Glucagon-Like Peptide-1 Receptor Agonism Predicts Roux-en-Y Gastric Bypass Metabolic Benefits in Rats
6/10/2012 12:00:00 PM
6/10/2012 2:00:00 PM
DIEGO PEREZ-TILVE, NICKKI OTTAWAY, JENNA HOLLAND, CHRISTINE RAVER, ERIN BARTLEY, JOSE BERGER, MOUHAMADOUL TOURE, TIMO D. MUELLER, PAUL T. PFLUGER, RANDY J.. SEELEY, DAVID A.. D'ALESSIO, MATTHIAS H. TSCHOP,
The sedentary and dietary life style, which has evolved during the last decades, has been paralleled by an increase in the incidence of metabolic disturbances such as dyslipidemia, obesity and type 2 diabetes. The morbidity and mortality associated with these disease states necessitates novel and effective treatments. Currently, bariatric interventions are the most effective therapies to stimulate weight loss and treat obesity-related comorbidities. A common feature in many of these procedures is a hypersecretion of Glucagon-like peptide 1 (GLP-1). While the therapeutic implications of GLP-1 are well known, we hypothesized that response to GLP-1 prior to intervention may be predictive of outcome after Roux-en-Y gastric bypass (RYGB). To test this hypothesis, 200 adult, male Long-evans rats were screened to establish response to GLP-1 receptor agonism. Populations of responders and non-responders (30 of each) were identified based on body weight, food intake and glycemic regulation. Ex4 treatment stimulated an 8.5±0.46% body weight decrease in responders, and a 2.1±0.25% decrease in non-responders. Ex4-stimulated body weight loss was associated with altered food intake (10.6±3.3 vs 15.0±3.3 g/day). Rats responsive to Ex4 stimulated weight-loss also displayed lower fasting glucose and greater glucose tolerance. RYGB was conducted in groups of responders and non-responders, while a small group with intermediate response served as sham controls. Following RYGB, responders and non-responders showed similar BW loss, but responders displayed enhanced glucose tolerance. While both groups displayed hypersecretion of total plasma GLP-1 in response to a mixed-meal challenge, the responder group was characterized by increased active GLP-1 and plasma insulin. Taken together, these data suggest that prior GLP1-R sensitivity predicts glucose tolerance after RYGB, which is associated with increased levels of active GLP-1 and insulin levels in rats identified as responders.
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