Experimental Research On The Effect Of Roux-en-Y Gastric Bypass Surgery On Renal Gluconeogenesis In Type2Diabetes Mellitus Rats

Study background and purpose: In the current diabetes is a kind of common endocrinediseases, and more than90%are type2diabetes mellitus. Traditional single drug treatmentor combination with a variety of methods contain diet control and strengthen sports can notcure diabetes completely, even can not prevent the occurrence of diabetes complicationsand more further. while the bariatric surgery represented by Roux-en-Y gastric bypasssurgery which has been achieved unexpected therapeutic results in patients with metabolicsyndrome and T2DM, but so far, the related mechanism is not fully clear for the treatmentof T2DM. Previous studies have confirmed that the gastric bypass surgery can increaseinsulin sensitivity and reactivity on insulin target organs such as skeletal muscle,liver andfat tissue, improve the function of glucose metabolism in those organs, increase the use ofglucose and reduce the production of endogenous glucose.Recent studies have shown thatkidney also plays an important role in maintaining blood glucose balance inside humanbody, in addition to liver, renal cortex also contains a lot of enzymes related togluconeogenesis,can produce enough glucose through the way of gluconeogenesis and thenrelease the glucose into the blood circulation under various of physiological conditions. Inthe condition of diabetes, kidney is also insulin resistant, and the output of renal glucose isincreased. Based on those understanding, the purpose of our study is to establish T2DM ratmodel for observing the effect of Roux-en-Y gastric bypass surgery on renalgluconeogenesis, explore its hypoglycemic effect and possible hypoglycemic mechanism.Methods: Diabetes mellitus animal models were induced by intraperitoneal injectionof streptozotocin (STZ,35mg/kg) and a high-fat diet. Diabetic rats were divided into threegroups randomly: diabetes model group (DM group, n=8),sham Roux-en-Y gastric bypassgroup (SRYGB group, n=8), Roux-en-Y gastric bypass group (RYGB group,n=14);Another8normal SD rats as the normal control group (NC group, n=8). The RYGB group receivedthe gastric bypass surgery，and the SRYGB group received transection and reanastomosis of the gastrointestinal tract, NC group and DM group did not receive surgical interventiontreatment．Plasma TG、TC and FFA were measured using utomatic biochemical analyzerrespectively before and4th week after the operation in each group rats;the fasting insulinwas measured using radioimmunoassay and oral glucose tolerance test (OGTT) was takenbefore and1st、2nd、4th week after the operation, calculate the area under the curve ofblood glucose concentration-time and insulin sensitivity index(ISI). The key enzymes ofrenal gluconeogenesis: G-6-P and PEPCK mRNA were detected using real-timefluorescence quantitative polymerase chain reaction (RT-PCR), G-6-P、PEPCK、InR-αandInR-βprotein were detected using western blot respectively4th week after the operation ineach group rats,.Results: Testing the indicators before and1st、2nd、4th week after the operation,wehad the following findings:1.The fasting blood glucose、blood-lipoid and AUC in DM group were higher thanthose in NC group before the operation at the same time point, ISI in DM group was lowerthan that in NC group,there were no difference in serum insulin level between the twogroup rats.2.The serum level of TC、TG and FFA in RYGB group were lower than those in DMand SRYGB groups4weeks after the operation.3.The blood glucose of fasting and2h after OGTT in RYGB group were lower thanthose in DM and SRYGB groups1、2and4weeks after the operation,compaired with DMand SRYGB groups, AUC in RYGB group was reduced, and ISI was increased.4.The expression of G-6-P and PEPCK mRNA and protein in DM and SRYGB groupswere higher than those in NC group4weeks after the operation,while the expression ofInR-α protein was decreased. The expression of G-6-P and PEPCK mRNA and protein inRYGB group were lower than those in DM and SRYGB groups4weeks after the operation,the expression of InR-α protein was increased in some degree,while the expression of InR-βprotein was no difference between groups.Conclusions:1.Combination intraperitoneal injection of small dose streptozotocinwith a high-fat diet could replicate the T2DM rats model, this rat model performed formoderately high blood glucose, insulin resistance and hyperlipidemia, glucose tolerancewas severely impaired, so it could better simulate the occurrence and development of human T2DM. Secondly the model rats showed renal insulin resistance, and the renalgluconeogenesis was increased.2.Roux-en-Y gastric bypass surgery could improve lipid metabolism in type2diabetesrats, decreased the blood lipid level.3.Roux-en-Y gastric bypass surgery could reduce the blood glucose level in type2diabetic rats significantly, improved the impaired glucose tolerance, increased insulinsensitivity, and relieved renal insulin resistance, reduced the expression of key enzymes ofrenal gluconeogenesis, weakened the renal gluconeogenesis, thus reduced part ofendogenous glucose production, this might be the possible mechanism of Roux-en-Y gastricbypass surgery reduced the blood glucose in type2diabetic rats.