A combined drug for treating diabetes and its application

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a combined drug for treating diabetes and its application. The combined drug for treating diabetes includes metformin and interleukin 2. Compared with interleukin 2 and metformin monotherapy, interleukin 2 and metformin as a combined drug for treating diabetes can also improve insulin resistance, restore pancreatic function, and enhance blood sugar metabolism when the drug dosage is reduced. The combined use of interleukin 2 and metformin can more effectively treat type 2 diabetes in mice with the advantage of low dosage.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a combined drug for treating diabetes and application thereof. Background Art

[0002] Diabetes is a group of metabolic diseases characterized by high blood sugar. High blood sugar is caused by defects in insulin secretion or its biological function, or both. Long-term diabetes can lead to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves.

[0003] Type 2 diabetes is a metabolic disease characterized by abnormally high blood sugar levels and has a genetic tendency. Among them, unhealthy lifestyles such as overnutrition and lack of exercise, as well as a family history of diabetes are the causes of type 2 diabetes. In patients in the early stages of type 2 diabetes, the liver, pancreas, and visceral adipose tissue will all be in an inflammatory state, resulting in a decrease in the tissue's ability to take up and metabolize insulin-stimulated glucose. This condition is called insulin resistance. At this time, insulin resistance causes pancreatic beta cells to compensatorily secrete large amounts of insulin to promote glucose uptake and metabolism. Long-term, large amounts of insulin secretion and pancreatic inflammation will eventually induce pancreatic beta cell apoptosis, leading to a lack of insulin secretion. In patients with type 2 diabetes, lack of insulin secretion and insulin resistance exist almost simultaneously.

[0004] At present, the treatment strategies for type 2 diabetes mainly include regular physical exercise, appropriate low-carbohydrate diet, and long-term drug treatment, such as oral chemical hypoglycemic drugs and insulin injections. In the past few decades, single hypoglycemic drugs such as insulin, sulfonylureas, biguanides and dipeptidyl peptidase 4 (DPP-4) inhibitors, although they can lower blood sugar levels, cannot inhibit or reverse the course of diabetes. Therefore, it is of great significance to develop a new drug for type 2 diabetes to achieve better treatment effects. Summary of the invention

[0005] In view of the problems that drugs for treating type 2 diabetes in the prior art, such as metformin, require large dosages and have average blood sugar regulation capabilities, the present invention provides a combined drug for treating diabetes and its application.

[0006] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0007] A combination drug for the treatment of diabetes comprising metformin and interleukin-2.

[0008] Preferably, it also includes a pharmaceutically acceptable carrier or excipient.

[0009] Preferably, the pharmaceutically acceptable carrier or excipient is selected from at least one of a diluent, a disintegrant, a binder, a lubricant or a dispersant.

[0010] The present invention further provides the use of the above-mentioned combined drug for treating diabetes in the preparation of a drug for treating type 2 diabetes.

[0011] Preferably, the metformin is taken orally daily, and the interleukin-2 is taken by subcutaneous injection or orally every other day.

[0012] Furthermore, the carrier of the interleukin-2 during oral administration is micro-nano particles.

[0013] The preferred micro-nano particles can be loaded into enteric-coated capsules as carriers to avoid degradation by pepsin and increase the bioavailability of interleukin-2.

[0014] Preferably, in mouse experiments, based on the body weight of the mice, the daily dosage of metformin is 50 mg / kg-150 mg / kg.

[0015] Preferably, at the mouse experimental level, the daily dosage of interleukin-2 is 2000 IU-25000 IU.

[0016] Preferably, the metformin is a pharmaceutically acceptable salt.

[0017] Preferably, the interleukin-2 is recombinant human interleukin-2 or a variant thereof.

