Application of indole-3-lactic acid in preparation of medicine for treating diabetes and complications

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of indole-3-lactic acid in preparation of medicines for treating diabetes and complications. A db / db mouse is utilized to simulate the pathological process of human diabetes, the db / db mouse is orally administered with indole-3-lactic acid, and after the db / db mouse orally administered with indole-3-lactic acid, the blood glucose and blood fat of the diabetic mouse can be reduced, the cardiac function impairment of the diabetic mouse is improved, and the brain cognitive dysfunction of the diabetic mouse is improved. It is proved that the indole-3-lactic acid has a treatment effect on diabetes and cardiovascular and cerebrovascular complications thereof.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to the application of indole-3-lactic acid in the preparation of medicines for treating diabetes and its complications. Background Art

[0002] Diabetes is a metabolic disease characterized by hyperglycemia, caused by impaired insulin secretion. Due to chronic hyperglycemia, diabetic patients experience damage and dysfunction in various tissues, particularly the eyes, kidneys, heart, blood vessels, and nerves. Controlling blood sugar through medication is currently and for a considerable period of time to come, the primary means of managing diabetes and reducing complications.

[0003] In many cases, diabetes is closely linked to cardiovascular disease, which is the leading cause of death in patients with type 2 diabetes. As diabetes cases increase, cognitive impairment is recognized as a significant complication of diabetes. While there are numerous glucose-lowering medications available, few offer cardiovascular benefits alongside glucose and lipid-lowering benefits.

[0004] Among the common drugs currently used to treat diabetes, metformin is a representative biguanide drug with a wide range of applications. It effectively lowers blood sugar levels by reducing glucose production in the liver, reducing intestinal absorption, and enhancing insulin sensitivity. However, metformin has many adverse reactions, such as chest discomfort, headache, sweating, hypoglycemia, and vitamin B6. 12 Levels are reduced, lactic acidosis, etc. Empagliflozin belongs to the SGLT2 inhibitor class of drugs, which lowers blood sugar by lowering the renal glucose threshold, reducing the renal reabsorption of glucose, and increasing urinary sugar excretion. However, its adverse reactions include hypotension, ketoacidosis, acute kidney injury, increased production of ketone bodies, increased risk of ketoacidosis, hypoglycemia when used with insulin, dyslipidemia, etc. Semaglutide is a GLP-1 receptor agonist, commonly used to treat type 2 diabetes, usually with blood sugar lowering, weight loss and cardiovascular protection effects. When using semaglutide, attention should also be paid to possible side effects, such as gastrointestinal reactions such as nausea, vomiting, and diarrhea, as well as the risk of hypoglycemia. Considering that these drugs have corresponding side effects and limitations. Therefore, new drugs for the treatment of diabetes and its complications have always been a hot spot for research and development.

[0005] It is becoming increasingly clear that the gut microbiome has a significant impact on human health. Gut bacteria, including various Clostridium, Bacteroides, Eubacterium, Lactobacillus, and Bifidobacterium genera, produce a variety of tryptophan metabolites through various metabolic pathways. For example, Clostridium species convert tryptophan into tryptamine, indole-3-lactic acid (ILA), and indole-3-propionic acid (IPA); while Lactobacillus species can convert tryptophan into indolealdehyde (IAld) and ILA. In a study by Liu Xingyin's research team at Nanjing Medical University, Lactobacillus plantarum L168 and its metabolite indole-3-lactic acid were found to improve intestinal inflammation, tumor growth, and intestinal dysbiosis. Other studies have shown that Lactobacillus reuteri inhibits colorectal tumorigenesis by breaking down the tryptophan metabolite indole-3-lactic acid (ILA).

[0006] Chinese patent application publication number CN118416056A discloses the use of indole-3-lactic acid in the preparation of a drug for treating ischemic stroke. This application established an ischemic stroke model in rats and conducted a series of experiments, from inflicting pathological damage to the rat brain structure to structural restoration. The results showed that oral administration of indole-3-lactic acid to rats with ischemic stroke significantly reduced Longa and mNSS neurological function scores, reduced cerebral infarction rate, repaired pathological damage to brain tissue, restored blood-brain barrier function, and significantly increased the number of neurons. The technical effect of this patent is more inclined towards restoring the normal structure of the rat brain. However, the patent does not mention its effect on improving cognitive function. Drugs that can improve stroke and reduce cerebral infarction rate may not necessarily be effective in improving cognitive function.

