Type 2 Diabetes Mitigation In The Diabetic Goto-Kakizaki Rat By Elevated Bile Acids Following A Common-bile-duct Surgery

Type 2 diabetes(T2DM),also known as adult onset diabetes,is a chronic systemic endocrine disorders caused by genetic and environmental factors.It is characterized by metabolic disorders and elevated blood glucose and accounts for over 90%of the diabetic patients.Until 2013,there are 382 million diabetic patients worldwide.While in China,with the continuous improvement of people’s living standards in recent years,the incidence of T2DM is increasing year by year due to a high calorie diet,lack of physical activity and various pressures caused by a high paced life style.China now has the largest diseased population in the world,in which case T2DM is seriously threatening people’s health and life.The pathogenesis of T2DM is not clear.According to the current research,treating T2DM patients with obesity through metabolic surgery can not only reduce weight,but also recover islet function and insulin sensitivity rapidly,so as to maintain glucostasis,improve blood lipid concentration and relieve clinical symptoms of T2DM and its complications.Acid bile plays an important role.It combines with nuclear receptor farnesoid X receptor(Farnesoid X reportor,FXR)and activates downstream signaling pathway,so as to lower plasma cholesterol,triglyceride and fatty acid levels,as well as regulate blood glucose metabolism.Acid bile involves in the signaling pathway of G-protein-couple(GPCR)receptor and activates TGR5,so as to regulate body energy and sugar metabolism.In addition,bile acids may also be involved in the regulation of insulin signal transduction pathway through a non receptor dependent signaling pathway.In summary,Acid bile plays a variety of functions in the T2DM,while its specific mechanism needs further experiments to improve and confirm.In this research,we successfully performed a surgical procedure(ligation of the common bile duct and external biliary drainage[LBD])on the GK rats,and at the same time,a complete control experiment was set up to study further the effect of acid bile in type 2 diabetes.Through comparing the plasma bile acid concentration of the rats in two groups before and after the operation,it was found that the plasma bile acid concentration of GK rats in the LBD operation group was significantly higher than that in sham operation group.Through comparing the weight and blood glucose concentration of the rats in two groups before and after the operation,it was found that the fasting blood glucose concentration in LBD group was significantly decreased compared with that in sham operation group,while there was no significant difference of weight between the two groups.The data from intraperitoneal glucose tolerance test(IPGTT)indicated that GK rats had lower blood glucose excursion curve after LBD operation.The area under the curve was significantly smaller than that of sham operation control group.And data from insulin tolerance test(ITT)showed that GK rats after LBD operation,compared with the sham operated control group GK rats,can better remove the blood glucose in the study time.IPGTT and ITT together demonstrate that LBD can significantly increase the body’s sensitivity to insulin,resulting in the effect of lowering blood glucose.To find out the factors involved in increasing liver’s sensitivity to insulin,after confirming that the livers of GK rats in the two groups was both normal in histology,we carried out the determination of the phosphorylation of AKT and its target protein GSK3.The result showed that AKT phosphorylation and GSK3 phosphorylation of GK rats were significantly increased after LBD operation.LXR signal transduction gene cluster detection can prove that LBD operation activated the LXR signaling pathway in GK rats.Detection and analysis of lipid metabolism and glucose metabolism related genes indicated that LBD can improve insulin sensitivity by inhibiting the abnormal glucose and endoplasmic reticulum stress in diabetic GK rats.After comparing,it can be found that the number of GK rat’s epididymis fat of LBD operation group was significantly less than that of sham operated control group.And even after the weight of rats was normalized,the decrease was still obvious.With comparison of the data of bile acids with other related data,together with clinical characteristics of GK rats after LBD operation,it can be inferred that the LBD operation can relieve type 2 diabetes and will not cause damage to the liver or kidney.Compared with sham operated control group,the change of metabolic parameters in GK rats in LBD operation group was the result of liver’s respond to the increase of bile acid synthesis.In summary,this research showed that bile acids played a vital role in treating and easing type 2 diabetes,which can be used as the target for the treatment of type 2 diabetes in further research and exploration.