[0018] Compared with the prior art, the combined drug for treating diabetes provided by the present invention and its application, wherein metformin is a first-line drug for treating type 2 diabetes. On the one hand, metformin can reduce the output of glucose in the liver by inhibiting gluconeogenesis and glycogenolysis in the liver, and inhibit the absorption of glucose in the intestine, thereby reducing the source of blood sugar; on the other hand, metformin can also inhibit the activity of dipeptidyl peptidase IV (DPP-IV), increase the secretion of glucagon-like polypeptide 1 (GLP-1), thereby enhancing GLP-1 to reduce blood sugar and promote insulin secretion, thereby promoting the uptake and utilization of blood glucose by peripheral target tissues, and producing a biological effect of reducing blood sugar. In addition, metformin is an activator of adenosine monophosphate (AMP) activated protein kinase (AMPK), which can inhibit the proliferation of Th1 cells and Th17 cells in effector T cells and inhibit inflammatory response. Interleukin 2 is a cytokine with multiple cell sources (mainly produced by activated T cells) and multi-directional effects (mainly promoting lymphocyte growth, proliferation, and differentiation). It plays an important role in the body's immune response and anti-viral infection, and can stimulate the proliferation of T cells that have been activated by specific antigens, activate T cells, and promote cytokine production; stimulate NK cell proliferation, enhance NK killing activity and produce cytokines, induce LAK cell production, promote B cell proliferation and secretion of antibodies; and can also activate macrophages. Therefore, high-dose interleukin 2 is often used in the treatment of malignant tumors such as renal cancer, malignant melanoma, and colon cancer. In the past decade, it has been found that low-dose interleukin 2 can specifically proliferate regulatory T cells, inhibit effector T cell proliferation, and inhibit autoimmune inflammation, and can be used clinically for the treatment of autoimmune diseases. The present invention provides a combination of interleukin 2 and metformin as a drug for treating type 2 diabetes. When the dosage of the drug is reduced, it can also effectively improve insulin resistance, restore pancreatic function, and enhance blood sugar metabolism. The combination of interleukin 2 and metformin effectively treats type 2 diabetes in mice with the advantage of low doses. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a fasting blood glucose concentration measurement diagram of Application Example 1 of the present invention, wherein * indicates P < 0.05;

[0020] Figure 2 This is a graph showing changes in blood sugar levels during an oral glucose tolerance test in Application Example 1 of the present invention;

[0021] Figure 3 This is a graph showing the calculation results of the area under the blood glucose curve in an oral glucose tolerance test in Application Example 1 of the present invention;

[0022] Figure 4 This is a graph showing changes in blood sugar levels in an insulin resistance test in Application Example 1 of the present invention;

[0023] Figure 5This is a graph showing the calculation results of the area under the blood glucose curve in the insulin resistance test in Application Example 1 of the present invention, wherein * indicates P < 0.05;

[0024] Figure 6 This is a graph showing the concentration of interleukin-6 in blood in Application Example 1 of the present invention, wherein * indicates P < 0.05;

[0025] Figure 7 This is a graph showing the concentration of blood tumor necrosis factor α in Application Example 1 of the present invention, where * indicates P < 0.05;

[0026] Figure 8 This is a graph showing the concentration of interleukin-10 in blood in Application Example 1 of the present invention, wherein NS indicates no significant difference;

[0027] Fig. 9 This is a graph showing the concentration of pancreatic interleukin-6 in Application Example 1 of the present invention, wherein * indicates P < 0.05;

[0028] Fig.10 This is a graph showing the concentration of pancreatic tumor necrosis factor α in Application Example 1 of the present invention, wherein NS indicates no significant difference;

[0029] Fig.11 This is a graph showing the concentration of pancreatic interleukin 10 in Application Example 1 of the present invention, wherein NS indicates no significant difference;

[0030] Fig.12 This is a graph showing the concentration of interleukin-6 in adipose tissue in Application Example 1 of the present invention, wherein NS indicates no significant difference;

[0031] Fig.13 This is a graph showing the concentration of adipose tumor necrosis factor α in Application Example 1 of the present invention, wherein * indicates P < 0.05;