[0007] The existing technology does not disclose any use of indole-3-lactic acid or bacteria that metabolize and synthesize indole-3-lactic acid in the preparation of drugs for treating diabetes and its complications (cardiovascular and cerebrovascular complications). Summary of the Invention

[0008] In view of this, and in view of the problems existing in the prior art, the object of the present invention is to provide the use of indole-3-lactic acid in the preparation of a drug for treating diabetes and its complications.

[0009] The specific technical solutions of the present invention are as follows: The present invention provides use of indole-3-lactic acid or bacteria capable of metabolizing and synthesizing indole-3-lactic acid in preparing medicines for treating diabetes and its complications.

[0010] Furthermore, the complications are cardiovascular and cerebrovascular complications.

[0011] In a specific embodiment of the present invention, the complication is one or more of hyperlipidemia, brain cognitive dysfunction or cardiac function damage.

[0012] Furthermore, the indole-3-lactic acid or the bacteria that metabolize and synthesize indole-3-lactic acid is an active ingredient of the drug.

[0013] Furthermore, the drug can be used in combination with diabetes treatment drugs to enhance the anti-diabetic effect.

[0014] Specifically, the diabetes therapeutic drug is selected from one or more of sulfonylurea insulin secretagogues, non-sulfonylurea insulin secretagogues, incretin analogs, and biguanides. Sulfonylurea insulin secretagogues include glibenclamide and gliclazide; non-sulfonylurea insulin secretagogues include repaglinide and nateglinide; biguanides include metformin; and incretin analogs, i.e., GLP-1 receptor agonists, include liraglutide and exenatide.

[0015] Furthermore, the drug comprises indole-3-lactic acid and pharmaceutically acceptable excipients.

[0016] Furthermore, the drug is administered orally, by injection, by inhalation, topically, sublingually or rectally.

[0017] Furthermore, the dosage form of the drug is pills, tablets, powders, capsules, granules, suspensions, injections or oral solutions. Suitable pharmaceutical carriers in the art can be selected for different dosage forms.

[0018] The pharmaceutical carrier used can be solid, liquid or gas. Examples of solid carriers include lactose, kaolin, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil and water.

[0019] When preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, ethanol, oils, alcohols, flavoring agents, preservatives, colorants, and the like can be used to form oral liquid formulations such as suspensions, elixirs, and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, emulsifiers, lubricants, binders, and disintegrants can be used to form oral solid formulations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units using solid pharmaceutical carriers due to their ease of administration. Tablets can be coated using standard aqueous or nonaqueous techniques.

[0020] Tablets containing indole-3-lactic acid can be prepared by tableting or molding, optionally with the use of one or more auxiliary ingredients or adjuvants. The active ingredient can be compressed in a free-flowing form (such as powder or granules) in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant to prepare the compressed tablet. Molded tablets can be molded in a suitable machine, i.e., a powdered compound mixture moistened with an inert liquid diluent. Each tablet preferably contains about 0.05 mg to about 5 g of active ingredient, and each sachet or capsule preferably contains about 0.05 mg to about 5 g of active ingredient. For example, a formulation intended for oral administration to humans may contain about 0.5 mg to about 5 g of active drug, mixed with an appropriate and convenient carrier material, which may account for about 5% to 95% of the total composition. Unit dosage forms will generally contain from about 1 mg to about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

[0021] In addition to the aforementioned carrier components, the pharmaceutical formulations may include (if applicable) one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. Furthermore, other excipients, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, colorants, and flavoring agents, may be added to render the formulation isotonic with the blood of the intended recipient. The components containing indole-3-lactic acid may also be prepared in powder or concentrated form.

[0022] Furthermore, the indole-3-lactic acid in the drug is used in a mouse animal dosage of 20 mg / kg.

