WO2021189390A1 - 一种预防/治疗2型糖尿病的药物以及用途 - Google Patents

一种预防/治疗2型糖尿病的药物以及用途 Download PDF

Info

Publication number
WO2021189390A1
WO2021189390A1 PCT/CN2020/081523 CN2020081523W WO2021189390A1 WO 2021189390 A1 WO2021189390 A1 WO 2021189390A1 CN 2020081523 W CN2020081523 W CN 2020081523W WO 2021189390 A1 WO2021189390 A1 WO 2021189390A1
Authority
WO
WIPO (PCT)
Prior art keywords
mir
mice
diabetes
21βko
medicine
Prior art date
Application number
PCT/CN2020/081523
Other languages
English (en)
French (fr)
Inventor
阮庆国
刘芮伶
贺晓珍
刘翠莲
杨浩然
Original Assignee
深圳先进技术研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳先进技术研究院 filed Critical 深圳先进技术研究院
Priority to PCT/CN2020/081523 priority Critical patent/WO2021189390A1/zh
Publication of WO2021189390A1 publication Critical patent/WO2021189390A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/713—Double-stranded nucleic acids or oligonucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • This application relates to the field of medicine technology, in particular to a medicine for preventing/treating type 2 diabetes and its use.
  • Diabetes is the third largest non-communicable disease after cardiovascular diseases and tumors. It affects more than 300 million people worldwide. The prevention, diagnosis and treatment of diabetes and its complications are key research and development researches in the field of medicine around the world. Major direction. At present, about 90% of diabetic patients belong to type 2 diabetes T2DM. Its significant pathophysiological feature is the decrease of insulin's ability to regulate glucose metabolism (insulin resistance) and the decrease (or relative decrease) of insulin secretion caused by the defect of pancreatic ⁇ -cell function. Abnormal pancreatic ⁇ -cell function is a key factor leading to abnormal glucose tolerance in people with normal glucose metabolism and the development of abnormal glucose tolerance into T2DM, and it is also a key factor in the gradual progression and deterioration of T2DM patients.
  • hypoglycemic drugs include: sulfonylureas, glinides, GLP-1 receptor agonists, DPP-4 inhibitors, biguanides, thiazolidinediones, direct injection of insulin, etc.
  • the method of controlling blood sugar may cause the release of insulin to be unregulated by blood sugar, or the release of blood sugar does not conform to the circadian rhythm, etc.
  • the main technical problem solved by this application is to provide a medicine for preventing/treating type 2 diabetes and its use, which can target miR-21 and achieve the purpose of lowering blood sugar by promoting islet function.
  • the first aspect of the present application provides a medicine for the prevention/treatment of type 2 diabetes.
  • the active ingredient in the medicine targets miR-21 and promotes miR-21.
  • the active ingredient of the drug includes an agonist of miR-21.
  • the active ingredient of the drug includes miR-21 mimics.
  • the active ingredient of the drug includes miR-21 analogs.
  • the gene sequence in the active ingredient of the drug includes:
  • Antisense strand 3'-AUCGAAUAGUCUGACUACAACU-5'.
  • a pharmaceutically acceptable carrier for the active ingredient also includes: a pharmaceutically acceptable carrier for the active ingredient.
  • the second aspect of the present application provides a use of miR-21 agonists in the preparation of drugs for preventing/treating type 2 diabetes.
  • the gene sequence of the miR-21 agonist includes:
  • Antisense strand 3'-AUCGAAUAGUCUGACUACAACU-5'.
  • the third aspect of the present application provides the use of miR-21 mimics in the preparation of drugs for preventing/treating type 2 diabetes.
  • the fourth aspect of the present application provides a use of miR-21 analogues in the preparation of drugs for the prevention/treatment of type 2 diabetes.
  • the active ingredients in the drugs for the prevention/treatment of type 2 diabetes target miR-21, target and promote miR-21, so as to increase Glut2 in the pancreatic islets of type 2 diabetes. Expression and insulin production, and significantly reduce its blood sugar level, thereby providing new means and strategies for clinical prevention and treatment of type 2 diabetes.
  • Figure 1a is a schematic diagram of the changes in blood glucose of 3-week-old miR-21 ⁇ KO mice and WT mice over time;
  • Figure 1b is a schematic diagram of blood glucose changes in 6-week-old miR-21 ⁇ KO mice and WT mice over time;
  • Figure 1c is a schematic diagram of blood glucose changes in 7-week-old miR-21 ⁇ KO mice and WT mice over time;
  • Figure 1d is a schematic diagram of changes in blood glucose of 10-week-old miR-21 ⁇ KO mice and WT mice over time;
  • Figure 1e is a schematic diagram of the changes in blood glucose of 27-week-old miR-21 ⁇ KO mice and WT mice over time;
  • Figure 2a is a comparison diagram of serum insulin content in 8-week-old miR-21 ⁇ KO mice and WT mice;
  • Figure 2b is a comparison diagram of in vitro insulin secretion between 8-week-old miR-21 ⁇ KO mice and WT mice;
  • Figure 3a is a schematic diagram of the expression levels of related Gluts in miR-21 ⁇ KO mice and WT mice;
  • Figure 3b is a schematic diagram of Glut2 fluorescence detection in miR-21 ⁇ KO mice and WT mice;
  • Figure 3c is a schematic diagram of the statistical results of Glut2 in miR-21 ⁇ KO mice and WT mice;
  • Figure 3d is a schematic diagram of the detection results of Glut2 protein levels in miR-21 ⁇ KO mice and WT mice;
  • Figure 4a is a schematic diagram of the weight control of 7-week-old WT and miR-21 ⁇ KO mice
  • Figure 4b is a schematic diagram of the weight control of 27-week-old WT and miR-21 ⁇ KO mice;
  • Figure 4c is a schematic diagram of blood glucose control in 7-week-old WT and miR-21 ⁇ KO mice;
  • Figure 4d is a schematic diagram of blood glucose control in 27-week-old WT and miR-21 ⁇ KO mice;
  • Figure 5a is a schematic diagram of immunofluorescence staining of 7-week-old WT and miR-21 ⁇ KO mice;
  • Figure 5b is a schematic diagram of immunofluorescence staining of 27-week-old WT and miR-21 ⁇ KO mice;
  • Figure 5c is a comparison diagram of the number of ⁇ cells in 7-week-old WT and miR-21 ⁇ KO mice;
  • Figure 5d is a comparison diagram of the size of ⁇ cells in 7-week-old WT and miR-21 ⁇ KO mice;
  • Figure 5e is a comparison diagram of the number of ⁇ cells in 27-week-old WT and miR-21 ⁇ KO mice;
  • Figure 5f is a comparison diagram of the ⁇ cell size of 27-week-old WT and miR-21 ⁇ KO mice;
  • Figure 6a is a schematic diagram of the detailed process of miR-21 agonist or NC treatment
  • Figure 6b is a schematic diagram of detecting blood glucose levels at different time points
  • Figure 7a is a comparison diagram of the expression level of miR-21 agonist and Glut2 after NC treatment
  • Figure 7b is a comparison diagram of the expression levels of miR-21 agonist and Glut2 and protein after NC treatment;
  • Figure 7c is a comparison diagram of insulin content after treatment with miR-21 agonist and NC;
  • Figure 8a is a schematic diagram of the results of measuring body weight at different time points
  • Figure 8b is a schematic diagram of the results of TG, TCHO, HDL-C, and LDL-C in mouse serum after the mice were sacrificed on the 11th day.