[0032] Fig.14 This is a graph showing the concentration of interleukin-10 in adipose tissue in Application Example 1 of the present invention, wherein * indicates P < 0.05;

[0033] Fig.15 This is a graph showing the determination of blood insulin levels in Application Example 1 of the present invention, wherein NS indicates no significant difference;

[0034] Fig.16 This is a graph showing the determination of pancreatic insulin levels in Application Example 1 of the present invention, wherein NS indicates no significant difference. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments and drawings. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0036] Modeling experiment

[0037] 50 Kunming mice (hereinafter referred to as mice) were purchased from the Animal Center of Hebei Medical University. After one week of adaptive feeding, 6 mice were selected as the blank control group and fed with basic feed. The remaining mice were fed with high-fat and high-sugar feed (66.5% basic feed, 20% sucrose, 10% lard, 2.5% cholesterol and 1% sodium cholate) for 4 weeks. The weight was weighed, among which the blank control group mice weighed 44g-48g, and the mice fed with high-fat and high-sugar feed weighed 39g-46g. The mice fasted for 8 hours and had free access to water. Then, streptozotocin was injected intraperitoneally at a dose of 40mg / kg; 72 hours later, a second streptozotocin injection was performed, and the streptozotocin injection dose was 70mg / kg; after another 72 hours, a third streptozotocin injection was performed at a dose of 100mg / kg. One week after the injection, the mice fasted for 8 hours, blood was collected from the tail vein, and the fasting blood glucose of the mice was quickly measured using a blood glucose meter. When the fasting blood glucose value of mice was ≥13.9mmol / l for two consecutive weeks, and accompanied by polydipsia, polyphagia and polyuria, it was considered to be the onset of type 2 diabetes. Type 2 diabetic mice with blood glucose values ​​of 20-25mmol / l were selected and randomly divided into groups.

[0038] Treatment Process

[0039] Divided into a blank control group, a model control group, a metformin treatment group, an interleukin 2 treatment group and an interleukin 2 + metformin combination group, 6 mice in each group, wherein the administration time, administration method and daily dosage of each group are shown in Examples 1-3. During the treatment period, except for the blank control group mice fed with basal feed, the remaining groups continued to be fed with high-fat and high-sugar feed. During the treatment period, fasting blood sugar was measured weekly, and the changes in fasting blood sugar were recorded. After the treatment, oral glucose tolerance test, insulin resistance test, insulin concentration determination, blood, visceral adipose tissue, and pancreatic cytokine levels were determined.

[0040] Fasting blood glucose concentration measurement

[0041] The mice were fasted for 8 h overnight and allowed free access to water. Blood was collected from the tail tip of the mice and measured using a Roche blood glucose meter and test strips;

[0042] Oral glucose tolerance test

[0043] Mice in each group were fasted for 8 h and allowed free access to water. On the second day, fasting blood glucose was measured from the tail venous blood of the mice as the 0-minute blood glucose value. A 20% D-glucose solution was prepared at a glucose dose of 2 g / kg. The gavage volume was 10 ml / kg and each group was gavaged with glucose solution. The blood glucose values ​​were measured 30 minutes, 60 minutes, 120 minutes, and 180 minutes after gavage. The blood glucose change curve was drawn, and the area under the blood glucose curve (AUC) was calculated.

[0044] Insulin resistance test

[0045] The mice were fasted for 12 hours at night and were given adequate drinking water. The blood glucose value was measured by taking tail vein blood as the 0-minute blood glucose value, and then each mouse was intraperitoneally injected with 100 μL / 10 g of insulin solution with a concentration of 0.1 U / mL. The blood glucose values ​​were measured at 15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after injection, and the blood glucose change curve was recorded and drawn, and the area under the blood glucose curve was calculated.

