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Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals with Obesity and Pre-Diabetes

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posted on 2023-10-24, 15:56 authored by Mona Mashayekhi, Hui Nian, Dustin Mayfield, Jessica K. Devin, Jorge L. Gamboa, Chang Yu, Heidi J. Silver, Kevin Niswender, James M. Luther, Nancy J. Brown

Metabolic effects of glucagon-like peptide-1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and pre-diabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin (9-39) and placebo were administered in a two-by-two crossover study during mixed meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA-IR, HOMA2 and the Matsuda index after two weeks, prior to weight loss. Liraglutide decreased fasting and post-prandial glucose, decreased insulin and C-peptide, and decreased fasting glucagon. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not Matsuda index, and did not decrease glucose. Sitagliptin increased endogenous GLP-1 and GIP without altering insulin sensitivity or fasting glucose, but decreased post-prandial glucose and glucagon. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose in all groups, increased Matsuda index and fasting glucagon during liraglutide, and increased endogenous GLP-1 during liraglutide and sitagliptin. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1.

Funding

Research reported in this publication was supported by the American Heart Association 17SFRN33520017 (M.M., H.N., D.M., J.R.K., C.Y., H.S., J.M.L, N.J.B), National Center for Advancing Translational Sciences 5UL1TR002243, National Institute of Diabetes and Digestive and Kidney Diseases T32DK007061 (M.M). This work utilized the core(s) of the Vanderbilt Diabetes Research and Training Center funded by grant DK020593 from the National Institute of Diabetes and Digestive and Kidney Disease. Novo Nordisk provided liraglutide and matching placebo.

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