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

Abstract

Reductions in β-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 β-cell structure and function. Male Zucker Diabetic Fatty (fa/fa; ZDF) rats were randomized to sham surgery (<i>n</i> = 16), RYGB surgery (<i>n</i> = 16), or pair feeding (<i>n</i> = 16). Age-matched lean (fa/+) rats (<i>n</i> = 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. β-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 (<i>P</i> < 0.05) and improved glucose tolerance (<i>P</i> < 0.05) compared with sham surgery. RYGB reduced fasting glucose compared with both sham (<i>P</i> < 0.01) and pair-fed controls (<i>P</i> < 0.01). Postprandial GLP-1 (<i>P</i> < 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 (<i>P</i> < 0.01) and did not differ from lean controls. Insulin content was greater after RYGB compared with the sham (<i>P</i> < 0.05) and pair-fed (<i>P</i> < 0.05) controls. RYGB improves insulin secretion and pancreatic islet function, which may contribute to the remission of type 2 diabetes following bariatric surgery.<b>NEW & NOTEWORTHY</b> 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.