Roux-en-Y gastric bypass restores islet function and morphology independent of body weight in ZDF rats.

Reductions in ß-cell number and function contribute to the onset type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) surgery can resolve T2D within days of operation, indicating a weight-independent mechanism of glycemic control. We hypothesized that RYGB normalizes glucose homeostasis by restoring ß-cell structure and function. Male Zucker Diabetic Fatty (fa/fa; ZDF) rats were randomized to sham surgery (n = 16), RYGB surgery (n = 16), or pair feeding (n = 16). Age-matched lean (fa/+) rats (n = 8) were included as a secondary control. Postprandial metabolism was assessed by oral glucose tolerance testing before and 27 days after surgery. Fasting and postprandial plasma GLP-1 was determined by mixed meal tolerance testing. Fasting plasma glucagon was also measured. ß-cell function was determined in isolated islets by a glucose-stimulated insulin secretion assay. Insulin and glucagon positive areas were evaluated in pancreatic sections by immunohistochemistry. RYGB reduced body weight (P < 0.05) and improved glucose tolerance (P < 0.05) compared with sham surgery. RYGB reduced fasting glucose compared with both sham (P < 0.01) and pair-fed controls (P < 0.01). Postprandial GLP-1 (P < 0.05) was elevated after RYGB compared with sham surgery. RYGB islets stimulated with 20 mM glucose had higher insulin secretion than both sham and pair-fed controls (P < 0.01) and did not differ from lean controls. Insulin content was greater after RYGB compared with the sham (P < 0.05) and pair-fed (P < 0.05) controls. RYGB improves insulin secretion and pancreatic islet function, which may contribute to the remission of type 2 diabetes following bariatric surgery.NEW & NOTEWORTHY The onset and progression of type 2 diabetes (T2D) results from failure to secrete sufficient amounts of insulin to overcome peripheral insulin resistance. Here, we demonstrate that Roux-en-Y gastric bypass (RYGB) restores islet function and morphology compared to sham and pair-fed controls in ZDF rats. The improvements in islet function were largely attributable to enhanced insulin content and secretory function in response to glucose stimulation.

Longer-Term Physiological and Metabolic Effects of Gastric Bypass Surgery.

Obesity is closely associated with the development of type 2 diabetes. Many strategies have been used in the past to combat these two conditions, but very few provide for stable and durable glycemic control. Bariatric surgery has emerged as a powerful tool for treating obesity and in over 70 % of cases provides a short-term cure for diabetes. While the acute metabolic effects of surgery are striking, it remains important for us to also consider the long-term effects. This review aims to summarize the chronic or long-term metabolic and physiological effects of Roux-en-Y gastric bypass (RYGB) surgery on pancreatic function, skeletal muscle and hepatic insulin sensitivity, and gastrointestinal remodeling. An increased understanding of the current state of research in these areas can provide the basis for stimulating further research that would contribute to new treatment and management strategies for obesity and diabetes.

Effects of gastric bypass surgery on expression of glucose transporters and fibrotic biomarkers in kidney of diabetic fatty rats.

BACKGROUND: Diabetic nephropathy is the leading cause of chronic kidney disease. Observational studies suggest Roux-en-Y gastric bypass (RYGB) reduces progression of diabetic nephropathy. OBJECTIVES: To unravel the mechanisms by which RYGB is beneficial and protective for diabetic nephropathy. SETTING: Academic laboratories. METHODS: Forty-eight Zucker diabetic fatty rats were randomized to RYGB, sham surgery (SHAM), or pair-fed (PF) groups. An oral glucose tolerance test was performed at 25 days post intervention and kidneys were harvested at 30 days. Primary outcome measures included expression of key genes and proteins in the glucose transport, oxidative stress, inflammation, and fibrosis pathways. RESULTS: Thirty days post intervention, RYGB rats weighed 349 ± 8 g, which was lower than SHAM (436 ± 14 g, P < .001), but not PF (374 ± 18 g) rats. RYGB rats had lower fasting glucose than PF animals and improved homeostatic model assessment of insulin resistance compared with PF and SHAM groups. These enhanced metabolic outcomes were accompanied by reduced sodium-glucose co-transporter 1 (Sglt1) gene expression (-23% versus PF, P = .01) in the kidney of RYGB rats. Expression of Sglt2, Glut1, or Glut2 mRNA, or oxidative stress and inflammation markers did not differ significantly. However, RYGB surgery induced a 19% lower expression of transforming growth factor (Tgfß) mRNA (P = .004) compared with SHAM treated animals. Notably, adenosine monophosphate-activated protein kinase phosphorylation was increased (P = .04) in kidneys of the RYGB surgery animals. CONCLUSIONS: Improvement of hyperglycemia after RYGB may reduce the glucose load on the kidney leading to a downregulation of specific glucose transporters. RYGB surgery may also attenuate kidney fibrosis through the adenosine monophosphate-activated protein kinase/TGFß pathway.