  • Type 2 diabetes T2DM also known as non-insulin-dependent diabetes, is a type of disease caused by insulin resistance and relatively insufficient insulin secretion. The importance of these two factors is different in different patients at different stages of the disease, from the main manifestation of insulin resistance with relatively insufficient insulin secretion to the main manifestation of insufficient insulin secretion with insulin resistance. Insulin resistance initiates the onset of T2DM, but normal pancreatic islet function or otherwise is the determinant of whether T2DM occurs.
  • this application provides a drug for the prevention/treatment of type 2 diabetes.
  • the active ingredient in the drug targets miR-21 and targets and promotes miR-21 to increase the amount of pancreatic islets in type 2 diabetes.
  • the active ingredient of the drug includes an agonist of miR-21; or, the active ingredient of the drug includes miR-21 mimics; or, the active ingredient of the drug includes miR-21 analogs.
  • miR-21 agonists or mimics or analogs can be artificially synthesized, and their effects are all to increase the level of miR-21, which can bind to the same site, but the form or modification is different.
  • the special chemical modification is for easier entry into the body , And not easily degraded, can play a stable role in the body.
  • miR-21 agonists or mimics or analogues can rapidly reduce the blood sugar of type 2 diabetic mice in the test, and provide new means and strategies for clinical prevention and treatment of type 2 diabetes; and miR-
  • the agonist or mimetics or the like of 21 has a small molecular weight, a simple structure, and a convenient way of administration.
  • gene sequences in the active ingredients of the above-mentioned drugs include:
  • Sense chain 5'-UAGCUUAUCAGACUGAUGUUGA-3' (SEQ ID NO.1);
  • Antisense strand 3'-AUCGAAUAGUCUGACUACAACU-5' (SEQ ID NO.2).
  • the above-mentioned drugs also include a pharmaceutically acceptable carrier for the active ingredient.
  • a pharmaceutically acceptable carrier for the active ingredient for example, inert diluents, fillers, water, etc.
  • the above-mentioned drugs may also contain additional ingredients, such as flavoring agents, binders, and the like.
  • the effective dose of the above-mentioned drugs depends on the patient's species, gender, weight, age, medical condition, route of administration, and the severity of the condition to be treated. Skilled physicians can easily determine and prescribe effective doses of drugs for disease prevention/treatment.
  • the above-mentioned medicines may also contain other active ingredients of medicines that help prevent/treat type 2 diabetes.
  • the medicine for preventing/treating type 2 diabetes in this embodiment includes at least two active components, namely the first active component and the second active component, wherein the first active component is the above-mentioned miR-21 agonist Or mimetics or the like, the second active component is other effective ingredients that help prevent/treat type 2 diabetes.
  • the first active component and the carrier can be formed by a conventional formulation process to form a first formulation
  • the second active component and carrier can be formed by a conventional formulation process to form a second formulation, and the patient takes the above-mentioned first formulation in turn.
  • the second preparation can be formed by a conventional formulation process to form a second formulation
  • the first active component, the second active component, and the carrier can be formed into a third preparation using conventional preparation techniques, and the patient takes the above-mentioned third preparation.
  • the effective dose ratio of the above-mentioned first active component and the second active component is 1:1, 2:1, 1:2, etc. The effective dose ratio can be adjusted by the physician according to the actual situation, which is not limited in this application .
  • This application also provides the use of a miR-21 agonist in the preparation of a medicine for preventing/treating type 2 diabetes.
  • the miR-21 agonist can increase the level of miR-21.
  • Experimental studies have shown that the above-mentioned miR-21 agonist can quickly reduce blood sugar in type 2 diabetic mice, providing a new method for clinical prevention and treatment of type 2 diabetes.
  • strategy and the agonist of miR-21 has a small molecular weight, a simple structure and a convenient way of administration.
  • the chemically modified miR-21 agonist has high stability and can function stably in vivo.
  • the gene sequence of miR-21 agonist includes:
  • Antisense strand 3'-AUCGAAUAGUCUGACUACAACU-5'.
  • This application also provides a use of miR-21 mimics in the preparation of drugs for the prevention/treatment of type 2 diabetes.
  • the miR-21 mimic can increase the level of miR-21.
  • Experimental studies have shown that the miR-21 mimic can quickly reduce blood sugar in type 2 diabetic mice, providing a new method for clinical prevention and treatment of type 2 diabetes. And strategy; and the miR-21 mimic has a small molecular weight, a simple structure and a convenient way of administration.
  • This application also provides a use of miR-21 analogues in the preparation of medicines for preventing/treating type 2 diabetes.
  • the miR-21 analog can increase the level of miR-21.
  • Experimental studies have shown that the miR-21 analog can quickly reduce blood sugar in type 2 diabetic mice, providing a new method for clinical prevention and treatment of type 2 diabetes. And strategy; and miR-21 analogues have a small molecular weight, simple structure and convenient way of administration.
  • miR-21 agonists or analogs or mimics provide an effective reference for the prevention/treatment of type 2 diabetes.
  • insulin resistance is caused by a pathological increase in the level of factors in the body that interfere with insulin signaling.
  • IR insulin receptors
  • it is more common in overweight or obese patients. Due to the reduced or defective IR number on the patient's cell membrane, insulin cannot fully exert its normal physiological effects, resulting in insulin resistance, and eventually T2DM.
  • Insulin is a hormone involved in metabolic regulation produced by ⁇ cells in response to increased blood sugar. Long-term chronic hyperglycemia (glycotoxicity) and hyperlipidemia (lipotoxicity) can lead to impaired ⁇ cell function.
  • miRNA is a type of single-stranded RNA molecule with a length of 21-25 nucleotides. It was originally found in eukaryotes and is a type of endogenous non-coding RNA that is highly conserved among different species. miRNA specifically binds to messenger ribonucleic acid (mRNA) to inhibit post-transcriptional gene expression and play an important role in regulating the cell cycle and the timing of biological development. Usually one miRNA can regulate dozens or even hundreds of genes. So far, thousands of human miRNAs have been discovered. According to preliminary estimates, they control 50-70% of human gene expression, but currently there are only a few miRNAs. The function has been confirmed. Among them, miR-21 is one of the human miRNAs discovered earlier.
  • mRNA messenger ribonucleic acid
  • miR-21 is closely related to tumorigenesis. It was originally found to be overexpressed in a series of solid tumors (including breast, lung, colon, stomach and pancreas), so miR-21 is closely related to tumorigenesis. However, in recent years, there has been no research on miR-21 in type 2 diabetes.
  • pancreatic ⁇ -cells of 3 weeks, 6 weeks, 7 weeks, 10 weeks, and 27 weeks to specifically knock out miR-21 (miR- 21 ⁇ KO) mice and wild-type (WT) mice (that is, miR-21 is not specifically knocked out in pancreatic ⁇ cells).