[0046] Plasma concentrations of interleukin-6, tumor necrosis factor-α, interleukin-10, and insulin

[0047] The fasting plasma of mice was collected and the assay was performed strictly according to the instructions of each mouse ELISA kit. Determination of the concentrations of interleukin-6, tumor necrosis factor-α, interleukin-10 and insulin in tissues

[0048] 1 gram of tissue was taken by wet weight, 9 ml of phosphate buffer (pH 7.4) was added, homogenized, centrifuged at 5000 rpm, and the supernatant was taken. The concentrations of interleukin-6, tumor necrosis factor-α and interleukin-10 were analyzed by ELISA kit; the insulin ELISA kit was used to measure the insulin level in the pancreas.

[0049] Application Example 1

[0050] The model mice were fed according to the modeling experiment, and 6 mice were selected in each group. The administration time, administration method and daily dosage of each group were as follows:

[0051] Interleukin-2 + metformin combined group: Kunming mice were given 150 mg / kg metformin by gavage every day; Kunming mice were injected with 25,000 IU of interleukin-2 by subcutaneous injection every other day, and interleukin-2 and metformin were administered simultaneously as required;

[0052] Model control group: compared with the interleukin-2 + metformin combination group, the same dose of normal saline was injected subcutaneously;

[0053] Blank control group: compared with the interleukin-2 + metformin combination group, the same dose of normal saline was injected subcutaneously;

[0054] Metformin treatment group: Kunming mice were given 150 mg / kg metformin by oral gavage daily;

[0055] Interleukin-2 treatment group: Kunming mice were injected with 25,000 IU of interleukin-2 by subcutaneous injection every other day;

[0056] The treatment cycle is 4 weeks.

[0057] During drug treatment, fasting blood glucose of mice was measured weekly. Figure 1 As shown, after four weeks of treatment, it was found that the blood glucose level of the model control group did not change significantly during the treatment period, while the blood glucose levels of the interleukin 2 treatment group, metformin treatment group and interleukin 2 + metformin combination group continued to decrease during the treatment period, especially the blood glucose level of the interleukin 2 + metformin combination group decreased from 24.1mmol / l before treatment to 11.9mmol / l, and the blood glucose levels of 4 mice out of 6 mice were lower than the threshold for type 2 diabetes (13.9mmol / l), which means that two-thirds of the mice were close to being cured. In addition, the blood glucose level of the interleukin 2 + metformin combination group (11.9±3.5mmol / l) was significantly lower than that of the interleukin 2 treatment group (17.15±2.3mmol / l) and the metformin treatment group (16.9±1.5mmol / l) (P<0.05);

[0058] After drug treatment, an oral glucose tolerance test is performed, such as Figure 3 As shown, compared with the blood glucose area under the curve of the model control group (4839.75±260), the blood glucose area under the curve of the interleukin 2 treatment group (4125±310), the metformin treatment group (4213±263), and the interleukin 2 + metformin combination group (3823±189) were all lower than that of the model control group, and the glucose tolerance of the mice was improved. The blood glucose area under the curve of the interleukin 2 + metformin combination group was the smallest, but there was no significant difference with the interleukin 2 treatment group and the metformin treatment group (P>0.05). These results show that after drug treatment, the mice have enhanced their ability to regulate blood glucose;

[0059] After drug treatment, the insulin resistance of mice was significantly improved. Figure 5As described above, compared with the blood glucose area under the curve of the model control group (2966±250), the blood glucose area under the curve of the mice in the interleukin 2 treatment group (1579±320), the metformin treatment group (1419±304), and the interleukin 2+metformin combination group (735±104) were significantly reduced, especially the blood glucose area under the curve of the interleukin 2+metformin combination group was significantly lower than that of the monotherapy group (P<0.05), and was close to the blood glucose area under the curve of the blank control group (419±74), and insulin resistance almost returned to normal. These results show that the therapeutic effect of the combined treatment group is significantly better than that of the monotherapy group, and it shows the potential to cure type 2 diabetes in disease model mice;

