obesity and metabolic diseases.N-acetyl valine can effectively prevent and treat obesity and related diseases by regulating energy intake and energy consumption, maintaining energy balance.N-acetyl valine, as a metabolite induced by exercise, has a double regulation mechanism: on the one hand, it regulates energy intake, and on the other hand, it promotes energy consumption, thereby achieving sustained metabolic regulation in a physiological environment; N-acetyl valine has a long in-vivo action time, small side effects and significant fat-reducing effect.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to drugs and their applications for the prevention or treatment of metabolic diseases. Background Technology

[0002] Obesity and metabolic diseases such as type 2 diabetes have become increasingly serious global public health problems, rooted in a long-term imbalance between energy intake and expenditure. Traditional treatments include medication, surgical intervention, and lifestyle modifications such as adjusting diet and exercise. While these methods can alleviate symptoms to some extent, they generally suffer from short-lasting effects, significant side effects, and poor patient adherence.

[0003] In recent years, scientific research has revealed the profound role of exercise in regulating metabolic health. Exercise not only improves muscle and cardiovascular function but also maintains energy balance by promoting the production of various metabolites. These metabolites, collectively known as "exercise factors" or "exerkines," play a crucial role in regulating appetite, promoting energy expenditure, and improving overall metabolic health. Therefore, this invention provides medicines and applications for the prevention or treatment of metabolic diseases. Summary of the Invention

[0004] The technical problem to be solved by this invention is to provide a drug and its application for the prevention or treatment of metabolic diseases. The objective is to provide a newly discovered exercise factor, N-acetylvaline.

[0005] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0006] Firstly, the application of N-acetylvaline in the preparation of products for the treatment or prevention of metabolic diseases.

[0007] The structure of N-acetylvaline is as follows: .

[0008] Furthermore, the metabolic diseases include obesity, diabetes, or metabolic syndrome.

[0009] Furthermore, the product includes pharmaceuticals.

[0010] In a second aspect, a medicine for treating or preventing metabolic diseases, said medicine comprising the aforementioned N-acetylvaline.

[0011] Furthermore, the drug also includes pharmaceutical excipients and / or carriers.

[0012] Furthermore, the dosage form of the drug includes at least one of injection, oral tablets, oral capsules, and oral liquid preparations.

[0013] Furthermore, when the drug is in the form of an injection, the drug further includes dimethyl sulfoxide (DMSO), Kolliphore (polysorbate), and physiological saline. DMSO serves as the main solvent, increasing the solubility of N-acetylvaline; polysorbate serves as an excipient; and physiological saline provides physiological compatibility, enabling the complex to be effectively absorbed after in vivo injection.

[0014] Furthermore, the volume ratio of the dimethyl sulfoxide, the polysorbate, and the physiological saline is 1:1:8, forming a solvent system.

[0015] The preparation method of the injection is as follows: commercially available N-acetylvaline is dissolved in the above solvent system in a certain proportion; the dissolution process is carried out at room temperature and requires gentle stirring until it is completely dissolved to obtain a stable solution.

[0016] This invention discovers a novel N-acetylvaline (NAV) exercise factor. Experimental results show that the concentration of N-acetylvaline in the blood increases significantly after exercise, and it can maintain energy balance through a dual mechanism of simultaneously regulating energy intake and expenditure. Although the specific mechanism of action of N-acetylvaline has not been fully elucidated, it has shown great potential as an exercise-induced metabolic regulator in the prevention and treatment of metabolic diseases.

[0017] This invention proposes a novel metabolic regulatory drug, functional food, or nutritional supplement based on N-acetylvaline for the prevention and treatment of obesity and metabolic diseases. N-acetylvaline maintains energy balance by regulating energy intake and expenditure, thereby effectively preventing and treating obesity and related diseases (such as type 2 diabetes). As an exercise-induced metabolite, N-acetylvaline has a dual regulatory mechanism: regulating energy intake on the one hand and promoting energy expenditure on the other, thus achieving sustained metabolic regulation in the physiological environment. N-acetylvaline has a long duration of action in the body, few side effects, and significant fat-reducing effects.

