Effect of liraglutide on dietary lipid‐induced insulin resistance in humans

Aims High saturated fatty acid (SFA) diets blunt peripheral insulin action. GLP-1 receptor agonists suppress postprandial lipids and endothelial dysfunction, which may counter SFA-induced insulin resistance. This study tested whether liraglutide suppresses postprandial elevations in lipids and thus protects against high SFA-diet induced insulin resistance. Materials and methods In a randomized placebo-controlled cross-over study, 32 subjects with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and following a 24-hr SFA-enriched diet after each treatment. Plasma glucose, insulin, triglycerides and non-esterified fatty acids (NEFA) were measured over the initial 8 hours (breakfast and lunch) on the SFA diet. A subset of participants had ex vivo measurements of insulin-mediated vasodilation of adipose tissue arterioles and glucose metabolism regulatory proteins in skeletal muscle. Results Liraglutide reduced plasma glucose, triglycerides and NEFA concentrations during the SFA-diet (by 50, 25 and 9% respectively), and the SFA-diet increased plasma glucose during the IST (by 36%) (all p < 0.01 vs. placebo). The SFA-diet induced impairment of vasodilation on placebo (−9.4% vs. baseline, p < 0.01) was ameliorated by liraglutide (−4.8%, p = 0.1 vs. baseline). In skeletal muscle, liraglutide abolished the SFA-induced increase in thioredoxin-interacting protein (TxNIP) expression (75% decrease, p < 0.01 vs. placebo) and increased 5'AMP-activated protein kinase (AMPK) phosphorylation (50% vs. -3%, p = 0.04 vs. placebo). Conclusions Liraglutide blunted the SFA-enriched diet-induced peripheral insulin resistance. This effect may be related to improved microvascular function and modulation of TxNIP and AMPK pathways in skeletal muscle.