[0023] The beneficial effects of the present invention are: The present invention has demonstrated through animal experimental studies that oral administration of ILA to mice can significantly reduce blood sugar levels and blood lipid levels, significantly improve the cardiac function of diabetic mice, restore the reduction of ventricular internal diameter, ejection fraction and shortening rate to normal, significantly reverse diastolic function, and improve the cognitive function of the mouse brain. The above effects indicate that ILA has a significant effect on the treatment of diabetes and its cardiovascular and cerebrovascular complications, and has important clinical application value. The present invention can achieve simultaneous treatment of the heart and brain for diabetes and its cardiovascular and cerebrovascular complications, and can make up for the shortcomings of existing drugs that have a single target and have gastrointestinal adverse reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The graphs show the blood glucose levels of each group of mice in Example 1. (a) is a line graph showing the fasting blood glucose values ​​of each group of mice; (b) is a line graph showing the results of the oral glucose tolerance test of each group of mice; (c) is a bar graph showing the area under the oral glucose tolerance curve of each group of mice ( Indicates that the group and db / m + Comparison, P < 0.05; # indicates the comparison between this group and db / db, P < 0.05).

[0025] Figure 2 is a bar graph showing the comparison of lipid levels of each group in Example 2 ( Indicates that the group and db / m + Comparison, P < 0.05; # Indicates that the group was compared with db / db, P < 0.05; ns indicates that there was no significant difference between the group and db / db); wherein, (a) is a bar graph showing the total cholesterol level of mice in each group; (b) is a bar graph showing the triglyceride level of mice in each group; (c) is a bar graph showing the low-density lipoprotein cholesterol level of mice in each group; (d) is a bar graph showing the high-density lipoprotein level of mice in each group.

[0026] Figure 3 The echocardiograms of the groups in Example 3 are shown; (a) is the echocardiogram of the control group mice; (b) is the echocardiogram of the model group mice; (c) is the echocardiogram of the treatment group mice; and (d) is the echocardiogram of the positive drug group mice.

[0027] Figure 4 The bar graph shows the left ventricular ejection fraction of each group of mice ( Indicates that the group and db / m + Comparison, P < 0.05; # indicates the comparison between this group and db / db, P < 0.05).

[0028] Figure 5 The bar graph shows the fractional shortening of the left ventricle in each group of mice ( Indicates that the group and db / m + Comparison, P < 0.05; # indicates the comparison between this group and db / db, P < 0.05).

[0029] Figure 6 is a bar graph showing the E / A ratio of each group of mice ( Indicates that the group and db / m + Comparison, P < 0.05; # indicates the comparison between this group and db / db, P < 0.05).

[0030] Figure 7 The bar graph shows the left ventricular end-diastolic diameter of each group of mice ( Indicates that the group and db / m + Comparison, P < 0.05; #indicates the comparison between this group and db / db, P < 0.05).

[0031] Figure 8 The bar graph shows the left ventricular end-systolic diameter of each group of mice ( Indicates that the group and db / m + Comparison, P < 0.05; # indicates the comparison between this group and db / db, P < 0.05).

[0032] Figure 9 is a bar graph showing the comparison of brain cognitive abilities of mice in each group in Example 3 ( Indicates that the group and db / m + Comparison, P < 0.05; # = ( ) indicates the comparison between this group and db / db, P < 0.05; ns indicates no significant difference between this group and db / db); (a) is a bar graph showing the percentage of time each group of mice spent in the target quadrant; (b) is a bar graph showing the number of times each group of mice crossed the platform; (c) is a bar graph showing the average swimming speed of each group of mice; and (d) is a bar graph showing the total swimming distance of each group of mice. DETAILED DESCRIPTION

[0033] Terms and Claims of the Present Invention: 1. The articles "a", "an" and "the" include plural referents unless expressly limited to one or more referents otherwise.

[0034] 2. Numerical ranges: Unless expressly stated otherwise, all ranges or ratios disclosed herein are to be understood to include any and all subranges or subratios contained therein. For example, a range or ratio stated as 1 to 30 is to be considered inclusive of any and all subranges or subratios, integers, decimals, or subranges or subratios comprised therein, between a minimum of 1 and a maximum of 30, including any subranges or subratios, integers, decimals, or subranges or subratios comprised therein.