[0018] The beneficial effects of this invention are:

[0019] (1) Long-lasting and comprehensive energy balance regulation: N-acetylvaline provides a dual-regulation metabolic management approach by simultaneously regulating energy intake and energy expenditure. Unlike traditional drugs that target only a single mechanism (such as suppressing appetite or increasing energy expenditure), this invention achieves a lasting and significant weight loss effect through this "dual-effect" mechanism, avoiding the problem of short-lived effects of traditional treatments.

[0020] (2) Few side effects and good tolerability: The experimental results of this invention show that N-acetylvaline has fewer side effects and good tolerability, especially at high doses it still shows good safety. Compared with existing obesity treatment drugs (such as hormone drugs and appetite suppressants) which are prone to causing serious side effects (such as cardiovascular disease, mental abnormalities, etc.), N-acetylvaline has higher physiological compatibility and safety because it is naturally present in the body and is induced by exercise.

[0021] (3) High in vivo absorption rate: The present invention significantly improves the in vivo solubility and bioavailability of N-acetylvaline by using a 1:1:8 DMSO:Kolliphore:physiological saline solvent system; the solvent combination effectively optimizes the stability of N-acetylvaline in vivo, so that it maintains a high concentration level in the blood for a longer period of time, thereby prolonging the duration of its metabolic regulation effect.

[0022] (4) Applicable to different types of metabolic diseases: This invention is not only applicable to the treatment of obesity, but also to the prevention and treatment of related diseases such as type 2 diabetes and metabolic syndrome; experimental data show that N-acetylvaline can effectively improve glucose tolerance and reduce weight, and has broad clinical application potential. Attached Figure Description

[0023] Figure 1 This invention presents the structure of N-acetylvaline (NAV) and its characteristic response to exercise intensity; wherein, A is the intersection of the top 20 most significant metabolites in serum untargeted metabolomics of three different forms of exercise compared to HIIT; B is a schematic diagram of the N-acetylvaline structure.

[0024] Figure 2 This is a dynamic change graph of the relative concentration of serum N-acetylvaline in human exercise according to the present invention; where AC represents the time-series non-targeted metabolomics characteristics of N-acetylvaline in response to different forms and intensities of exercise; all data are expressed as Mean ± Sd, and the variance between groups was calculated using two-way repeated measures ANOVA. P The correlation between NAV and lactate was calculated using Pearson correlation analysis.

[0025] Figure 3 This is a correlation diagram of N-acetylvaline and lactic acid in this invention;

[0026] Figure 4This diagram illustrates the absolute concentration changes of N-acetylvaline in serum of animals and humans after exercise according to this invention. Figure A shows the absolute quantitative analysis of serum N-acetylvaline after a single exhaustive exercise session in mice; Figure B shows the absolute quantitative analysis of serum N-acetylvaline after different forms of HIIT exercise. All data are expressed as Mean ± Sd. Two-way ANOVA was used for Figure A, and paired-samples t-tests were used for Figure B to calculate intergroup differences. P value;

[0027] Figure 5 This is a correlation analysis diagram of N-acetylvaline of the present invention with obesity, type 2 diabetes, high BMI risk and physical activity level; where A represents obesity; B represents type 2 diabetes; C represents high BMI risk; and D represents physical activity level.

[0028] Figure 6 This diagram illustrates the acute effects of different concentrations of N-acetylvaline on food intake, water consumption, and body weight in lean mice. Figure A shows the effect of acute injection of different concentrations of N-acetylvaline on food intake and water consumption in lean mice; Figure B shows the acute changes in body weight in mice after injection of different concentrations of N-acetylvaline. All data are expressed as Mean ± Sd; p-values ​​were calculated using an independent samples t-test.

