| 1,BackgroundThe incidence of diabetes mellitus(DM) increases significantly in the recent years, with a prevalence rate of 5.5% in adult Chinese, and is presently affecting more than 30 million people in China. Medical therapy in DM has its limitation, and each hypoglycemic drug has its special target. Many patients need multiple drugs in order to effectively control their blood glucose. In reality, the glucose levels of many patienst can't get satisfactory control because of irregular drug use. These increase its life-threatening complications in cardiovascular, brain, kidney and other important organs. To date, no effectively therapy can prevent the progressive failure of pancreatic islet cell function in DM patients.It is established by the follow-up study of patients after bariatric surgery that many patients achieve normal glycemia, with decreased insulin resistance, improved cholesterol and blood pressure control accompanied with weight loss, and these changes occure in the early phase of post-operative period when patients are still over weight. This clinical phenomenon triggers a clinical and experimental study of possible surgical treatment of diabetes.Many experiments proved significant changes of some gastrointestinal hormones and neuropeptides that related to energy metabolism owing to anatomical and physiological changes after surgeries. Some of these molecules can promote food absorption including Ghrelin, GIP, NPY, GHRF and Orexin, others can inhibit food absorption incuding PYY3-36, Leptin, POMC, GLP-1, Obestatin, Insulin, CCK, etc. These peptides molecular correlate to glucose metabolism, islet cell function and insulin sensitivity. But to our knowledge, there is no report on the changing of glucose transporters(GLUTs) distributing in body organs after gastric bypass surgery.2,ObjectiveGK rats can be used to establish a variety of animal models in experimental surgical treatment of type 2 diabetes. Expression of glucose transporter's mRNA and proteins in intestine, liver, muscle at different time spots through the postoperative periods were studied to unveil the different influence by surgical methods on glucose transporters expression, and in order to explain the therapeutic mechanism of surgery for type 2 diabetes in terms of glucose absorption, transformation, and utilization.3,Methods 40 GK rats of SPF-class male,9 weeks old, weight 340±20g; and 40 SPF SD rats, male,9 weeks old, weight 340±20g were used; After adaptional feeding of 2 weeks without any intervention, all GK rats were randomly divided into five groups: duodenal jejuna bypass group(DJB,n=8), sleeve gastrectomy group(SG,n=8), mini-gastric bypass group(MGBP,n=8), sham-operated group(SHAM,n=8) and control group(CONT,n=8); SD rat were grouped in the same way. Post-operative diet and water intake was daily weighed, and body weight was measured every three days; Fasting blood glucose was tested on the third day after surgery, and in week 1, week 2, week 4, week 6, and week 8 after surgery. OGTT was performed at postoperative week 4 and week 8; 4 and 8 weeks after surgery, blood samples were harvested from vena angularis of each group and were used to check the levels of insulin, ghrelin, and obestatin. After eight weeks, the rats were killed in batches to obtain the small intestine, liver, and muscle tissue to detect mRNA and protein expression of GLUT2, GCK, and GLUT4. Immunohistochemistry method of TUNEL was used to detect the apoptosis of pancreatic tissue cell of GK rat in each group.4,ResultsPreoperatively, there was no significant difference in blood glucose and body weight of GK and SD rats in each group; Eighth week after surgery, surviving rats in each group were more than six, the overall survival rate of GK rats reached 82.5%, and for SD rats up to 95%.3 days after surgery, rats began to resume diet,2 weeks after operation, food intake in DJB, MGBP, and SG was significantly lower than in SHAM (P<0.01); 8 weeks after surgery, food intake in DJB, MGBP was significantly lower than SG (P <0.01), and SG was significantly lower than SHAM and CONT(P<0.01); 2 weeks after surgery, body weight of DJB, MGBP and SG was significantly lower than SHAM, DJB and MGBP was significantly lower than SG (P<0.01) at 8 weeks, and SG was significantly lower than SHAM (P<0.01); 3 days after surgery, blood glucose of GK rats in DJB, MGBP, SG, and SHAM had statistically