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

Aims: To test whether liraglutide suppresses postprandial elevations in lipids and thus protects against high saturated fatty acid (SFA) diet-induced insulin resistance. Methods: In a randomized placebo-controlled crossover study, 32 participants with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and after a 24-hour 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 underwent 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 <.01 vs placebo). The SFA diet-induced impairment of vasodilation on placebo (−9.4% vs baseline; P <.01) was ameliorated by liraglutide (−4.8%; P =.1 vs baseline). In skeletal muscle, liraglutide abolished the SFA-induced increase in thioredoxin-interacting protein (TxNIP) expression (75% decrease; P <.01 vs placebo) and increased 5′AMP-activated protein kinase (AMPK) phosphorylation (50% vs −3%; P =.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.