CN105031619A - Application of secretion factor GREM2 in preparation of medicament for treating type 2 diabetes - Google Patents
Application of secretion factor GREM2 in preparation of medicament for treating type 2 diabetes Download PDFInfo
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the technical field of medicine preparation, and particularly relates to application of a secretion factor GREM2 in preparation of a medicine for treating type 2 diabetes. The research proves that the sugar tolerance of the GREM2 transgenic mouse is obviously improved, and the insulin sensitivity is obviously increased. Further experiments show that the downstream P-AKT signal channel of the liver insulin of the transgenic mouse is obviously enhanced, which indicates that the liver insulin sensitivity is increased. The ob diabetic mouse model is utilized to discover that after the ob mouse is administered with adenovirus over-expression GREM2 protein, blood sugar is obviously improved, fatty liver is obviously improved, and insulin sensitivity is obviously increased. Therefore, GREM2 can be applied to the preparation of hypoglycemic drugs and drugs for improving type 2 diabetes, and provides a new drug target for the clinical treatment of type 2 diabetes.
Description
Technical field
Field of medicine preparing technology of the present invention, particularly excreted factor GREM2 is preparing the application in type 2 diabetes mellitus medicine.
Background technology
The clinical syndrome of diabetes to be a kind of with hyperglycemia be principal character.Type 2 diabetes mellitus accounts for the total crowd more than 95% of diabetes.Diabetes have become global health problem, and up till now, the whole world has diabetics more than 1.71 hundred million, and according to statistics, to the year two thousand thirty, global diabetics is by breakthrough 3.7 hundred million.Diabetes are the trend of sharp increase at the number of patients of China, and how effectively treating diabetes is the researcheres urgently problem of generation solution and focuses of research.
The seriousness of diabetes is the various acute and chronic complicating diseases that chronic hyperglycemia causes.Complication mainly comprises the diabetes heart, brain, peripheral blood vessel pathological changes, diabetic nephropathy, diabetic renal papillary necrosis and ocular complications, diabetic neuropathy etc.Complication is very harmful, and mortality rate is high, has a strong impact on patients ' life quality.Diabetes have become the important diseases of serious harm human survival and quality of life, are one of the three large killers of 21 century harm humans health, are only second to cardiovascular disease and tumor.How to control blood glucose, reduce complication, improve the main target that long-term prognosis is treating diabetes.
Type 2 diabetes mellitus be the coefficient result in h and E two aspect, and pathophysiological basis is insulin resistant and B cell hyposecretion.The natural history of type 2 diabetes mellitus is from insulin resistant, and insulin secretion, by excessively compensatory, compensatory, transfer defect of insulin secretion gradually to and namely loses compensatory.The major reason of type 2 diabetes mellitus startup and progress is the insulin resistant organizing particularly skeletal muscle, fat, liver of peripheral insulin sensitivity.Drug therapy at present for type 2 diabetes mellitus treatment mainly contains five large classes, that is: insulin short secretes agent, biguanides, the inhibitor of alpha-glucosidase, thiazolidinediones and secretin (Incretin).Sulphur urine class uses for a long time clinically as Insulin secretagogues, and can prevent microvascular complication, but there is secondary failure due to its loss β cell function, be not ideal selection.In addition, as the sensitizer thiazolidinediones of insulin, rosiglitazone in such medicine, because its cardiovascular risk causes the concern of U.S. food Drug Administration.Traditional hypoglycemic medicine can not stop the progress of the deterioration of islet function volume and type 2 diabetes mellitus effectively, is difficult to continuously and effectively control blood glucose for a long time.Because current medicine still has larger limitation, the hyperglycemia how effectively controlling diabetes is still an emphasis challenge of modern medicine with the complication risk reducing diabetes.For this reason, people are always in the new way constantly exploring treatment diabetes.