[0029] Figure 7 This is a graph showing the acute effects of N-acetylvaline of the present invention on food intake, water intake, and body weight in diet-induced obese mice; where A represents the effect of different concentrations of N-acetylvaline on food intake and water intake in obese mice; B represents the acute body weight changes in DIO mice after injection of different concentrations of N-acetylvaline; all data are expressed as Mean ± Sd; p-values ​​were calculated using an independent samples t-test;

[0030] Figure 8 This is a pharmacokinetic diagram of N-acetylvaline in lean and obese mice according to the present invention;

[0031] Figure 9 This is a graph showing the acute effects of N-acetylvaline on energy metabolism parameters in lean mice. A, F represent the effects of a 100 mg / kg dose of N-acetylvaline injection on food intake, energy expenditure, activity level, and energy metabolism parameters (oxygen uptake, carbon dioxide production, and respiratory quotient) in lean mice, respectively. The gray area in the graph represents the night cycle. All data are expressed as Mean ± Sd. Two-way repeated measures ANOVA was used to calculate the differences between groups. P value;

[0032] Figure 10This is a graph showing the acute effects of N-acetylvaline (NAV) on energy metabolism parameters in obese mice. A, F, and F represent the effects of a 100 mg / kg NAV injection on food intake, energy expenditure, activity level, and energy metabolism parameters (oxygen uptake, carbon dioxide production, and respiratory quotient) in obese mice, respectively. The gray area in the graph represents the nighttime cycle. All data are expressed as Mean ± Sd. Two-way repeated measures ANOVA was used to calculate the intergroup variance. P value;

[0033] Figure 11 This is a graph showing the effect of a single N-acetylvaline injection of the present invention on the changes in food intake and body weight in obese mice over one week; all data are expressed as Mean ± Sd. Independent samples t-tests were used for Figures A and D, and two-way repeated measures ANOVA was used for Figures B and C. P value;

[0034] Figure 12 This is a graph showing the long-term effects of N-acetylvaline on body weight and food intake in obese mice. A represents the effect of continuous N-acetylvaline injection (10 days) on body weight in DIO mice; BC represents the effects of continuous N-acetylvaline intervention (10 days) on changes in food intake and body weight in obese mice. All data are expressed as Mean ± Sd and calculated using two-way repeated measures ANOVA. P value;

[0035] Figure 13 This diagram illustrates the effects of N-acetylvaline on fat weight, body composition, and tissue weight in obese mice. A represents the effect of continuous N-acetylvaline intervention on brown and white adipose tissue in mice; B represents the effect of continuous N-acetylvaline intervention on body composition; C represents the effect of N-acetylvaline intervention on fat and tissue weight in obese mice; and D represents the effect of N-acetylvaline intervention on body fat percentage in obese mice. All data are expressed as Mean ± Sd and calculated using an independent samples t-test. P value;

[0036] Figure 14 This diagram illustrates the long-term effects of N-acetylvaline on glucose tolerance, fasting blood glucose, and energy metabolism parameters in obese mice. AE represents the effects of continuous N-acetylvaline intervention on fasting blood glucose and energy metabolism parameters (oxygen uptake, carbon dioxide production, respiratory quotient, and activity level) in obese mice. All data are expressed as Mean ± Sd and calculated using an independent samples t-test. P value. Detailed Implementation

[0037] The principles and features of this invention are described below. The examples given are for illustrative purposes only and are not intended to limit the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they should be performed according to the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0038] Example 1

[0039] 1. The response of N-acetylvaline to acute exercise and its physiological relevance.

[0040] 1.1 Experimental reagents and materials.

[0041] (1) Experimental reagents: Acetonitrile (Honeywell, AH015-4), methanol (Honeywell, AH230-4), N-acetylvaline standard (MedChemExpress, HY-W015466), N15-acetylvaline standard (CIL, 355808-21-8), Kolliphor EL (Sigma, C5135-500G), dimethyl sulfoxide (Sigma, D8418-50ML), formic acid (Honeywell, 64-18-6), pure water, physiological saline;

[0042] (2) Experimental instruments: Agilent 1290 Infinity II ultra-high performance liquid chromatography system, Waters ACQUITY HSS-T3 column (3.0 × 100 mm, 1.8 μm), Waters ACQUITY BEH Amide column (2.1 × 100 mm, 1.7 μm), 5600 Triple TOF Plus (AB Sciex, equipped with an electron spray ionization source), Shimadzu LC-MS8050 system (for targeted metabolomics analysis), Shim-pack GIST C18-AQ HP column (3 μm, 2.1 × 100 mm), and low-temperature high-speed centrifuge.