[0035] The following non-limiting examples are provided to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way. The following are merely illustrative of the scope of the present invention, and those skilled in the art may make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0036] The present invention will be further described below by way of specific examples. The various chemical reagents used in the examples of the present invention were obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all by weight. Unless otherwise specified, it is understood that the experiments were conducted at room temperature.

[0037] In the following examples, the chemical formula of indole-3-lactic acid is C 11 H 11 NO3, molecular weight 205.21, purchased from KKLMED, product number 301326-22-7.

[0038] In the following examples, the sources of some reagents are as shown in Table 1: Table 1

[0039] Solution preparation: 10 mg of indole-3-lactic acid purchased from the above manufacturer was dissolved in 5 mL of distilled water and used in the treatment group.

[0040] experimental animals Animals used in Examples 1-3: 30 male db / db mice and 10 db / m + SPF mice, weighing approximately 20 g, were provided by Guangdong Saiye (Suzhou) Biotechnology Co., Ltd. (license number: SCXK(Su)2022-0016). They were maintained at a temperature of 22–24°C and a relative humidity of 40–60% with free access to food and water. Experiments were conducted after one week of acclimatization to a natural circadian light cycle. All animal studies were conducted in accordance with protocols and guidelines approved by the Animal Ethics Committee of the Laboratory Animal Center of Guangdong Pharmaceutical University (ethics number: gdpulacspf2022621).

[0041] Grouping and treatment: Control group: 10 db / m + mice; Model group: 10 db / db mice, once a day; Treatment group: 10 db / db mice were given ILA 0.1 mL / 10 g once a day; Positive drug group: 10 db / db mice were given metformin (MET) 0.1 mL / 10 g, once a day.

[0042] All mice had free access to water and food for 8 consecutive weeks.

[0043] The above mice were subjected to blood glucose level testing, blood lipid testing and cardiac function testing, namely, Example 1 to Example 3.

[0044] Blood glucose evaluation in the db / db mouse model: When the blood glucose level of db / db mice is greater than 11.1 mmol / L, it indicates that the diabetes model has been successfully established.

[0045] Example 1: Blood glucose level test (1) Fasting blood glucose testing Before each test, mice in each group fasted for 8 hours without food or water, and then had their fasting blood glucose measured. During the test, the tip of the mouse's tail was wiped with an alcohol pad. Once dry, a single-use blood collection needle (with a silicone oil coating on the tip) was used to squeeze blood from the base of the tail toward the tip. The first drop of blood was discarded, and the blood was placed on a blood glucose meter for testing. At the end of the test, the tail tip was disinfected again with an alcohol pad.

[0046] (2) Oral glucose tolerance test First, each group of mice was fasted for 12 hours, and the blood glucose level of the mice was measured at 0 min. Then, glucose solution was orally gavaged to each group of mice, and the blood glucose level of each group of mice was measured and recorded at 15 min, 30 min, 60 min, 90 min and 120 min after gavage.

[0047] The results are as follows Figure 1 As shown. In the fasting blood glucose test, compared with the control group, db / db mice showed elevated blood glucose, while the indole-3-lactic acid group effectively reduced the abnormal increase in blood glucose. The results of the oral glucose tolerance test showed that compared with the control group, the area under the curve of the model group mice was significantly increased, while the treatment group was able to reverse the trend of elevated blood glucose ( Indicates that the group and db / m + Comparison, P < 0.05; # indicates the comparison between this group and db / db, P < 0.05).

[0048] Example 2: Blood lipid detection Mouse serum extraction: For experimental mouse samples, mice were placed in an anesthesia machine and anesthetized by inhalation of isoflurane. Blood was then collected from the eye using an anticoagulant-treated glass capillary tube. The collected blood was allowed to stand at room temperature for half an hour and then centrifuged at 3000 rpm at 25°C for 15 minutes. The supernatant was the mouse serum. Triglyceride, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels in the mice were measured using the various kits listed in Table 1.