  • Figure 1a is a schematic diagram of the blood glucose changes of miR-21 ⁇ KO mice and WT mice aged 3 weeks
  • Figure 1b is a 6-week miR Schematic diagram of blood glucose changes over time in -21 ⁇ KO mice and WT mice
  • Figure 1c is a schematic diagram of blood glucose changes over time in 7-week-old miR-21 ⁇ KO mice and WT mice
  • Figure 1d is a schematic diagram of 10-week-old miR-21 ⁇ KO mice.
  • Figure 1e is a schematic diagram of the changes of blood glucose over time in miR-21 ⁇ KO mice and WT mice of 27 weeks old.
  • the results of the 2-hour blood glucose tolerance test show that the blood glucose change trend within 2 hours of the injection of glucose solution is: increase within 0-15 minutes, and decrease to fasting level within 15 minutes-2 hours.
  • the blood glucose of miR-21 ⁇ KO mice of 3 weeks, 6 weeks, 7 weeks, 10 weeks, and 27 weeks of age dropped significantly more slowly in 15 minutes to 90 minutes than WT mice, and miR-21 ⁇ KO mice of 27 weeks decreased in 90 minutes. It also showed a trend of slowing down within 120 minutes.
  • the above results indicate that the blood glucose tolerance maintenance ability of miR-21 ⁇ KO mice is defective, and the glucose tolerance ability is significantly reduced.
  • Figure 2a shows the comparison of serum insulin levels in 8-week-old miR-21 ⁇ KO mice and WT mice.
  • Figure 2b shows the 8-week-old miR-21 ⁇ KO mice and WT mice in vitro. Insulin secretion comparison chart. It can be seen from Figure 2a that mice about 8 weeks old were tested for in vivo blood glucose tolerance. Serum was collected for 30 minutes, and the insulin in the serum was detected by ELISA. The results showed that at 30 minutes, the serum insulin of miR-21 ⁇ KO mice The content was significantly lower than that of the WT group.
  • pancreatic islets in the process of glucose-stimulating pancreatic islets to produce insulin, the first step that occurs is that glucose enters pancreatic ⁇ -cells through glucose transporters (Gluts), so we tested the mRNA expression of five major Gluts.
  • the pancreatic islets of WT and miR-21 ⁇ KO mice were separated and detected by real-time quantitative PCR to obtain the expression levels of five Gluts in WT and miR-21 ⁇ KO mice.
  • Figure 3a shows miR-21 ⁇ KO mice and WT mice. Schematic diagram of related Gluts expression levels.
  • FIG. 3b is a schematic diagram of Glut2 fluorescence detection in miR-21 ⁇ KO mice and WT mice
  • Figure 3c is a schematic diagram of Glut2 statistical results in miR-21 ⁇ KO mice and WT mice. It can be seen from the figure that immunofluorescence was used to detect ⁇ -cell Glut2 in situ. Fluorescence and statistical results showed that the expression of Glut2 in the pancreatic islets of miR-21 ⁇ KO mice was significantly lower than that of the WT group.
  • FIG. 3d is a schematic diagram of the detection results of Glut2 protein levels in miR-21 ⁇ KO mice and WT mice.
  • western blot was used to detect the level of Glut2 protein in the pancreatic islets of mice, and the results showed that the level of Glut2 protein in the pancreatic islets of miR-21 ⁇ KO mice was significantly lower than that in the WT group. That is, the above results indicate that the absence of miR-21 in pancreatic ⁇ cells leads to a decrease in the expression of Glut2. Since Glut2 plays a very important role in glucose metabolism and insulin secretion, the above results suggest that miR-21 may promote glucose-stimulated insulin secretion by promoting the expression of Glut2.
  • miR-21 agonists are a double-stranded small RNA that has been specially labeled and chemically modified, and it modulates the biological function of the target gene by simulating endogenous miRNA.
  • db/db mice type 2 diabetic mouse model
  • NC-agonist is a long gene fragment similar to the miR-21 agonist, but it will not bind to the site and will not have an effect, and detects changes in blood sugar, body weight and lipid metabolism.
  • the specific logical process is:
  • Figures 4a-4d show that the body weight of 7-week and 27-week-old WT and miR-21 ⁇ KO mice, as well as mouse blood glucose.
  • Figures 4a-4d show that Figure 4a is the weight control of 7-week-old WT and miR-21 ⁇ KO mice Schematic diagram
  • Figure 4b is a schematic diagram of the weight control of 27-week-old WT and miR-21 ⁇ KO mice
  • Figure 4c is a schematic diagram of the blood glucose control of 7-week-old WT and miR-21 ⁇ KO mice
  • Figure 4d is a schematic diagram of the 27-week-old WT and miR-21 ⁇ KO Schematic diagram of mouse blood glucose control.
  • the results showed that the body weight and blood glucose of miR-21 ⁇ KO mice were not significantly different from those of WT mice.
  • FIG. 5a-5f Schematic diagram of immunofluorescence staining of large and small WT and miR-21 ⁇ KO mice.
  • Figure 5b is a schematic diagram of immunofluorescence staining of 27-week-old WT and miR-21 ⁇ KO mice.
  • Figure 5c shows the number of ⁇ -cells in 7-week-old WT and miR-21 ⁇ KO mice.
  • Comparison chart, Fig. 5d is a comparison chart of the ⁇ cell size of 7-week-old WT and miR-21 ⁇ KO mice, Fig.
  • FIG. 5e is a comparison chart of the ⁇ -cell number of 27-week-old WT and miR-21 ⁇ KO mice
  • Fig. 5f is a 27-week-old Comparison of ⁇ cell size between WT and miR-21 ⁇ KO mice. The results showed that after knocking out the ⁇ -cell miR-21, there was no significant difference in the size and number of ⁇ -cells between 7-week and 27-week-old mice, indicating that the knock-out of ⁇ -cell miR-21 did not affect the development of mouse pancreatic islets.
  • FIG. 6a is a schematic diagram of the detailed process of miR-21 agonist or NC treatment.
  • Figure 6b is a schematic diagram of detecting blood glucose levels at different time points. The results show that miR-21 agonist treatment can effectively reduce blood glucose levels in type 2 diabetic mice.
  • FIG. 7a shows the miR-21 agonist and Comparison of the expression levels of Glut2 after NC treatment.
  • Figure 7b is a comparison diagram of the expression levels of miR-21 agonist and Glut2 and protein after NC treatment. Serum was taken from the sacrificed mice to detect insulin levels. The results are shown in the figure. 7c, Fig. 7c is a comparison diagram of insulin content after miR-21 agonist and NC treatment. The results show that treatment with miR-21 agonists can increase insulin production.
  • Figure 8a is a schematic diagram of the results of measuring body weight at different time points. The results show that the body weight of the miR-21 agonist treatment group is not significantly different from that of the NC group.
  • Figure 8b is a schematic diagram of the results of TG, TCHO, HDL-C, and LDL-C in the serum of the mice after the mice were sacrificed on the 11th day.
  • TG is triglycerides
  • TCHO is total cholesterol
  • HDL-C high-density lipoprotein cholesterol
  • LDL-C low-density lipoprotein cholesterol
  • the above realization process showed that the blood glucose of mice was significantly reduced after miR-21 agonist treatment, but body weight and lipid metabolism did not change significantly.
  • the blood insulin level of mice was significantly higher than that of the NC group, and the mRNA and protein expression of Glut2 in the pancreas were significantly increased compared with the control group. This indicates that miR-21 agonists may increase the expression of Glut2. , Which produces more insulin and eventually leads to a decrease in blood sugar.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