[0043] 1.2 Experimental methods.

[0044] 1.2.1 Human subjects and grouping.

[0045] Human Subjects: This study was approved by the Ethics Committee for Sports Science Research of Beijing Sport University (2022188H). The subjects in this study cohort were healthy adults (n=100). All participants were randomly assigned to three main exercise groups: swimming, running, and cycling, each further subdivided into moderate-intensity training (MICT) and high-intensity interval training (HIIT). Each main exercise group consisted of swimming (n=40, with MICT n=20 and HIIT n=20), running (n=40, MICT n=20 and HIIT n=20), and cycling (n=20, MICT n=10 and HIIT n=10). Inclusion criteria included: healthy adults aged 18 to 35 years, without a fixed exercise routine, and voluntary participation, understanding of the study content, and signing of informed consent. Exclusion criteria included: individuals with cardiovascular disease, metabolic disease, or other chronic health problems; individuals who had participated in other clinical studies within the past six months; and individuals with a history of drug allergies or known allergies to any substances used in the study. All participants signed informed consent forms before participating in the experiment, confirming their understanding and agreement to the purpose, procedures, and potential risks of the experiment.

[0046] 1.2.2 Experimental animals and grouping.

[0047] Experimental Animals and Grouping: This experimental protocol has been approved by the Sports Science Ethics Committee of Beijing Sport University. Eight- to twelve-week-old C57BL6J mice (n=24) were used in the experiment, sourced from Vital River Pharmaceuticals. The experiment was divided into two groups: a pre-exercise group (n=6) and an exhaustive exercise group (n=18). The exhaustive exercise group was further subdivided into three time points: 0 minutes (n=6), 15 minutes (n=6), and 30 minutes (n=6) after exercise. Blood samples were collected from the mice at these specific time points using ocular hemorrhage for subsequent biochemical analysis.

[0048] 1.2.3 Collection of human and animal blood samples.

[0049] Human and Animal Blood Sample Collection: In this experiment, specific time points were used to collect blood samples from human subjects and animals. These time points included 0 minutes before exercise and 15 minutes after exercise for human subjects; for animals, samples were collected at 0 minutes, 15 minutes, and 30 minutes after exercise. The collection procedure first ensured that all tools and containers were sterile. Blood was drawn from a vein in the forearm for human subjects and from a vein behind the eye for animals. The blood samples were immediately placed in test tubes containing anticoagulant and gently shaken to mix. The samples were then centrifuged at 3000 rpm for 10 minutes at room temperature to separate the plasma to the top of the test tube. The plasma was then extracted using a pipette and transferred to a new sterile test tube for cryopreservation or biochemical analysis as needed.

[0050] 1.2.4 Serum non-targeted metabolomics test.

[0051] Serum Untargeted Metabolomics Assay: Untargeted metabolomics studies were conducted at LipidALL Technologies in Changzhou, China. Metabolites were extracted from 50 μL of serum by adding 200 μL of ice-cold methanol containing 0.28 mM phenylhydrazine. Chromatographic separation was performed using an ultra-high performance liquid chromatography (UHPLC) system (Agilent 1290 Infinity II; Agilent Technologies). For reversed-phase chromatography, polar metabolites were separated on a Waters ACQUITY HSS-T3 column (3.0 × 100 mm, 1.8 μm), while hydrophilic interaction liquid chromatography was performed using a Waters ACQUITY BEH Amide column (2.1 × 100 mm, 1.7 μm). Mass spectrometry analysis was performed using a high-resolution mass spectrometer equipped with an electron spray ionization source (5600 Triple TOF Plus, AB Sciex). MS / MS analysis of metabolites was performed in information-dependent acquisition mode with a collision energy set to (-) 35 ± 15 eV. Data processing was performed using MarkerView (version 1.3, AB Sciex) and PeakView (version 2.2, AB Sciex) software. Metabolite identification was accomplished by comparison with standard references in the HMDB (https: / / hmdb.ca) and METLIN (https: / / metlin.scripps.edu) databases.

