Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes

• Published in: Diabetes (New York, N.Y.) Vol. 73; no. 1; pp. 38 - 50
• Main Authors: Mashayekhi, Mona, Nian, Hui, Mayfield, Dustin, Devin, Jessica K, Gamboa, Jorge L, Yu, Chang, Silver, Heidi J, Niswender, Kevin, Luther, James M, Brown, Nancy J
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.01.2024
• Subjects: Agonists; Antidiabetics; Blood Glucose - metabolism; Body weight loss; Cross-Over Studies; Diet, Reducing; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Fasting; Glucagon; Glucagon - metabolism; Glucagon-like peptide 1; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - agonists; Glucose; Humans; Hypocaloric diet; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin Resistance; Liraglutide - pharmacology; Liraglutide - therapeutic use; Obesity; Obesity - drug therapy; Peptides; Prediabetic State - drug therapy; Sitagliptin Phosphate - pharmacology; Sitagliptin Phosphate - therapeutic use; Weight control; Weight Loss
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db23-0356

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 prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a 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 for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.