提供了一种预防/治疗2型糖尿病的药物以及用途，所述药物中的活性成分以miR-21为靶点，靶向促进miR-21；达到促进胰岛功能达到降低血糖的目的。

Description

一种预防/治疗2型糖尿病的药物以及用途 技术领域
本申请涉及药物技术领域，特别是涉及一种预防/治疗2型糖尿病的药物以及用途。
背景技术
糖尿病是居心血管疾病和肿瘤之后的第三大非传染性疾病，在全球范围内影响着三亿多人，围绕糖尿病及其并发症展开的相关的预防、诊断和治疗是世界各国医药领域研发攻关的重大方向。目前，约90％的糖尿病病人属于2型糖尿病T2DM，其显著的病理生理学特征为胰岛素调控葡萄糖代谢能力的下降(胰岛素抵抗)伴随胰岛β细胞功能缺陷所导致的胰岛素分泌减少(或相对减少)。胰岛β细胞功能的异常是导致糖代谢正常人群出现糖耐受异常和糖耐受异常人群发展成为T2DM的关键因素，也是T2DM患者病情逐渐进展和恶化的关键因素。
目前治疗T2DM的方式包括：降糖药物治疗、代谢手术治疗和胰岛移值。其中，降糖药物包括：磺脲类、格列奈类、GLP-1受体激动剂，DPP-4抑制剂、双胍类、噻唑烷二酮类、直接注射胰岛素等，该降糖药物治疗主要是控制患者的血糖水平，需长期坚持使用，影响患者的生活质量。且控制血糖的方法可能会引起胰岛素释放不受血糖调控，或者血糖释放不符合生理节律等，患者的血糖往往波动较大，且容易引起低血糖晕厥等较大药物不良反应。代谢手术需要多学科共同协作，进行术前、术中及术后的全程管理，疗效存在个体性差异以及手术的有效性和安全性问题的控制。胰岛移植可以延缓患者对胰岛素注射的依赖，但不能根本解决胰岛细胞的抗体、机体自身的排异反应及免疫抑制剂对β细胞本身的毒害作用，同时同源胰岛来源困难、移植后胰岛存活率低、免疫抑制剂的副作用及移植成本高昂。
因此，有必要开发出一种新型的降血糖药物，为临床预防和治疗2型糖尿病提供新的手段和策略。
发明内容
本申请主要解决的技术问题是提供一种预防/治疗2型糖尿病的药物以及用 途，能够以miR-21为靶点，通过促进胰岛功能达到降低血糖的目的。
为了解决上述问题，本申请第一方面提供了一种用于预防/治疗2型糖尿病的药物，所述药物中的活性成分以miR-21为靶点，靶向促进miR-21。
其中，所述药物的活性成分包括miR-21的激动剂。
其中，所述药物的活性成分包括miR-21的模拟物。
其中，所述药物的活性成分包括miR-21的类似物。
其中，所述药物的活性成分中的基因序列包括：
正义链:5'-UAGCUUAUCAGACUGAUGUUGA-3'；
反义链:3'-AUCGAAUAGUCUGACUACAACU-5'。
其中，还包括：医药上可接受的所述活性成分的载体。
为了解决上述问题，本申请第二方面提供了一种miR-21的激动剂在预防/治疗2型糖尿病的药物制备中的用途。
其中，所述miR-21的激动剂的基因序列包括：
正义链:5'-UAGCUUAUCAGACUGAUGUUGA-3'；
反义链:3'-AUCGAAUAGUCUGACUACAACU-5'。
为了解决上述问题，本申请第三方面提供了一种miR-21的模拟物在预防/治疗2型糖尿病的药物制备中的用途。
为了解决上述问题，本申请第四方面提供了一种miR-21的类似物在预防/治疗2型糖尿病的药物制备中的用途。
区别于现有技术情况，本申请所提供的用于预防/治疗2型糖尿病的药物中的活性成分以miR-21为靶点，靶向促进miR-21，以增加2型糖尿病胰岛中Glut2的表达和胰岛素的产生，并显著降低其血糖水平，从而为临床预防和治疗2型糖尿病提供新的手段和策略。
【附图说明】
为了更清楚地说明本申请实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图，其中：
图1a为3周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图；
图1b为6周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图；
图1c为7周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图；
图1d为10周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图；
图1e为27周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图；
图2a为8周大小的miR-21βKO小鼠以及WT小鼠体内血清胰岛素含量对比图；
图2b为8周大小的miR-21βKO小鼠以及WT小鼠体外胰岛素分泌对比图；
图3a为miR-21βKO小鼠以及WT小鼠相关Gluts表达水平示意图；
图3b为miR-21βKO小鼠以及WT小鼠中Glut2荧光检测示意图；
图3c为miR-21βKO小鼠以及WT小鼠中Glut2统计结果示意图；
图3d为miR-21βKO小鼠以及WT小鼠中Glut2蛋白水平检测结果示意图；
图4a为7周大小的WT和miR-21βKO小鼠体重对照示意图；
图4b为27周大小的WT和miR-21βKO小鼠体重对照示意图；
图4c为7周大小的WT和miR-21βKO小鼠血糖对照示意图；
图4d为27周大小的WT和miR-21βKO小鼠血糖对照示意图；
图5a为7周大小的WT和miR-21βKO小鼠免疫荧光染色示意图；
图5b为27周大小的WT和miR-21βKO小鼠免疫荧光染色示意图；
图5c为7周大小的WT和miR-21βKO小鼠β细胞数目对比图；
图5d为7周大小的WT和miR-21βKO小鼠β细胞大小对比图；
图5e为27周大小的WT和miR-21βKO小鼠β细胞数目对比图；
图5f为27周大小的WT和miR-21βKO小鼠β细胞大小对比图；
图6a为miR-21激动剂或NC处理的详细过程示意图；
图6b为在不同的时间点检测血糖水平示意图；
图7a为miR-21的激动剂和NC处理后的Glut2的表达水平对比图；
图7b为miR-21的激动剂和NC处理后的Glut2和蛋白的表达水平对比图；
图7c为miR-21的激动剂和NC处理后的胰岛素含量对比图；
图8a为在不同的时间点测量体重的结果示意图；
图8b为在第11天处死小鼠后小鼠血清中TG、TCHO、HDL-C、LDL-C的结果示意图。
【具体实施方式】
下面将结合本申请实施例中的附图，对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，均属于本申请保护的范围。
2型糖尿病T2DM又称为非胰岛素依赖性糖尿病，是由胰岛素抵抗和胰岛素分泌相对不足而引起的一类疾病。不同患者在疾病的不同阶段这两种因素的重要性有所差别，从主要表现为胰岛素抵抗伴胰岛素分泌相对不足到主要表现为胰岛素分泌不足伴胰岛素抵抗。胰岛素抵抗启动了T2DM的发病，但是胰岛功能正常与否则是T2DM是否发生的决定因素。