[0052] 1.2.5 Absolute quantification of N-acetylvaline.

[0053] Absolute quantification of N-acetylvaline: Targeted metabolomics analysis was performed using a Shimadzu LC-MS8050 system in negative ion mode via electrospray ionization (ESI). Operating parameters were set as follows: ESI source gas temperature 250°C, flow rate 12 L / min, nebulizer pressure 25 psi, sheath gas temperature 300°C, sheath gas flow rate also 12 L / min, and capillary voltage 3500 V. Chromatographic separation was performed using a Shimadzu Shim-pack GIST C18-AQ HP column (3 μm, 2.1 × 100 mm). Mobile phase A consisted of 95% water, 5% acetonitrile, and 0.1% formic acid; mobile phase B consisted of 100% acetonitrile. The initial flow rate was set to 0.2 mL / min, and the mobile phase ratio was gradually adjusted from 60%A:40%B to 90%B:10%A. Under these conditions, the elution time of N-acetylvaline was 0.95 min. Quantitative analysis employed the internal standard method, using N15-labeled N-acetylvaline as the internal standard. Endogenous metabolite concentrations were calculated by preparing a standard curve containing the target metabolite and the internal standard. All sample analyses utilized a standardized triple quadrupole mass spectrometry method, including identical instrument settings and operating procedures, ensuring the consistency and accuracy of the experimental results. Furthermore, the plasma dilution effect during sample preparation was considered during quantification, thereby improving data precision.

[0054] 1.2.6 Mendelian randomization analysis.

[0055] Mendelian randomization analysis: To explore the causal relationship between N-acetylvaline (NAV) and the risk of metabolic diseases, this invention employed Mendelian randomization analysis. This analysis utilizes genetic variation as an instrumental variable to assess the causal relationship between exposure factors (in this case, NAV levels) and outcomes such as BMI, obesity, and the risk of type 2 diabetes. The data used in this invention were derived from the METSIM study, a single-point cohort study encompassing 10,197 men aged 45 to 74 years in Kuopio, Finland, focusing on exploring risk factors for type 2 diabetes and cardiovascular disease. Through untargeted metabolomics analysis of EDTA plasma samples from 6,136 non-diabetic men in the METSIM database, this invention identified associations between multiple metabolites and genetic variations. Following single-variable genome-wide association analysis (GWAS) of 1,391 metabolites, a total of 2,030 independent genetic loci associated with metabolite levels were identified.

[0056] 1.3 Experimental results.

[0057] like Figure 1As shown, after various forms of human exercise such as swimming, running, and cycling, non-targeted serum metabolomics analysis revealed that metabolites closely related to exercise, such as L-lactic acid, pyruvate, oxoglutaric acid, L-Phenylalanine, L-malic acid, N-acetylvaline, 2-ketobutyric acid, Fumaric acid, Pantothenic acid, Xanthosine, and N-lactoyl-Phenylalanine, all showed high levels of significant activity. Figure 1 (A). N-acetylvaline ( Figure 1 (B) is one of the most significant metabolites in the high-intensity and moderate-intensity contrast of all forms of exercise. Figure 2 (A to C), and has a very high correlation with the known intensity-dependent metabolite lactate ( Figure 3 These results support the possibility that N-acetylvaline may be a potential exercise-induced metabolite.

[0058] Precise measurement of NAV by targeting NAV confirmed that N-acetylvaline levels were significantly elevated after all types of high-intensity exercise. Figure 4 (B). In a mouse exhaustive exercise model, serum N-acetylvaline concentration increased fourfold ( Figure 4 These results (A) validate that N-acetylvaline is a characteristic factor induced by high-intensity exercise.

