Study On The Anti-type 2 Diabetes Activity Of PEG-17P

The number of patients with type 2 Diabetes has been increasing year by year to since the twentieth century,the morbidity rate has been increasing and especially in some developing countries.To the 2020 now,type 2 Diabetes has become a killer of human health,and one of the major diseases that endanger human health after cancer or cardiovascular or cerebrovascular diseases.People with type 2 Diabetes will inherently suffer from impaired function of their own liver and pancreatic islets and other organs,reduced insulin sensitivity,and insulin resistance.At the same time,there will be impaired function of pancreatic islet beta cells leading to insufficient insulin secretion,and the inability to autonomously synthesize glycogen in the liver and a series of other diseases.Therefore,patients with type 2 Diabetes can not regulate blood glucose by their own insulin,which leads to blood glucose and metabolic disorders.Because the insulin sensitivity of type 2 diabetic patients is reduced,external insulin injection alone can not regulate blood glucose well,enhance insulin sensitivity,reduce insulin resistance,and repair damaged organs is the fundamental treatment.As we know the Exendin-4,a small-molecule polypeptide previously found in a saurid,has been marketed in the United States as a new drug against type 2 Diabetes.Exendin-4,as a GLP-1 analogue,has a higher activity and half-life than GLP-1,and its GLP-1R binding capacity is 2.5 times that of GLP-1,and the literature reported that Exendin-4 has a certain protective effect on the liver and islets of patients with type 2 Diabetes.Nevertheless,the half-life of Exendin-4 in plasma was only 26 min,and patients with type 2 Diabetes had to be injected frequently to maintain blood glucose stability because of its rapid degradation rate.Therefore,based on Exendin-4,an Exendin-4 mimetic peptide containing 12 amino acids was designed by high-throughput peptide library screening,and its activity was not lower than that of Exendin-4.A PEG-17 P was obtained by combining this 12-peptide with a 5-peptide small molecule GLP-1R agonist reported in previous literature and PEG modification at its N-terminal.In this design of this experiment,PEG-17 P was obtained by solid-pHase peptide synthesis technology,and the experiment was divided into two parts,in vivo and invitro.In vitro,its stability in plasma was first examined,and the mode of Administration for in vivo experiments was determined.The affinity of PEG-17 P with GLP-1R was detected,Exendin-4 was used as a positive control,and the effect of PEG-17 P on INS-1 cells was explored.In vivo experiment,C57BL/6J male mice were selected to construct type 2 Diabetes model.After seven weeks of treatment with PEG-17 P,the effects of PEG-17 P on blood glucose and body weight of C57BL/6J type 2 diabetic mice were examined.Intraperitoneal glucose tolerance test and insulin tolerance test were conducted to examine the effect of PEG-17 P on dyslipidemia in type 2 diabetic mice,and to explore its protective effect on liver and islets in mice.The experimental results showed that PEG-17 P had good stability in vitro,high activity in promoting INS-1 cell proliferation and insulin release,and high affinity with GLP-1R.Animal in vivo experiments proved that PEG-17 P had better anti-glycemic activity in type 2 diabetic mice.Seven weeks of continuous treatment could effectively reduce fasting blood glucose,improve insulin sensitivity and glucose tolerance,improve dyslipidemia in mice,and PEG-17 P could repair liver and islet injury in type 2 diabetic mice to some extent.In conclusion,we conclude that PEG-17 P exhibits high antiglycemic activity in type 2 diabetic mice and is expected to be an emerging drug for the treatment of type 2 Diabetes.