The intervention being found to be diabetes of new excreted factor provides new potential target spot.Research shows that autocrine/paracrine factor FGF1 improves the blood glucose of diabetic mice by improving insulin sensitivity.In recent years, along with going deep into of research, the important function of excreted factor BMP (bone morphogenetic protein(BMP)) family in energy metabolism is also revealed.There is natural antagonist in BMP family, the antagonist GREM2 being wherein similarly excreted factor causes our concern in vivo.Up to now, there is no the effect of research report GREM2 in blood glucose regulation.GREM2 is a kind of glycosylated protein of secretion, belongs to CAN (cerberusanddan) subfamily in bmp antagonist family, and its C holds containing 8 cystine rings.This family comprises GREM1, GREM22 member, and wherein GREM2 expresses far above its hetero-organization in metabolism linked groups.GREM2 gene is positioned at people's No. 1 chromosome 1q43 section, comprises 2 exons, total length 4,170bps, 168 aminoacid of encoding.GREM2 can be combined with corresponding BMP, and the final activation suppressing BMP signal path, previously report is relevant to bone formation.At present GREM2 biological function is known little, especially there is no in blood glucose regulation and relate to.
Summary of the invention
The invention provides a kind of excreted factor GREM2 and prepare the application in type 2 diabetes mellitus medicine.Provide the new therapy approach improving diabetes.
The present invention relates to excreted factor GREM2 and prepare the application in type 2 diabetes mellitus medicine.Described excreted factor GREM2 improves blood glucose by improving hepatic insulin sensitivity.
The present invention utilizes GREM2 transgenic mice animal model, and this research finds that GREM2 transgenic mice carbohydrate tolerance obviously improves, and insulin sensitivity obviously increases.Further experiment shows, transgenic mice hepatic insulin downstream P-AKT signal path significantly strengthens, and prompting hepatic insulin sensitivity increases.Utilize ob mice (diabetic mouse model), after this research finds that ob mice gives adenovirus process LAN GREM2 albumen, blood glucose obviously improves, fatty liver obviously improves, insulin sensitivity significantly increases.The present invention provides excreted factor GREM2 first and is used for the treatment of the evidence of type 2 diabetes mellitus on animal model, and prompting excreted factor GREM2 may have some improvement to diabetes tool clinically.So GREM2 can be applied to and prepare hypoglycemic medicine, improves in the medicine of type 2 diabetes mellitus, for clinical treatment type 2 diabetes mellitus provides new drug target.
Beneficial effect: the present invention is the treatment relation that have studied excreted factor GREM2 and type 2 diabetes mellitus, shown by Research of Animal Model for Study, excreted factor GREM2 can be used for treating type 2 diabetes mellitus, for the treatment of excreted factor GREM2 to diabetes provides theoretical foundation and experimental data clinically.
Accompanying drawing explanation
Fig. 1 is transgenic mice process LAN efficiency qualification figure.
Fig. 2 be in normal diet situation GREM2 to the comparison diagram of Mouse Weight, blood glucose and insulin tolerance.
Fig. 3 be in high fat diet situation GREM2 to the comparison diagram of Mouse Weight, blood glucose and insulin tolerance.
Fig. 4 is the liver glyconeogenesis of GREM2 transgenic mice, liver, liver and adipose tissue insulin affect comparison diagram.
Diabetic mice body weight, blood glucose, carbohydrate tolerance and insulin sensitivity variation diagram after Fig. 5 adenovirus process LAN GREM2 albumen.
Diabetic mice fatty liver variation diagram after Fig. 6 adenovirus process LAN GREM2 albumen.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described:
Embodiment
1, GREM2 transgenic mice blood glucose obviously improves
1) whole body process LAN GREM2 Establishment of mouse model.
We with C57BL/6J mice for background, experience vector construction, DNA linearisation and purification, linearisation DNA microinjection is to 200 germ cell, these germ cell are transmitted back to the medium experiment flow of the female Mus fallopian tube of 3-4 replace-conceive again, finally identify that the positive head of acquisition 10 genotype results qualifications builds Mus (Founder) through PCR, remove after three obsolete founder:GAfounder have given birth to F1 generation, no longer give birth to; GEfounder does not bear positive mice; It is low that GJfounder gives birth to positive rate, do not have yet enough mices for the identification of, as shown in Figure 1, through expression efficiency qualification, GF mice process LAN efficiency is higher, for subsequent experimental for the process LAN efficiency of 7 remaining founder.
2) phenotype analytical under whole body process LAN GREM2 mice normal diet and high fat fed conditions.