significant difference (P<0.01) compared with the CONT, glucose of DJB, MGBP, and SG group was significantly lower than CONT group (P<0.01) at 2 weeks after surgery, while there was no significant difference (P=0.067) between SHAM and CONT,8 weeks after surgery, glucose of DJB, MGBP and SG was significantly lower than SHAM and CONT (P<0.01), and glucose of DJB, MGBP and SG group was significantly lower than there preoperative value (P<0.01);OGTT results of GK rats in postoperative week 4 and 8 showed that blood glucose AUC of DJB, MGBP and SG was significantly less than that of the SHAM and CONT (P<0.01), but no different between SHAM and CONT (P> 0.05); Blood glucose and OGTT results of SD rats had no difference after surgery; postoperative insulin levels in GK rats of DJB, MGBP, and SG tended to increase, but no significant difference was founded when compared with there preoperative value (P>0.05), and there were no significant differences between DJB, MGBP and SG group at 8 weeks after surgery(P>0.05). Grelin of GK rats in DJB and MGBP was increased (P<0.01) at 5 weeks after sugery.The expression levels of Intestinal GLUT2 mRNA and protein in DJB, MGBP and SG was significantly higher than CONT (P<0.05); The expression levels of liver GLUT2 mRNA was significantly higher than CONT(P<0.05), but there was not significant difference among SG,SHAM and CONT(P>0.05); Expression of liver GLUT2 protein in DJB and MGBP was significantly higher than CONT (P<0.001), while SG was significantly lower than CONT (P<0.001), and there was no significant difference between SHAM and CONT (P<0.05);The mRNA and protein expression of liver GCK in DJB and MGBP was significantly higher than CONT (P<0.01), SG was significantly lower than CONT (P<0.001); The expression of muscle GLUT4 mRNA and protein of GK rats in DJB, MGBP, SG was significantly higher than CONT(P<0.01), there was not significant defference between SHAM and CONT(P> 0.05), But among different groups of SD rats there was not significant difference (P> 0.05); The results of pancreatic cell apoptosis by TUNEL showed significant less in DJB, MGBP, and SG than CONT (P<0.001), but no significant between SHAM and CONT (P> 0.05).5,Conclusions①It is feasible to build surgical model to treat type 2 diabetes by performing gastrointestinal reconstruction using GK rats.②GK rats show a similar changes in body weight and diet with SD rats after DJB, MGBP, SG, SHAM surgery. Both in GK rats and SD rats, food intake and body weight continue to rise slowly after SG surgery, while remained at a lower level 2 weeks after DJB and MGBP surgery. Gastric capacity has not changed after DJB surgical, but the food intake is similar with MGBP, which indicate that the DJB surgical inhibbit appetite.③DJB, MGBP, and SG can significantly improve blood glucose control of the GK rat, but no effec to SD rats. The changes of blood glucose caused by surgery disappear at 2 weeks after surgery. DJB and MGBP are more effective than SG in controlling blood glucose, and they are also better than SG in terms of long-term benefits. As far as SG is concerned, blood glucose level is obviously correlation to food intake and body weight of GK rat.④DJB, MGBP, and SG surgeries cause limited in improvement in pancreatic fuction and insulin secretion of GK rat, but no significant changes were detected before and after surgery. However, DJB, MGBP, and SG can significantly decreased the apoptosis of pancreatic cells.⑤The glucose transportation ability of residual intestine is significantly enhanced after DJB, MGBP,SG surgery, which indicates that intestinal has adaptive regulation to the change of glucose intake.⑥DJB and MGBP can significantly improve liver GLUT2 and GCK expression level of GK rats and SD rat, improve liver glucose metabolism, and increased regulatory capacity of blood glucose. For SD rats with euglycemia, increased expression of liver GLUT2 can enhance reserved capacity of blood glucose adjustment. Liver expression of GLUT2 and GCK are stimulated by the intake of sugar, but are also affected by hormones factor.⑦DJB, MGBP, and SG can significantly improve muscle GLUT4 expression in GK rats, enhance glucose utilization in muscle, decrease insulin resistance, and increase the control of blood glucose. DJB, MGBP, and SG don't affect muscle GLUT4 expression in SD rats.
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