[0049] (1) Serum total cholesterol content determination method: According to the kit detection method, add samples according to Table 2 in a 96-well plate: Table 2 Sample addition method for determination of serum total cholesterol content

[0050] After adding the sample, mix the solution in each well and incubate at 37°C for 10 minutes. Measure the absorbance of each well at 500 nm using a microplate reader. Calculate the serum T-CHO content according to the kit's assay protocol: T-CHO (mmol / L) = [(OD value of serum sample well - OD value of blank well) / (OD value of standard well - OD value of blank well)] × standard solution concentration (mmol / L). The standard solution concentration is 2.68 mmol / L.

[0051] (2) Serum triglyceride content determination method: According to the kit detection method, add samples according to Table 3 in a 96-well plate: Table 3 Sampling method for determination of serum triglyceride content

[0052] After adding the sample, mix the solution in each well and incubate at 37°C for 10 minutes. Measure the absorbance of each well at 500 nm using a microplate reader. Calculate the serum TG content according to the kit's assay protocol: TG (mmol / L) = [(OD value of serum sample well - OD value of blank well) / (OD value of standard well - OD value of blank well)] × standard solution concentration (mmol / L). The standard solution concentration is 2.68 mmol / L.

[0053] (3) Determination of low-density lipoprotein cholesterol content: According to the kit detection method, add samples according to Table 4 in a 96-well plate: Table 4 Sample addition method for low-density lipoprotein cholesterol determination

[0054] Add distilled water, calibrators, samples, and the kit's working solution R1 to the wells, mix thoroughly, and incubate at 37°C for 5 minutes. Measure the absorbance (A1) of each well at 550 nm using a microplate reader. Add the kit's working solution R2, mix again, and incubate at 37°C for 10 minutes. Measure the absorbance (A2) of each well at 550 nm using a microplate reader. Calculate according to the kit's assay protocol. Serum LDL-C concentration is calculated as follows: LDL-C (mmol / L) = [(serum sample A2 - serum sample A1) - (blank control A2 - blank control A1)] / [(standard A2 - standard A1) - (blank control A2 - blank control A1)] × standard solution concentration (mmol / L). The standard solution concentration is 4.89 mmol / L.

[0055] (4) Determination of high-density lipoprotein cholesterol content: According to the test kit method, add samples according to Table 5 in a 96-well plate: Table 5 Sample addition method for high-density lipoprotein cholesterol determination

[0056] Add distilled water, calibrators, samples, and kit working solution R1 to the wells, mix thoroughly, and incubate at 37°C for 5 minutes. Measure the absorbance (A1) of each well at 550 nm using a microplate reader. Add kit working solution R2, mix again, and incubate at 37°C for 10 minutes. Measure the absorbance (A2) of each well at 550 nm using a microplate reader. Calculate according to the kit assay protocol. Serum HDL-C concentration is calculated as follows: HDL-C (mmol / L) = [(Serum sample A2 - Serum sample A1) - (Blank control A2 - Blank control A1) / (Standard A2 - Standard A1) - (Blank control A2 - Blank control A1)] × standard solution concentration (mmol / L). The standard solution concentration is 1.83 mmol / L.

[0057] (5) Test results The results are as follows Figure 2 As shown in the results, compared with the control group, the total cholesterol, triglyceride and low-density lipoprotein cholesterol levels of the model group mice were significantly increased, and the high-density lipoprotein cholesterol was significantly decreased; and after administration of indole-3-lactic acid, the total cholesterol and low-density lipoprotein cholesterol of the mice were significantly reduced, while the triglyceride level was relatively reduced and the high-density lipoprotein cholesterol was relatively increased, effectively reversing the dyslipidemia of diabetic mice, and the reversal ability in the two tests of triglyceride and high-density lipoprotein was no less than that of metformin ( Indicates that the group and db / m + Comparison, P < 0.05; # = means P < 0.05 for the comparison between this group and db / db; ns means there is no significant difference between this group and db / db).