为了提高胰岛功能，本申请提供了一种用于预防/治疗2型糖尿病的药物，该药物中的活性成分以miR-21为靶点，靶向促进miR-21，以增加2型糖尿病胰岛中Glut2的表达和胰岛素的产生，并显著降低其血糖水平，从而为临床预防和治疗2型糖尿病提供新的手段和策略。
在一个实施例中，药物的活性成分包括miR-21的激动剂；或者，药物的活性成分包括miR-21的模拟物；或者，药物的活性成分包括miR-21的类似物。上述miR-21的激动剂或模拟物或类似物可人工合成，其作用均为增加miR-21的水平，能够结合同一个位点，只是形式或修饰不同，特殊化学修饰是为了更容易进入体内，且不容易降解，可以在体内稳定地发挥作用。经试验研究表明，上述miR-21的激动剂或模拟物或类似物在试验中可快速降低2型糖尿病小鼠的血糖，为临床预防和治疗2型糖尿病提供新的手段和策略；且miR-21的激动剂或模拟物或类似物的分子量较小，结构简单，给药方式方便。
进一步，上述药物的活性成分(例如，miR-21的激动剂或模拟物或类似物)中的基因序列包括：
正义链:5'-UAGCUUAUCAGACUGAUGUUGA-3'(SEQ ID NO.1)；
反义链:3'-AUCGAAUAGUCUGACUACAACU-5'(SEQ ID NO.2)。
此外，上述药物还包括医药上可接受的活性成分的载体。例如，惰性稀释剂、填充剂、水等。若需要，上述药物还可包含另外的成分，例如，调味剂、 粘合剂等。
在本申请中，上述药物的有效剂量取决于患者的物种、性别、体重、年龄、医学状况、给药途径以及所治疗病症的严重程度。熟练的医师可以很容易地确定和规定预防/治疗疾病的药物有效剂量。
当然，在其他实施例中，上述药物中也可包含其他有助于预防/治疗2型糖尿病的药物的有效成分。例如，本实施例中预防/治疗2型糖尿病的药物包括至少两种活性组分，分别为第一活性组分和第二活性组分，其中第一活性组分为上述miR-21的激动剂或模拟物或类似物，第二活性组分为其他有助于预防/治疗2型糖尿病的有效成分。在本实施例中，可以将第一活性组分和载体采用常规制剂工艺以形成第一制剂，将第二活性组分和载体采用常规制剂工艺以形成第二制剂，患者依次服用上述第一制剂和第二制剂。或者，可以将第一活性组分、第二活性组分和载体采用常规制剂工艺以形成第三制剂，患者服用上述第三制剂。此外，上述第一活性组分和第二活性组分的有效剂量比为1:1、2:1、1:2等，该有效剂量比可由医师根据实际情况进行调整，本申请对此不作限定。
本申请又提供了一种miR-21的激动剂在预防/治疗2型糖尿病的药物制备中的用途。该miR-21的激动剂可以增加miR-21的水平，经试验研究表明，上述miR-21的激动剂可快速降低2型糖尿病小鼠的血糖，为临床预防和治疗2型糖尿病提供新的手段和策略；且miR-21的激动剂分子量较小，结构简单，给药方式方便。此外，通过化学修饰的miR-21的激动剂具有较高稳定性，可以在体内稳定地发挥作用。
在本实施例中，miR-21的激动剂的基因序列包括：
正义链:5'-UAGCUUAUCAGACUGAUGUUGA-3'；
反义链:3'-AUCGAAUAGUCUGACUACAACU-5'。
本申请又提供了一种miR-21的模拟物在预防/治疗2型糖尿病的药物制备中的用途。该miR-21的模拟物可以增加miR-21的水平，经试验研究表明，上述miR-21的模拟物可快速降低2型糖尿病小鼠的血糖，为临床预防和治疗2型糖尿病提供新的手段和策略；且miR-21的模拟物分子量较小，结构简单，给药方式方便。
本申请又提供了一种miR-21的类似物在预防/治疗2型糖尿病的药物制备中的用途。该miR-21的类似物可以增加miR-21的水平，经试验研究表明，上述miR-21的类似物可快速降低2型糖尿病小鼠的血糖，为临床预防和治疗2型糖 尿病提供新的手段和策略；且miR-21的类似物分子量较小，结构简单，给药方式方便。
下面以具体的数据来说明miR-21的激动剂或类似物或模拟物为预防/治疗2型糖尿病提供了有效的借鉴作用。
目前大多数的研究认为，胰岛素抵抗是由于干扰胰岛素信号的体内因子水平病理性升高所致。研究发现，胰岛素抵抗与胰岛素受体(insulin receptor，IR)的数目以及它们与胰岛素的亲和力有关，即IR数目越多或亲和力越强，组织对胰岛素越敏感；反之，IR数目越少或亲和力减弱，组织对胰岛素越不敏感，即组织对胰岛素产生了抵抗。临床上多见于超重或肥胖的患者，由于患者细胞膜上的IR数目减少或存在缺陷，导致胰岛素不能充分发挥其正常的生理效应，产生胰岛素抵抗，最终引起T2DM。而胰岛素是由β细胞应对血糖升高而产生的一种参与代谢调节的激素，长期慢性的高血糖(糖毒性)和高血脂(脂毒性)会导致β细胞功能受损。
miRNA是一类长度为21-25个核甘酸大小的单链RNA分子，最初是在真核生物中发现且在不同物种间高度保守的一类内源性非编码RNA。miRNA通过与信使核糖核酸(mRNA)特异性结合，从而抑制转录后基因表达，在调控细胞周期和生物体发育时序等方面发挥重要作用。通常一个miRNA可以调控数十甚至上百个基因，到目前为止，已经发现了数以千记的人类的miRNA，据初略估计它们控制了50-70％的人类基因表达，但目前只有少数miRNA的功能得到了确定。其中，miR-21是较早发现的人类miRNA之一，其作为癌基因参与转录后基因调控，在细胞的分化、增殖和凋亡等都起着重要的作用。miR-21与肿瘤发生的关系密切，它最初是被发现在一系列实体瘤中(包括乳腺、肺、结肠、胃和胰腺)过度表达，因此miR-21与肿瘤发生的关系密切。但近年来，并未有关于miR-21在2型糖尿病方面的研究。
为了研究胰岛β细胞中的miR-21在调控胰岛功能中的作用，我们构建了3周、6周、7周、10周和27周大小的胰岛β细胞特异性敲除miR-21(miR-21βKO)小鼠以及野生型(WT)小鼠(即胰岛β细胞中未特异性敲除miR-21)。
请参阅图1a、图1b、图1c、图1d和图1e，其中，图1a为3周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图、图1b为6周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图、图1c为7周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图、图1d为10周大小的miR-21 βKO小鼠以及WT小鼠血糖随时间的变化示意图、图1e为27周大小的miR-21βKO小鼠以及WT小鼠血糖随时间的变化示意图。从图中可以看出，2小时血糖耐量实验结果显示注射葡萄糖溶液2小时内血糖的变化趋势是：0-15分钟内升高，15分钟-2小时内降低至空腹水平。3周、6周、7周、10周和27周大小的miR-21βKO小鼠的血糖在15分钟-90分钟内下降显著比WT小鼠下降缓慢，且27周的miR-21βKO小鼠在90分钟-120分钟内也呈现出下降减缓的趋势。以上结果表明，miR-21βKO小鼠的血糖耐受维持能力有缺陷，糖耐受能力显著降低。
