Abstract 614: TRAIL Deletion in Mice Promotes Vascular Insulin Resistance

Abstract

TNF-related apoptosis-inducing ligand (TRAIL) is protective in cardiovascular disease and diabetes; whether it regulates insulin resistance and inflammation in the vessel wall is unknown. Wildtype and Trail -/- mice were placed on a high fat diet (HFD) for 12 w. Plasma chemistries were assessed; glucose and insulin tolerance tests performed. Histological GLUT4 expression in skeletal muscle was assessed. Aortic inflammatory marker expression and downstream insulin signaling was also measured; myography was performed. In response to a HFD for 12 w, wildtype mice had increased aortic IL-1beta, MCP-1, IL-6, TNF-alpha and TRAIL mRNA, with reduced circulating TRAIL levels. Compared to 12 w HFD-fed wildtype mice, Trail -/- mice had significantly increased plasma glucose, insulin, and cholesterol levels. Insulin intolerance was worse with TRAIL deletion, with reduced GLUT4 expression and glucose uptake in skeletal muscle. In response to insulin, Trail -/- aortas displayed impaired vasorelaxation and reduced aortic p-Akt expression. Importantly, aortic insulin resistance was associated with > 20-fold increased aortic mRNA expression for IL-1beta, IL-6, and TNF-alpha. We show that TRAIL protects against insulin resistance and type-2 diabetes, in part by regulating downstream insulin signals and inflammation in the vessel wall. These findings suggest that TRAIL may offer a novel therapeutic solution to combat inflammation and insulin resistance in diabetic vascular diseases.