Roux-en-Y Gastric Bypass Improves Hepatic Glucose Metabolism Involving Upregulation of Sirt1 in Type 2 Diabetes Mellitus

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is the most effective treatment for type 2 diabetes mellitus (T2DM). Previous studies have reported that silent information regulator 1 (Sirt1) closely relates to many pathological processes of glucose metabolism and insulin resistance (IR). However, it is unclear whether Sirt1 is involved in the hepatic glucose metabolism of T2DM after RYGB. METHODS: T2DM rats were randomly divided into four groups: Control, DM, Diet and RYGB. Normal rats were served as the control group. Hematoxylin and eosin (H&E) staining and Masson staining assays were performed to explore the changes of liver fibrous tissue after RYGB. The effect of RYGB on the protein expression of Sirt1 was detected by the Western blotting assay and immunohistochemical assay. Next, we built the insulin resistance model of human hepatocyte cell lines (FL62891 and HHL5) using the human recombinant insulin. Western blotting assay was applied to determine the expression of Sirt1 and the expression change of IRS1/mTOR2 /PKB pathway-related proteins in FL62891 and HHL5 cells. Additionally, the effects of Sirt1 on the expression of PTP1B and FGF-21 in insulin-resistant FL62891 and HHL5 cells were investigated using Western blotting and immunofluorescence assay. RESULTS: Our results showed that following RYGB improved the pathological changes of liver and increased the expression of Sirt1 in rats with T2DM compared with the diabetic rats. In experiments in vitro, the expression of Sirt1 was downregulated in insulin-resistance FL62891 and HHL5 cells. Moreover, overexpression of Sirt1 significantly increased the expression of FGF-21 whereas decreased the expression of PTP1B in insulin-resistance FL62891 and HHL5 cells. These above changes were alleviated in RYGB and Diet groups. Furthermore, RYGB could improve the glucose metabolism through activating IRS1/mTOR2/PKB pathways by regulating Sirt1 in rats with T2DM. CONCLUSION: RYGB could significantly improve hepatic glucose metabolism and increase the expression of Sirt1 in T2DM rats, which is related to the IRS1/mTOR2 /PKB pathway.