[0060] After treatment, the pancreatic tumor necrosis factor-α, interleukin-6, and interleukin-10 in the blood of Kunming mice were measured and the results showed that Figure 6 and Figure 7 As shown in the figure, compared with the model control group, the levels of interleukin-6 and tumor necrosis factor-α in the blood of mice in the interleukin-2 treatment group, metformin treatment group and interleukin-2 + metformin combination group were lower than those in the model control group, and the interleukin-2 + metformin combination group was significantly lower than that in the monotherapy group (P<0.05). These results indicate that the combined treatment of interleukin-2 and metformin more effectively reduced the level of systemic inflammation in mice, thereby more effectively improving insulin resistance; while the concentration of interleukin-10 in the blood of mice in the interleukin-2 treatment group, metformin treatment group and interleukin-2 + metformin combination group was higher than that in the model control group ( Figure 8 ), the interleukin-2+metformin combination group increased the most, but the degree of increase was not significantly different from that of the single-drug treatment group (P>0.05), indicating that the combined use of interleukin-2 and metformin enhanced the ability of mice to inhibit inflammation;

[0061] like Figure 9-11 As shown, after treatment, the levels of tumor necrosis factor α and interleukin 6 in the pancreas decreased, and the interleukin 6 level in the interleukin 2 + metformin combination group was significantly lower than that in the interleukin 2 treatment group and the metformin treatment group (P<0.05), while the concentration of interleukin 10 in the pancreas of mice in the interleukin 2 treatment group, the metformin treatment group and the interleukin 2 + metformin combination group increased compared with the model control group, and the interleukin 2 + metformin combination group increased the most, indicating that the interleukin 2 + metformin combination group more effectively reduced the level of pancreatic inflammation in type 2 diabetic Kunming mice than the interleukin 2 treatment group and the metformin treatment group, enhanced the pancreas' ability to inhibit inflammation, and was more conducive to restoring the function of the mouse pancreas;

[0062] Analysis of blood insulin levels found that Fig.15As shown, after treatment with interleukin-2, metformin and interleukin-2 + metformin, the insulin levels of each group were higher than those of the model control group (93.3 mU / L) to varying degrees, and the blood insulin level of the interleukin-2 + metformin group (100.7 mU / L) was higher than that of the interleukin-2 group (97.9 mU / L) and the metformin group (95.9 mU / L).

[0063] Analysis of pancreatic insulin levels revealed that Fig.16 As shown in the data, after treatment with the interleukin-2 treatment group, the metformin treatment group and the interleukin-2 + metformin combination group, the pancreatic insulin levels of each group were higher than that of the model control group (40.2 mU / L), and the pancreatic insulin level of the interleukin-2 + metformin combination group (52.9 mU / L) was higher than that of the interleukin-2 treatment group (42.3 mU / L) and the metformin treatment group (48.2 mU / L), indicating that the pancreatic function was improved after treatment and more insulin could be secreted.

[0064] Application Example 2

[0065] Compared with Application Example 1, the differences are the administration time, administration method and daily dosage of each group, as follows:

[0066] Interleukin-2 + metformin combined group: Kunming mice were given 100 mg / kg metformin by oral gavage every day; Kunming mice were injected with 5000 IU of interleukin-2 by subcutaneous injection every other day, and interleukin-2 and metformin were administered simultaneously as required;

[0067] Model control group: compared with the interleukin-2 + metformin combination group, the same dose of normal saline was injected subcutaneously;

[0068] Blank control group: compared with the interleukin-2 + metformin combination group, the same dose of normal saline was injected subcutaneously;

[0069] Metformin treatment group: Kunming mice were given 100 mg / kg metformin by oral gavage daily;

[0070] Interleukin-2 treatment group: Kunming mice were injected with 5000 IU of interleukin-2 by subcutaneous injection every other day;

[0071] The treatment cycle is 4 weeks.