[0058] Example 3: Cardiac function testing At 16 weeks of age, mice were assessed for cardiac function using a Vevo 2100 small animal ultrasound system. First, the mice were weighed and injected intraperitoneally with an anesthetic solution (2.7 g tribromoethanol + 1.43 mL tert-amyl alcohol + 100 mL normal saline, protected from light) at a dose of 0.1 mL / g body weight. After the mice became unconscious, depilatory cream was applied to the chest to remove hair. After depilation, the mice were secured to the operating table with medical tape. The isoflurane gas anesthesia tank was activated, and a gas anesthesia mask was placed. Conductive adhesive was liberally applied to the depilated chest area. The Doppler ultrasound probe was then aligned vertically over the mouse's chest. After accurate positioning, dynamic and static echocardiograms were captured. The probe was then rotated 90 degrees clockwise to the short axis to obtain dynamic and static echocardiograms of the mouse. Then adjust the position of the temperature control plate, use the probe to detect the blood flow velocity of the mouse mitral valve within a reasonable heart rate range, find the exact position of the mitral valve based on the blood flow velocity, and then capture dynamic and static images. Use the analysis system in the instrument to calculate various indicators of cardiac function, and manually locate each indicator of each mouse three times in a row, and take the average value. Manually select the position of the static images captured in the experiment on the Doppler ultrasound instrument, and the instrument automatically calculates various indicators of mouse cardiac function based on the selected position. Manually locate each indicator of each mouse three times, and take the average value. Echocardiograms of each group are shown in Figure 3 .

[0059] The results are as follows Figure 4-Figure 8 As shown, the model group mice showed obvious cardiac dysfunction, manifested as impaired diastolic function, decreased ejection fraction and ventricular dilatation. After intervention with indole-3-lactic acid, the cardiac function of diabetic mice was significantly improved, the ventricular internal diameter was reduced, the ejection fraction and shortening rate returned to normal, and the diastolic function was significantly reversed, indicating that indole-3-lactic acid has a significant repair effect on diabetic-induced cardiac function lesions, effectively reducing heart damage and improving heart function ( Indicates that the group and db / m + Comparison, P < 0.05; # indicates the comparison between this group and db / db, P < 0.05).

[0060] Example 4: Brain Cognitive Ability Test Experimental animals: 30 8-week-old male db / db mice and 10 8-week-old db / m+ mice, weighing approximately 20 g, were provided by Guangdong Saiye (Suzhou) Biotechnology Co., Ltd., license number: SCXK(Su)2022-0016. Animals were housed with free access to food and water, at a temperature of 22-24°C and a relative humidity of 40-60%. Experiments were conducted after one week of acclimatization to a natural circadian light cycle. All animal studies were conducted in accordance with protocols and guidelines approved by the Animal Ethics Committee of the Laboratory Animal Center of Guangdong Pharmaceutical University (ethics number: gdpulac2022621).

[0061] Grouping and treatment: Control group: 10 db / m + mice; Model group: 10 db / db mice, once a day; Treatment group: 10 db / db mice were given ILA 0.1 mL / 10 g once a day; Positive drug group: Ten db / db mice were administered metformin (MET) 0.1 mL / 10 g once daily. All mice had free access to water and food. After 12 weeks of continuous drug administration, the mice were then tested in a water maze to assess their spatial learning and memory abilities.

[0062] The experiment was conducted using the Morris water maze, a 214 cm diameter, 50 cm height, 30 cm depth, and white ground. The Morris water maze is one of the most classic and widely used experimental paradigms in behavioral neuroscience. Developed by Richard G. Morris in 1981, it is primarily used to assess spatial learning and memory in rodents (such as rats and mice), with a particular focus on spatial reference memory, which relies on the hippocampus and related brain regions. Its core principle is to test the animal's ability to use fixed distal visual cues in the environment to construct a "cognitive map" to navigate and locate a hidden underwater escape platform.

[0063] At the beginning of the experiment, titanium dioxide was dropped into the water to dye the water white. Four colored marking points were marked on the wall of the pool in a clockwise direction at equal distances, dividing the pool into four quadrants: west, south, east, and north. A circular platform with a diameter of 10 cm and a height of 28 cm was placed in the center of the north quadrant of the pool. A camera was installed directly above the pool so that it could clearly capture the entire pool. The experiment was carried out in a quiet, artificially lit room. The water temperature was controlled at 20-23°C during the experiment. The water in the pool was changed every day. The mice were fasted for 4 hours before the experiment, and the experimental mice were blown dry with a hair dryer after the experiment.