[0059] Two-sample Mendelian randomization analysis using the METSIM database showed a direct causal relationship between high circulating NAV and lower BMI, and may reduce the risk of obesity (OB) and type 2 diabetes mellitus (T2DM). Furthermore, plasma NAV levels were negatively correlated with physical activity levels, suggesting that NAV may play a role in the regulation of energy balance in the body. Figure 5 (A to D in the middle).

[0060] Example 2

[0061] 1. The effects of N-acetylvaline intervention on metabolic health in mice.

[0062] 1.1 Experimental reagents and materials.

[0063] (1) Experimental reagents: N-acetylvaline, physiological saline, DMSO, Kolliphore, isoflurane;

[0064] (2) Experimental instruments: high-precision electronic balance, metabolic cage;

[0065] (3) Experimental animals: 20-week-old C57BL6 / J mice (Vitalliwa).

[0066] 1.2 Experimental methods.

[0067] 1.2.1 Animal grouping.

[0068] Animal grouping: Twenty-four 6-week-old male C57BL6 / J mice were purchased from Vital River Biotechnology Co., Ltd. Mice were randomly divided into a normal diet group and a high-fat diet group. Mice in each category were further randomly assigned to an N-acetylvaline intervention group (NAV) and a corresponding solvent control group (Veh). Specifically, lean mice were divided into the NAV intervention group (NAV-WT) and the solvent control group (Veh-WT), and obese mice were similarly divided into the NAV intervention group (NAV-DIO) and the solvent control group (Veh-DIO).

[0069] 1.2.2 Diet-induced obesity model.

[0070] Diet-induced obesity model: In this study, a diet-induced obesity model was established using a high-fat diet supplied by Keo Cooperation Company. Starting at 6 weeks of age, C57BL / 6J mice were fed a diet containing 60% fat as energy for 12 weeks to promote the development of obesity and related metabolic abnormalities. The standard for obese mice was defined as mice fed the high-fat diet exceeding the body weight of their littermates on a normal diet by more than 30%.

[0071] 1.2.3 N-acetylvaline intervention regimen.

[0072] N-Acetylvaline Intervention Protocol: This experiment involved acute and long-term intervention with N-acetylvaline via intraperitoneal injection in mice. N-acetylvaline was dissolved in a 1:1:8 mixture of DMSO, Kolliphore, and physiological saline. In the acute intervention, mice received single injections of 25 mg / kg, 50 mg / kg, and 100 mg / kg, respectively, while the control group received the same volume of the solution. Food intake, water intake, and body weight changes were recorded 12 and 24 hours post-injection. In the long-term intervention, all mice received intraperitoneal injections of N-acetylvaline at a dose of 100 mg / kg / day for 10 days. The control group received the same volume of the solution. During this period, the following parameters were measured: fasting blood glucose, glucose tolerance, insulin tolerance, food intake, body weight, tissue weight, body fat percentage, oxygen uptake, carbon dioxide production, and activity level. All parameters were recorded periodically throughout the experiment, and the results were analyzed and compared at the end of the experiment.

[0073] 1.2.4 Metabolic cage analysis of acute food intake and energy metabolism parameters in mice.

[0074] Metabolic cage analysis of acute food intake and energy metabolism parameters in mice: In this study, the SablePromethion system (model PROMETHION BZ1) was used to measure acute food intake and energy metabolism parameters in mice. First, the system was calibrated and the required parameters were set, including oxygen consumption, carbon dioxide production, food intake, water intake, and animal activity. Mice were acclimatized to the system for 24 hours before measurement, and then placed individually in metabolic cages equipped with food and water for continuous monitoring for 24 hours. The system automatically recorded the weight of food and water at the beginning and end of the experiment. Simultaneously, by analyzing changes in the gas composition within the cage, the energy consumption and respiratory exchange ratio of the mice were continuously calculated. After the experiment, the accompanying software was used to process the data, outputting detailed parameters including food intake, water intake, energy consumption, respiratory quotient, and activity level, and further data standardization and statistical analysis were performed.