进一步，请参阅图2a-图2b，图2a为8周大小的miR-21βKO小鼠以及WT小鼠体内血清胰岛素含量对比图，图2b为8周大小的miR-21βKO小鼠以及WT小鼠体外胰岛素分泌对比图。从图2a中可以看出，约8周大小的小鼠进行体内血糖耐量实验，收集30分钟时间段的血清，ELISA检测血清中的胰岛素，结果显示在30分钟时，miR-21βKO小鼠血清胰岛素含量显著低于WT组。从图2b中可以看出，分离WT和miR-21βKO小鼠的胰岛后，在体外分别用低浓度的葡萄糖(2.8mM)和高浓度葡萄糖(16.7mM)进行刺激，结果显示在低浓度葡萄糖刺激下，两组胰岛分泌的胰岛素无明显差异，而在高浓度葡萄糖刺激下，miR-21βKO小鼠的胰岛分泌的胰岛素显著低于WT组。以上结果表明β细胞miR-21的缺失导致葡萄糖刺激下的胰岛素分泌减少，即小鼠在胰岛β细胞特异性敲除miR-21后，其胰岛的GSIS(葡萄糖刺激介导的胰岛素分泌)能力降低。
此外，葡萄糖刺激胰岛产生胰岛素过程中，第一步发生的是葡萄糖通过葡萄糖转运体(Gluts)进入胰岛β细胞，因此我们检测了5种主要Gluts的mRNA表达。分离WT和miR-21βKO小鼠的胰岛，通过实时定量PCR检测，获得WT和miR-21βKO小鼠中5种Gluts表达水平，具体请参阅图3a，图3a为miR-21βKO小鼠以及WT小鼠相关Gluts表达水平示意图。从图中可以看出，miR-21βKO小鼠胰岛中，只有Glut2的mRNA水平显著低于WT组。请参阅图3b和图3c，图3b为miR-21βKO小鼠以及WT小鼠中Glut2荧光检测示意图，图3c为miR-21βKO小鼠以及WT小鼠中Glut2统计结果示意图。从图中可以看出，用免疫荧光对β细胞Glut2进行原位检测，荧光及统计结果显示miR-21βKO小鼠胰岛中Glut2的表达显著低于WT组。请参阅图3d，图3d为miR-21βKO小鼠以及WT小鼠中Glut2蛋白水平检测结果示意图。在本实施例中，利用蛋白质 印迹法western blot对小鼠胰岛中的Glut2蛋白水平进行检测，结果显示miR-21βKO小鼠胰岛中Glut2蛋白水平显著低于WT组。即以上结果表明胰岛β细胞miR-21的缺失导致Glut2的表达降低。由于Glut2在葡萄糖代谢和胰岛素分泌过程中发挥着非常重要的作用，因此上述结果提示miR-21可能通过促进Glut2的表达来促进葡萄糖刺激介导的胰岛素分泌。
为了验证增加胰岛中miR-21是否可以增加葡萄糖刺激介导的胰岛素分泌和降低血糖水平，我们利用靶向小鼠胰腺的转染试剂向小鼠的胰腺中导入miR-21的激动剂。miR-21的激动剂是经过特殊标记和化学修饰的双链小RNA，通过模拟内源性的miRNA来调节靶基因的生物学功能。在本实验中，我们利用db/db小鼠(2型糖尿病小鼠模型)，每三天对实验组小鼠给予miR-21的激动剂进行治疗，对照组小鼠给与NC-激动剂，其中NC-激动剂是与miR-21的激动剂类似长的基因片段，但不会和位点结合，不会发生作用，并检测血糖、体重和脂代谢的变化。具体逻辑过程为：
首先，测量7周和27周大小的WT和miR-21βKO小鼠体重以及小鼠血糖，具体结果可参见图4a-4d，其中，图4a为7周大小的WT和miR-21βKO小鼠体重对照示意图，图4b为27周大小的WT和miR-21βKO小鼠体重对照示意图，图4c为7周大小的WT和miR-21βKO小鼠血糖对照示意图，图4d为27周大小的WT和miR-21βKO小鼠血糖对照示意图。结果显示miR-21βKO小鼠的体重以及血糖与WT小鼠相比无显著差异。
接着，再取7周和27周大小的WT和miR-21βKO小鼠的胰腺进行冰冻切片并进行胰岛素(insulin)的免疫荧光染色，具体结果如图5a-图5f所示，图5a为7周大小的WT和miR-21βKO小鼠免疫荧光染色示意图，图5b为27周大小的WT和miR-21βKO小鼠免疫荧光染色示意图，图5c为7周大小的WT和miR-21βKO小鼠β细胞数目对比图，图5d为7周大小的WT和miR-21βKO小鼠β细胞大小对比图，图5e为27周大小的WT和miR-21βKO小鼠β细胞数目对比图，图5f为27周大小的WT和miR-21βKO小鼠β细胞大小对比图。结果显示敲除β细胞的miR-21后，7周和27周大小的小鼠其β细胞的大小和数目无显著差异，表明β细胞miR-21的敲除不影响小鼠胰岛的发育。
再接着，一方面，对8周大小的db/db小鼠注射miR-21的激动剂或NC，请参阅图6a和图6b，图6a为miR-21的激动剂或NC处理的详细过程示意图，图6b为在不同的时间点检测血糖水平示意图。结果显示miR-21的激动剂处理 能有效地降低2型糖尿病小鼠的血糖水平。
另一方面，对8周大小的db/db小鼠注射miR-21的激动剂或NC，第11天处死小鼠，miR-21的激动剂或NC处理的详细过程可参见图6a。将处死后的小鼠取胰岛细胞检测Glut2的mRNA和蛋白的表达，结果显示miR-21的激动剂处理增加Glut2的表达，其结果参见图7a和7b，图7a为miR-21的激动剂和NC处理后的Glut2的表达水平对比图，图7b为miR-21的激动剂和NC处理后的Glut2和蛋白的表达水平对比图；将处死后的小鼠取血清检测胰岛素水平，其结果参见图7c，图7c为miR-21的激动剂和NC处理后的胰岛素含量对比图。结果显示miR-21的激动剂的处理可以增加胰岛素的产生。
再一方面，对8周大小的db/db小鼠注射miR-21的激动剂或NC，在第11天处死小鼠，miR-21的激动剂或NC处理的详细过程可参见图6a。请参阅图8a，图8a为在不同的时间点测量体重的结果示意图，结果显示miR-21激动剂处理组的体重与NC组无显著差异。请参阅图8b，图8b为在第11天处死小鼠后小鼠血清中TG、TCHO、HDL-C、LDL-C的结果示意图。其中，TG为甘油三酯、TCHO为总胆固醇、HDL-C为高密度脂蛋白胆固醇、LDL-C为低密度脂蛋白胆固醇；结果显示miR-21激动剂处理组的上述指标与NC组无显著差异。这些结果表明miR-21激动剂处理不影响小鼠的体重和脂代谢。
综上，上述实现过程显示miR-21激动剂处理后小鼠的血糖显著降低，而体重和脂代谢没有发生明显的改变。另外，miR-21激动剂处理后小鼠血液中胰岛素水平较NC组显著增升高，胰腺中Glut2的mRNA以及蛋白表达较对照组显著增加，这表明miR-21激动剂可能通过增加Glut2的表达，从而产生较多的胰岛素并最终导致血糖的降低。
以上所述仅为本申请的实施方式，并非因此限制本申请的专利范围，凡是利用本申请说明书及附图内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本申请的专利保护范围内。

