GLP-1R Responsiveness Predicts Individual Gastric Bypass Efficacy on Glucose Tolerance in Rats

Abstract

Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y gastric bypass (RYGB) produces substantial body weight (BW) loss and enhanced glucose tolerance, and is associated with increased secretion of the gut hormone glucagon-like peptide 1 (GLP-1). Given the success of GLP-1–based agents in lowering blood glucose levels and BW, we hypothesized that an individual sensitivity to GLP-1 receptor agonism could predict metabolic benefits of surgeries associated with increased GLP-1 secretion. One hundred ninety-seven high-fat diet–induced obese male Long-Evans rats were monitored for BW loss during exendin-4 (Ex4) administration. Stable populations of responders and nonresponders were identified based on Ex4-induced BW loss and GLP-1–induced improvements in glucose tolerance. Subpopulations of Ex4 extreme responders and nonresponders underwent RYGB surgery. After RYGB, responders and nonresponders showed similar BW loss compared with sham, but nonresponders retained impaired glucose tolerance. These data indicate that the GLP-1 response tests may predict some but not all of the improvements observed after RYGB. These findings present an opportunity to optimize the use of bariatric surgery based on an improved understanding of GLP-1 biology and suggest an opportunity for a more personalized therapeutic approach to the metabolic syndrome.

GLP-1 and Glucose Tolerance After Sleeve Gastrectomy in Morbidly Obese Subjects With Type 2 Diabetes

“…Nonetheless, in line with our data, in that study the postsurgical GLP-1 response was not an independent predictor of glucose tolerance status. We also acknowledge data obtained in rodents suggesting that differences in the sensitivity to GLP-1 could be implicated in the effects of RYGB on glucose tolerance (13). Nonetheless, though limited by our cross-sectional design, the current association study supports the notion that GLP-1 secretion does not play a critical role in the outcome of T2DM after SG.…”

GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents

“…7,12,43). Exogenous administration of GLP-1 or its stable analog exendin-4, as well as PYY(3-36), has been shown in numerous preclinical and clinical studies to suppress food intake and lower body weight (e.g., (2,4,5,9,15,19,24,27,40,57,59) or to suppress hepatic glucose production (52), in some of them by directly acting on the brain. The stable GLP-1 receptor agonist exendin-4 is widely used by Type 2 diabetic patients to stabilize glucose levels and reduce body weight (30,43).…”

The potential of glucagon-like peptide 1 to reverse high-fat, high-sugar diet-related metabolic damage

“…However, vertical sleeve gastrectomy equally improves body weight and glycemic control in GLP-1R knockout (ko) and wild-type mice, indicating that GLP-1 action is not required for the metabolic benefits induced by the surgery [6]. Nevertheless, a recent study in rats showed that the presurgical responsiveness to GLP-1-induced weight loss predicts the postsurgical efficacy on improvement of glycemic control [7]. Furthermore, GLP-1R agonism enhances the weight-lowering efficacy of adjustable gastric banding and suggests that GLP-1 therapy is a valuable adjunct to adjustable gastric banding to optimize the efficacy of this minimally invasive surgery [8].…”