[0072] During the treatment period, the fasting blood glucose of mice was measured weekly. After four weeks of treatment, it was found that the blood glucose level of the model control group did not change significantly during the treatment period, while the blood glucose levels of the interleukin 2 treatment group, metformin treatment group and interleukin 2 + metformin combination group continued to decrease during the treatment period, especially the blood glucose level of the interleukin 2 + metformin combination group decreased from 22.9 ± 2.9 mmol / l before treatment to 12.5 ± 3.2 mmol / l. The blood glucose levels of 3 mice out of 6 mice were lower than the threshold for type 2 diabetes (13.9 mmol / l), which means that half of the mice were close to being cured. In addition, the blood glucose level of the interleukin 2 + metformin combination group was significantly lower than the interleukin 2 treatment group (17.2 ± 3.2 mmol / l) and the metformin treatment group (17.8 ± 2.4 mmol / l) (P < 0.05);

[0073] After the drug treatment, an oral glucose tolerance test was performed, and it was found that compared with the blood glucose area under the curve of the model control group (4923.35±231), the blood glucose area under the curve of the interleukin 2 treatment group (4215±240), the metformin treatment group (4484±223) and the interleukin 2 + metformin combination group (3734±129) were all lower than that of the model control group, and the glucose tolerance of the mice was improved. The blood glucose area under the curve of the interleukin 2 + metformin combination group was the smallest, but there was no significant difference with the interleukin 2 treatment group and the metformin treatment group (P>0.05). These results show that after drug treatment, the mice have enhanced their ability to regulate blood glucose. After the drug treatment, insulin resistance was significantly improved. Compared with the blood glucose area under the curve of the model control group (2834±195), the blood glucose area under the curve of the mice in the interleukin 2 treatment group (1463±297), metformin treatment group (1567±292) and interleukin 2 + metformin combination group (677±113) was significantly reduced, especially the blood glucose area under the curve of the interleukin 2 + metformin combination group was significantly lower than that of the single drug treatment group (P<0.05), and was close to the blood glucose area under the curve of the blank control group (426±74), and insulin resistance almost returned to normal. These results show that the therapeutic effect of the interleukin 2 + metformin combination group is significantly better than that of the single drug treatment group, and it shows the potential to cure type 2 diabetes in sick mice.

[0074] Application Example 3

[0075] Compared with Application Example 1, the differences are the administration time, administration method and daily dosage of each group, as follows:

[0076] Interleukin-2 + metformin combined group: Kunming mice were given 50 mg / kg metformin by gavage every day; Kunming mice were injected with 2000 IU of interleukin-2 by subcutaneous injection every other day, and interleukin-2 and metformin were administered simultaneously as required;

[0077] Model control group: compared with the interleukin-2 + metformin combination group, the same dose of normal saline was injected subcutaneously;

[0078] Blank control group: compared with the interleukin-2 + metformin combination group, the same dose of normal saline was injected subcutaneously;

[0079] Metformin treatment group: Kunming mice were given 50 mg / kg metformin by oral gavage daily;

[0080] Interleukin-2 treatment group: Kunming mice were injected with 2000 IU of interleukin-2 by subcutaneous injection every other day;

[0081] The treatment cycle is 4 weeks.

[0082] During the treatment period, the fasting blood glucose of mice was measured weekly. After the treatment cycle, it was found that the blood glucose level of the model control group did not change significantly during the treatment period, while the blood glucose levels of the interleukin 2 treatment group, metformin treatment group and interleukin 2 + metformin combination group continued to decrease during the treatment period, especially the blood glucose level of the interleukin 2 + metformin combination group decreased from 21.5 ± 3.4 mmol / l before treatment to 15.1 ± 2.7 mmol / l. The blood glucose levels of 2 mice out of 6 mice were lower than the threshold for type 2 diabetes (13.9 mmol / l), which means that one-third of the mice were close to being cured. In addition, the blood glucose level of the interleukin 2 + metformin combination group was significantly lower than that of the interleukin 2 treatment group (19.5 ± 4.1 mmol / l) and the metformin treatment group (19.1 ± 2.6 mmol / l) (P < 0.05);