Claims (10)

  1. 一种用于预防/治疗2型糖尿病的药物，其中，所述药物中的活性成分以miR-21为靶点，靶向促进miR-21。
  2. 根据权利要求1所述的药物，其中，
    所述药物的活性成分包括miR-21的激动剂。
  3. 根据权利要求1所述的药物，其中，
    所述药物的活性成分包括miR-21的模拟物。
  4. 根据权利要求1所述的药物，其中，
    所述药物的活性成分包括miR-21的类似物。
  5. 根据权利要求1-4任一项所述的药物，其中，
    所述药物的活性成分中的基因序列包括：
    正义链:5'-UAGCUUAUCAGACUGAUGUUGA-3'；
    反义链:3'-AUCGAAUAGUCUGACUACAACU-5'。
  6. 根据权利要求1所述的药物，其中，还包括：
    医药上可接受的所述活性成分的载体。
  7. 一种miR-21的激动剂在预防/治疗2型糖尿病的药物制备中的用途。
  8. 根据权利要求7所述的用途，其中，所述miR-21的激动剂的基因序列包括：
    正义链:5'-UAGCUUAUCAGACUGAUGUUGA-3'；
    反义链:3'-AUCGAAUAGUCUGACUACAACU-5'。
  9. 一种miR-21的模拟物在预防/治疗2型糖尿病的药物制备中的用途。
  10. 一种miR-21的类似物在预防/治疗2型糖尿病的药物制备中的用途。
PCT/CN2020/081523 2020-03-27 2020-03-27 一种预防/治疗2型糖尿病的药物以及用途 WO2021189390A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/081523 WO2021189390A1 (zh) 2020-03-27 2020-03-27 一种预防/治疗2型糖尿病的药物以及用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/081523 WO2021189390A1 (zh) 2020-03-27 2020-03-27 一种预防/治疗2型糖尿病的药物以及用途

