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

Abstract

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.

Article highlights: 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.

Graphical abstract

Figure 1

Effects of treatment on glucose, insulin, and C-peptide levels after mixed-meal tolerance test. Plots show mean ± SEM for glucose (A), insulin-to-glucose ratio (B), and C-peptide–to–glucose ratio (C) at baseline, 2 weeks, and 14 weeks of treatment. Panels indicate treatment arm. Time after ingestion of mixed meal is shown on the x-axis. Statistical comparisons are provided in Table 2.

Figure 2

Effects of treatment on glucagon, GLP-1, and GIP levels after mixed-meal tolerance test. Plots show mean ± SEM for glucagon (A), active GLP-1 (B), and active GIP (C) at baseline, 2 weeks, and 14 weeks of treatment. Panels indicate treatment arm. Time after ingestion of mixed meal is shown on the x-axis. Statistical comparisons are provided in Table 2.

Figure 3

Effects of GLP-1R antagonism on glucose and C-peptide levels. Plots show mean ± SEM for glucose (A) and C-peptide–to–glucose ratio (B). Panels indicate treatment arm and study period. Baseline measurements before randomization are shown by black circles. Time after ingestion of mixed meal is shown on the x-axis. Statistical comparisons are provided in Table 3.

Figure 4

Effects of GLP-1R antagonism on GLP-1 and glucagon. Plots show mean ± SEM for active GLP-1 (A) and glucagon (B). Panels indicate treatment arm and study period. Baseline measurements before randomization are shown by black circles. Time after ingestion of mixed meal is shown on the x-axis. Statistical comparisons are provided in Table 3.