For detecting GREM2 to the regulating action of blood glucose, we improve the metabolic phenotype analysis of GREM2 transgenic mice under normal diet and high fat fed conditions on the basis of previous work.Adopt SPF level C57BL/6 mice, in standard mice cage, cage is divided to feed by following condition: normal diet is normal business mouse feed (4.5% fat, 4% cellulose, 21% protein), high fat feed for nursing is purchased from ResearchDiet (60%Fat).Freely ingest and drink water, the stable artificial lighting cycle (6:00 to 18:00 illumination, 18:00 to 6:00 is dark).
Main Testing index is as follows:
A. WT mice and GREM2TG (Transgenicmice) Mouse Weight growth curve record under normal diet and high smectic state;
B. the mensuration of carbohydrate tolerance and insulin tolerance: by glucose tolerance test (IPGTT) and insulin stimulating test (ITT), analyzes GREM2 transgenic mice to tolerance, the insulin sensitivity of glucose.Carbohydrate tolerance experimentation is as follows: mice is after hungry 16 hours, and through the glucose of lumbar injection, the consumption of glucose is 1g/kg, then 15min, 30min, 60min, 120min record blood sugar level after injection respectively.Insulin tolerance tests (ITT) process is as follows: after hungry 6 mices of mice, through lumbar injection recombinant human insulin 0.75U/kg (normal diet mice) or 1.5u/kg (high fat diet mice), record blood sugar level respectively at 15min, 30min, 60min, 120min after injection of insulin.
First under observing normal diet situation, GREM2 is on the impact of blood glucose.We select the control mice 10 in 8 week age altogether, GREM2 transgenic mice 9, after full diet feeds 16 weeks, observe the impact of GREM2 on Mouse Weight and blood glucose.Result shows, and compared with control mice, without obviously changing, (a), carbohydrate tolerance obviously improves Fig. 2 transgenic mice body weight (Fig. 2 b).Insulin tolerance result shows, and transgenic mice insulin sensitivity obviously strengthens (Fig. 2 c).
Equally, under we observe high fat diet situation again, GREM2 is on the impact of mouse blood sugar and insulin sensitivity.We choose mice in 8 week age equally, control mice 15, GREM2 transgenic mice 14.The impact of GREM2 on Mouse Weight and blood glucose is observed after mice High-fat diet 16 weeks.Result display (Fig. 3), compared with control mice, GREM2 transgenic mice body weight is without obvious change, and through the display of abdominal cavity glucose tolerance test result, transgenic mice carbohydrate tolerance obviously improves.Hunger experimental result of taking food again shows equally, and GREM2 transgenic mice carbohydrate tolerance significantly improves.Same, transgenic mice insulin sensitivity obviously strengthens.
2, GREM2 transgenic mice hepatic insulin sensitivity obviously strengthens
Show from experimental result, GREM2 transgenic mice fasting glucose obviously reduces, and carbohydrate tolerance obviously improves, and insulin sensitivity obviously strengthens.Fasting glucose regulates by liver glyconeogenesis, transgenic mice fasting glucose is improved, that the decline of glyconeogenesis ability causes? next, first we have detected the expression of key gene FBP1, G6Pase, Pepck, Pgc-1 α of liver glyconeogenesis, and result shows transgenic mice liver glyconeogenesis, and without obviously changing, (Fig. 4 a).In order to detect the impact of GREM2 on liver further, the method that we are dyeed by HE detects liver morphology.The normal diet mouse liver tissue paraformaldehyde of 4% is fixed, after specimens paraffin embedding slices, through steps such as roasting sheet-dewaxing-aquation-brazilwood extract dyeing-dehydration-eosin stains-dehydrations-transparent, and basis of microscopic observation after resinene mounting.Mouse liver HE coloration result display (Fig. 4 b), control mice liver occurs that more little fat drips, and the fat in transgenic mice liver drips less, and prompting transgenic mice fatty infiltration of liver is few.