[0075] 1.2.5 Glucose tolerance and insulin tolerance test.

[0076] Glucose tolerance and insulin tolerance tests: For the glucose tolerance test, mice were fasted for 6 hours starting at 7:00 AM (free access to water), followed by an intraperitoneal injection of 2 g / kg body weight glucose. Blood glucose levels were measured at 0, 20, 40, 60, and 120 minutes using a blood glucose meter. For the insulin tolerance test, mice were fasted for 6 hours starting at 7:00 AM (free access to water), followed by an intraperitoneal injection of 0.75 U / kg body weight insulin dissolved in saline. Blood glucose levels were measured at 0, 20, 40, 60, and 120 minutes using a blood glucose meter. Data from both tests were recorded based on blood glucose levels at each time point, and the area under the blood glucose curve (AUC) was calculated. One-way ANOVA was used to compare differences between groups to assess glucose tolerance and insulin sensitivity in mice.

[0077] 1.2.6 Dual-energy X-ray absorptiometry (DEXA) was used to measure mouse body composition.

[0078] Dual-energy X-ray absorptiometry (DEXA) was used to measure body composition in mice: After fasting for 4 hours (with free access to water), body composition was measured using a DEXA bone densitometer (LunarIDXA GE Healthcare). Mice were mildly anesthetized with isoflurane prior to the test to minimize movement interference. Total body fat percentage, lean body mass, and overall body fat percentage were obtained via DEXA scanning.

[0079] 1.3 Experimental Results.

[0080] Experimental results are as follows Figures 6 to 14 As shown, it can be seen that: (1) After acute NAV injection (dose of 25 mg / kg, 50 mg / kg, and 100 mg / kg) into wild-type (WT) mice, it was observed that the food intake, water intake, body weight, and energy metabolism parameters of the mice were not significantly affected at these doses. Figure 6 (A to B). (2) In the DIO mouse model, this mouse model can simulate a metabolically abnormal state. A 50 mg / kg dose of NAV injection significantly reduced food intake within 12 hours; while a 100 mg / kg dose led to a significant decrease in food intake and body weight for 4 consecutive days. In addition, a 100 mg / kg dose of NAV injection also reduced CO2 production and respiratory quotient in DIO mice, indicating that NAV may have altered the energy metabolism pattern of DIO mice ( Figure 7 From A to B, Figure 8 , Figure 9 From A to F, Figure 10 (3) In a 10-day NAV intervention experiment, using a diet-induced obesity (DIO) mouse model, compared with the control group, the NAV treatment group showed a significant reduction in food intake, body weight, body fat percentage, and white adipose tissue weight, and a significant improvement in glucose tolerance, while the size of other organs remained unchanged. Figure 11 From A to D, Figure 12 From A to D, Figure 13 From A to D, Figure 14 (A to E). This indicates that NAV improves obesity and glucose homeostasis by reducing energy intake.

[0081] In summary, the N-acetylvaline of this invention is a characteristic exercise-induced metabolite that acts on the energy balance of obese patients from both the aspects of energy intake and energy expenditure, thereby reducing their weight and improving glucose tolerance. This substance has a long duration of action in the body, few side effects, and a significant fat-reducing effect.

[0082] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. The application of N-acetylvaline as the sole active ingredient in the preparation of products for the treatment or prevention of metabolic diseases, characterized in that, The metabolic disease mentioned is obesity or diabetes.

2. The application according to claim 1, characterized in that, The product in question is a medicine.

3. The application according to claim 2, characterized in that, The drug also includes pharmaceutical excipients.

4. The application according to claim 2, characterized in that, The dosage form of the drug includes at least one of the following: injection, oral tablets, oral capsules, and oral liquid preparations.

5. The application according to claim 2, characterized in that, When the dosage form of the drug is an injection, the drug further includes dimethyl sulfoxide, polysorbate, and physiological saline.

6. The application according to claim 5, characterized in that, The volume ratio of the dimethyl sulfoxide, the polysorbate, and the physiological saline is 1:1:8.

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