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

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.