Skeletal muscle, liver, fat are the important target organs of insulin.Next, we detect the sensitivity of mouse liver and adipose tissue insulin further.Mice is divided into two groups: the mice under base state after the mice of (basal) and insulin stimulating.Insulin processed group: mouse peritoneal insulin injection 1.5U/kg, the rapid separating mouse fatty tissue of 15min clock and liver after insulin process.Further extraction liver and visceral adipose tissue albumen, Westernblot method detects the change of insulin downstream signaling pathway p-AKT.Result display (Fig. 4 c), under base state (basal), transgenic mice hepatic insulin downstream signaling pathway p-AKT obviously strengthens, and close to the level after insulin stimulating, prompting GREM2 transgenic mice hepatic insulin sensitivity is apparently higher than control mice.And transgenic mice visceral adipose tissue insulin sensitivity and matched group no significant difference (Fig. 4 d).
3, after ob mouse adenovirus process LAN GREM2 albumen, blood glucose obviously improves
The homozygote mice (Lepob, usually writing ob or ob/ob) of fat spontaneous mutation is the mice of leptin gene mutation.Phenotype can be seen during the about surrounding of ob mice.Homozygous mutation Mouse Weight increases sharply, and can reach three times of wild type control Mus normal type.Except obesity, sudden change Mus also shows hyperphagia, diabetes sample hyperglycemia syndrome, and carbohydrate tolerance is bad, and plasma insulin raises.Ob mice is conventional type 2 diabetes mellitus mouse model.
GREM2 is a kind of secretory protein.Next, we adopt the method for tail vein injection to be injected in ob Mice Body by GREM2 adenovirus.The ob mice in 8 week age of this research employing, matched group virus treated 4, GREM2 adenovirus processed group 4, the dosage of adenovirus is 10
9iU/ only.After injected in mice adenovirus, the expression of general 3 ~ 4 days destination proteins peaks, and declines gradually after one week, and the continuous expression time was at about two weeks.Continuous Monitoring Blood Glucose and body weight after adenovirus process.After giving the process of GREM2 adenovirus, we detect mice random blood sugar in the 5th day, the 7th day, the 9th day after virus treated respectively, result shows, after ob mice gives adenovirus process LAN GREM2 albumen, mice random blood sugar obviously improves (Fig. 5 b), and carbohydrate tolerance improves (Fig. 5 c), insulin sensitivity obviously strengthens (Fig. 5 d).
Equally, we are by the change of HE staining examine liver morphology.Result shows, and ob mice exists serious fatty liver, and the mouse adipose liver of GREM2 adenovirus process is obviously improved (Fig. 6).
More than study by transgenic mice and diabetic mice (ob mice) two kinds of animal models, disclose excreted factor GREM2 and improve blood glucose, improve the New function of insulin sensitivity, for clinical treatment type 2 diabetes mellitus provides new drug target.
The above is preferred embodiment of the present invention, but the present invention should not be confined to the content disclosed in this embodiment.The equivalence completed under not departing from spirit disclosed in this invention so every or amendment, all fall into the scope of protection of the invention.
Claims (2)
1. excreted factor GREM2 is preparing the application in type 2 diabetes mellitus medicine.
2. application according to claim 1, is characterized in that: described excreted factor GREM2 improves blood glucose by improving hepatic insulin sensitivity.
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| CN109289039A (en) * | 2018-12-04 | 2019-02-01 | 上海交通大学医学院附属瑞金医院 | Application of transcription factor YY1 in preparation of targeted drug for treating diabetes |
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| CN115105524A (en) * | 2021-03-18 | 2022-09-27 | 南京壹盛康品生物科技有限公司 | Application of alpha-cyclodextrin in preparing functional food or health product and medicine for improving and protecting pancreatic islet function |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109289039A (en) * | 2018-12-04 | 2019-02-01 | 上海交通大学医学院附属瑞金医院 | Application of transcription factor YY1 in preparation of targeted drug for treating diabetes |
| CN112190690A (en) * | 2020-09-23 | 2021-01-08 | 南方医科大学 | Application of LIFR protein as biomarker and therapeutic target point of diabetes |
| CN115105524A (en) * | 2021-03-18 | 2022-09-27 | 南京壹盛康品生物科技有限公司 | Application of alpha-cyclodextrin in preparing functional food or health product and medicine for improving and protecting pancreatic islet function |
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