Do GLP-1 receptor agonists improve insulin sensitivity and reduce lipid accumulation in skeletal muscles and the liver independent of weight loss?

Increased body mass index and excessive lipid accumulation are associated with enhanced production of toxic lipid species and impairedoxidation of free fatty acids (FFAs), a phenomenon defined as lipotoxicity. It is an important predictor of etabolic disorders such astype 2 diabetes (T2D). Increased lipid accumulation leads to decreased glucose uptake in skeletal muscle and enhanced hepatic glucoseproduction. Thus, ectopic fat accumulation impairs insulin signalling and decreases insulin sensitivity (IS). Scientific data demonstratethat glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can improve IS and decrease lipid accumulation in peripheral tissues mainlythrough weight loss. However, experimental studies indicate that GLP-1 RAs exert direct effects on glucose and lipid metabolic pathways,although the precise mechanisms remain incompletely understood. GLP-1 RAs may directly modulate fatty acid β-oxidation, lipogenesis,and 5'-AMP-activated protein kinase (AMPK) phosphorylation. In this review, we discuss the mechanisms by which liraglutide and subcutaneoussemaglutide affect IS and lipid accumulation in key insulin-responsive tissues.