Publications (1)

Publication Number Publication Date
WO2021189390A1 true WO2021189390A1 (zh) 2021-09-30

Family

ID=77889886

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/081523 WO2021189390A1 (zh) 2020-03-27 2020-03-27 一种预防/治疗2型糖尿病的药物以及用途

Country Status (1)

Country Link
WO (1) WO2021189390A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2530157A2 (en) * 2003-07-31 2012-12-05 Regulus Therapeutics, Inc Oligomeric compounds and compositions for use in modulation of small non-coding rnas
CN107083385A (zh) * 2012-04-20 2017-08-22 艾珀特玛治疗公司 产热的miRNA调节剂
CN108165546A (zh) * 2017-03-23 2018-06-15 上海立迪生物技术股份有限公司 一种miRNA生物标志物、组合物及其用途
CN110747266A (zh) * 2018-07-23 2020-02-04 深圳先进技术研究院 miR-21和miR-21拮抗剂在抑制预防/治疗1型糖尿病中的应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2530157A2 (en) * 2003-07-31 2012-12-05 Regulus Therapeutics, Inc Oligomeric compounds and compositions for use in modulation of small non-coding rnas
CN107083385A (zh) * 2012-04-20 2017-08-22 艾珀特玛治疗公司 产热的miRNA调节剂
CN108165546A (zh) * 2017-03-23 2018-06-15 上海立迪生物技术股份有限公司 一种miRNA生物标志物、组合物及其用途
CN110747266A (zh) * 2018-07-23 2020-02-04 深圳先进技术研究院 miR-21和miR-21拮抗剂在抑制预防/治疗1型糖尿病中的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN QIAN, QIU FANGFANG, ZHOU KELU, MATLOCK H. GREG, TAKAHASHI YUSUKE, RAJALA RAJU V.S., YANG YANHUI, MORAN ELIZABETH, MA JIAN-XIN: "Pathogenic Role of microRNA-21 in Diabetic RetinopathyThrough Downregulation of PPARα", DIABETES, vol. 66, no. 6, 30 June 2017 (2017-06-30), US, pages 1671 - 1682, XP055854283, ISSN: 0012-1797, DOI: 10.2337/db16-1246 *
SEKAR DURAIRAJ; VENUGOPAL BASAM; SEKAR PUNITHA; RAMALINGAM KRISHNAN: "Role of microRNA 21 in diabetes and associated/related diseases", GENE, vol. 582, no. 1, 27 January 2016 (2016-01-27), NL, pages 14 - 18, XP029441181, ISSN: 0378-1119, DOI: 10.1016/j.gene.2016.01.039 *
WU BIN; LIU WEN-WEI; HE YONG; HU YING-SONG; ZHANG ZHEN-LU: "Analysis on Related Metabolic Influencing Factors for mi R-21 Expression Levels in Type 2 Diabetic Patients", MODERN PREVENTIVE MEDICINE, vol. 42, no. 12, 25 June 2015 (2015-06-25), pages 2218 - 2222, XP009531184, ISSN: 1003-8507 *

Similar Documents

Publication Publication Date Title
US11426422B2 (en) SHP2 inhibitors and methods of use thereof
Takahashi et al. High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b
JP6861795B2 (ja) アモジアキンおよび抗糖尿薬物を有効成分として含有する糖尿病の予防または治療用薬学的組成物
Tao et al. MiR‐144 protects the heart from hyperglycemia‐induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis
Fu et al. Metformin restores electrophysiology of small conductance calcium-activated potassium channels in the atrium of GK diabetic rats
CN102921007B (zh) 防治胰岛素抵抗和糖尿病的方法和试剂
Li et al. A microRNA, mir133b, suppresses melanopsin expression mediated by failure dopaminergic amacrine cells in RCS rats
WO2021189390A1 (zh) 一种预防/治疗2型糖尿病的药物以及用途
CN111450253A (zh) 一种预防/治疗2型糖尿病的药物以及用途
US20160244755A1 (en) Treating diseases associated with pgc1-alpha by modulating micrornas mir-130a and mir-130b
CN114432333B (zh) MiR-503簇海绵在制备用于治疗2型糖尿病药物中的应用
Yang et al. Effect of Semaglutide and Empagliflozin on Pulmonary Structure and Proteomics in Obese Mice
KR101652957B1 (ko) ATF3 유전자 발현을 억제하는 신규 siRNA 및 이의 용도
US20110281852A1 (en) Pharmaceutical compositions containing berberine for treatment or prevention of weight gain and obesity associated with anti-psychotic drugs
Li et al. Decrypting the circular RNAs does a favor for us: Understanding, diagnosing and treating diabetes mellitus and its complications
US9468669B2 (en) Methods to treat dysregulated blood glucose disorders
US20220088010A1 (en) Co-Administration of inhibitors to produce insulin producing gut cells
CN112195181A (zh) MiR-29海绵在制备用于治疗2型糖尿病的药物中的应用
WO2020237803A1 (zh) Mrg15蛋白或基因作为靶点在代谢疾病治疗和预防中的应用
KR101303920B1 (ko) 프로토포르피린 ＩＸ 구조를 갖는 화합물을 포함하는, 저산소상태 유도성인자1α 또는 혈관내피세포성장인자 과다 발현으로 기인하는 질병의 예방 및 치료에 유용한 조성물
CN109893655B (zh) miR-327抑制剂和/或FGF10促进剂在预防和/或治疗糖尿病的药物中的应用
US20160138017A1 (en) Microrna and uses in brown fat differentiation
EP3456824A1 (en) Obesity-related disease therapeutic agent by hepatic secretory metabolic regulator inhibitory action
WO2022061962A1 (zh) 一种l型氨基酸转运蛋白抑制剂或拮抗剂有效干预糖尿病的方法
JPWO2004096277A1 (ja) 眼内血管新生疾患の予防又は治療剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20926806

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20926806

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 20926806

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 04.07.2023)

122 Ep: pct application non-entry in european phase

Ref document number: 20926806

Country of ref document: EP

Kind code of ref document: A1