[0083] After the drug treatment, oral glucose tolerance test and insulin resistance test were performed, and it was found that compared with the blood glucose area under the curve of the model control group (4943.6±195), the blood glucose area under the curve of the interleukin 2 treatment group (4167±298), the metformin treatment group (4522±345) and the interleukin 2 + metformin combination group (3975±263) were all lower than that of the model control group, and the glucose tolerance of mice was improved, and the blood glucose area under the curve of the interleukin 2 + metformin combination group was the smallest, but there was no significant difference compared with the interleukin 2 treatment group and the metformin treatment group (P>0.05). These results show that after drug treatment, the mice's ability to regulate blood glucose is enhanced, and the interleukin 2 + metformin combination group has better improvement;

[0084] After the drug treatment, insulin resistance was significantly improved. Compared with the blood glucose area under the curve of the model control group (3106±250), the blood glucose area under the curve of the mice in the interleukin 2 treatment group (1852±293), metformin treatment group (1622±285) and interleukin 2 + metformin combination group (867±153) was significantly reduced, especially the blood glucose area under the curve of the interleukin 2 + metformin combination group was significantly lower than that of the single drug treatment group (P<0.05), and was close to the blood glucose area under the curve of the blank control group (475±81), and insulin resistance almost returned to normal. These results show that the therapeutic effect of the interleukin 2 + metformin combination group is significantly better than that of the single drug treatment group, and shows the potential to cure type 2 diabetes in model mice.

[0085] Oral administration of interleukin-2 can also achieve basically equivalent technical effects.

[0086] In summary, the present invention provides a combined drug for treating diabetes, which includes metformin and interleukin 2. The combination of the two can significantly and effectively reduce the blood sugar level of type 2 diabetic mice, improve insulin resistance, and the insulin sensitivity is close to that of normal mice. It can more effectively reduce the levels of pro-inflammatory cytokines IL-6 and TNF-α in the blood of type 2 diabetic mice, increase the level of anti-inflammatory cytokine IL-10, and more effectively reduce the level of inflammation in mice and enhance the ability to inhibit inflammation. Compared with interleukin 2 and metformin monotherapy, interleukin 2 and metformin as a combined drug for treating diabetes can more effectively reduce the level of inflammation in type 2 diabetic mice when the drug dosage is reduced, improve insulin resistance, restore pancreatic function, and enhance blood sugar metabolism. The combination of interleukin 2 and metformin can more effectively treat type 2 diabetes in mice with the advantage of low doses.

[0087] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. Use of a combined drug in the preparation of a drug for treating type 2 diabetes, characterized in that: The combined drug includes metformin and interleukin-2.

2. Use of the combined drug according to claim 1 in the preparation of a drug for treating type 2 diabetes, characterized in that: The combination drug also includes a pharmaceutically acceptable excipient.

3. The combined drug according to claim 2 is used in the preparation of a drug for treating type 2 diabetes, characterized in that: The pharmaceutically acceptable excipient is selected from at least one of a diluent, a binder, a lubricant or a dispersant.

4. Use of the combined drug according to claim 1 in the preparation of a drug for treating type 2 diabetes, characterized in that: The metformin is taken orally daily, and the interleukin-2 is taken by subcutaneous injection or orally at intervals of one day.

5. Use of the combined drug according to claim 1 or 4 in the preparation of a drug for treating type 2 diabetes, characterized in that: In mouse experiments, the daily dosage of metformin is 50 mg / kg-150 mg / kg based on the body weight of the mice.

6. Use of the combined drug according to claim 1 or 4 in the preparation of a drug for treating type 2 diabetes, characterized in that: In mouse experiments, the daily dosage of interleukin 2 is 2000 IU-25000 IU.

7. Use of the combined drug according to claim 6 in the preparation of a drug for treating type 2 diabetes, characterized in that: The interleukin-2 is recombinant human interleukin-2.

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