[0064] (1) Positioning navigation test: For five consecutive days, four entry points were selected outside the platform quadrant (different each day). During the experiment, the animal was gently lowered into the water facing the pool wall without disturbing the water surface. The time it took for the mouse to climb onto the platform, known as the escape latency, was recorded. The mouse was then allowed to remain on the platform for 15 seconds. If the mouse failed to find the platform within 120 seconds, the escape latency was recorded as 120 seconds, and the mouse was placed on the platform to rest for 15 seconds. The arithmetic mean of the four escape latencies was used as the score for that day and statistically analyzed. The escape latency represents the mouse's spatial learning ability.

[0065] (2) Space Exploration Experiments: One day after the navigation test, the platform was removed and the mice were placed in the water from the quadrant opposite to the platform. The swimming path of the mice in the pool and the number of times they entered the target area within 120 seconds after entering the water were recorded as indicators for evaluating the memory performance of the mice.

[0066] (3) Experimental results like Figure 9 As shown in the figure, in the spatial exploration test on the 6th day, the time that the model group mice stayed in the target quadrant decreased (p<0.05), indicating that the mice's memory ability was significantly reduced; while the treatment group mice and the control group showed different degrees of improvement compared with the positive drug group (p<0.05). Among them, in terms of the number of times crossing the platform and the time staying in the target quadrant, the effect of ILA was no less than that of metformin ( Indicates that the group and db / m + Comparison, P < 0.05; # = means P < 0.05 for the comparison between this group and db / db; ns means there is no significant difference between this group and db / db).

[0067] The results of the aforementioned efficacy evaluation indicate that indole-3-lactic acid can lower blood glucose levels and improve fasting glucose tolerance in diabetic mice. It can also control various blood lipid profiles in diabetic mice, reducing total cholesterol, triglycerides, and low-density lipoprotein cholesterol while increasing high-density lipoprotein cholesterol. In terms of cognitive function, it can increase target quadrant dwell time and platform crossing times, as well as average swimming time and total swimming distance, with comparable effects to metformin. It can also improve cardiac function, with a reduction in ventricular internal diameter, normalization of ejection fraction and fractional shortening, and significant reversal of diastolic function. These results suggest that indole-3-lactic acid can lower blood glucose and reverse cardiovascular and cerebrovascular complications caused by diabetes, and therefore has significant potential clinical value.

[0068] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. Use of indole-3-lactic acid or bacteria that metabolize and synthesize indole-3-lactic acid in the preparation of drugs for treating diabetes and its complications.

2. The use according to claim 1, characterized in that The complications are cardiovascular and cerebrovascular complications.

3. The use according to claim 2, characterized in that The complications are one or more of hyperlipidemia, cardiac function damage, and brain cognitive dysfunction.

4. The use according to any one of claims 1 to 3, characterized in that The indole-3-lactic acid or the bacteria that metabolizes and synthesizes indole-3-lactic acid is the active ingredient of the medicine.

5. The use according to claim 4, characterized in that The drug is used in combination with a diabetes therapeutic drug.

6. The use according to claim 5, characterized in that The diabetes treatment drug is selected from one or more of sulfonylurea insulin secretagogues, non-sulfonylurea insulin secretagogues, incretin analogs, and biguanides.

7. The use according to any one of claims 1 to 3, characterized in that The medicine comprises indole-3-lactic acid and pharmaceutically acceptable excipients.

8. The use according to any one of claims 1 to 3, characterized in that The drug can be administered orally, by injection, by inhalation, topically, sublingually or rectally.

9. The use according to any one of claims 1 to 3, characterized in that The dosage form of the medicine is pill, tablet, powder, capsule, granule, suspension, injection or oral solution.

10. The use according to any one of claims 1 to 3, characterized in that The dosage of indole-3-lactic acid in mice in the drug is 20 mg / kg.

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