GLP-1R Responsiveness Predicts Individual Gastric Bypass Efficacy on Glucose Tolerance in Rats
- Kirk M. Habegger1,
- Kristy M. Heppner1,
- Sarah E. Amburgy1,
- Nickki Ottaway1,
- Jenna Holland1,
- Christine Raver1,
- Erin Bartley1,
- Timo D. Müller2,
- Paul T. Pfluger2,
- Jose Berger1,
- Mouhamadoul Toure1,
- Stephen C. Benoit1,
- Richard D. DiMarchi3,
- Diego Perez-Tilve1,
- David A. D’Alessio1,
- Randy J. Seeley1 and
- Matthias H. Tschöp2⇑
- 1Metabolic Diseases Institute, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Cincinnati, Cincinnati, OH
- 2Institute for Diabetes and Obesity, Helmholtz Zentrum München and Technische Universität München, Munich, Germany
- 3Department of Chemistry, Indiana University, Bloomington, IN
- Corresponding author: Matthias H. Tschöp, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0511/-/DC1.
See accompanying commentary, p. 399.
- Received March 29, 2013.
- Accepted October 1, 2013.
- © 2014 by the American Diabetes Association.
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