109-OR: GIP Acutely Blunts Insulin- and GLP-1–Induced Muscle Microvascular Perfusion

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Though vascular endothelium expresses GIP receptors, GIP’s vascular action has not been well defined. To assess the effect of GIP on muscle microvascular perfusion, adult male rats were fed either a chow or high-fat diet (HFD) for 2 weeks, fasted overnight, and randomly assigned to one of the following subgroups: 1) saline or GIP (4 pmol/kg/min) infusion for 120 min; 2) euglycemic hyperinsulinemic clamp (3 mU/kg/min) plus saline or GIP infusion for 120 min; 3) glucagon-like peptide 1 (GLP-1, 30 pmol/kg/min) plus saline or GIP infusion for 120 min. Compared to chow rats, HFD-fed rats exhibited increased visceral adiposity and higher fasting levels of serum insulin, GIP, and GLP-1. Hindlimb muscle microvascular perfusion was measured using contrast-enhanced ultrasound. Neither saline nor GIP infusion altered muscle microvascular perfusion in chow or HFD-fed rats. Insulin and GLP-1 infusion each significantly enhanced muscle microvascular perfusion in chow rats within 30 min and this effect lasted during the entire infusion period. GLP-1, but not insulin, also enhanced muscle microvascular perfusion in HFD-fed rats. Superimposing GIP infusion to either insulin or GLP-1 infusion completely abolished insulin-mediated microvascular perfusion in chow rats or GLP-1-induced microvascular perfusion in either chow- or HFD-fed rats, without altering serum levels of insulin or GLP-1. In cultured primary microvascular endothelial cells isolated from rat hindlimb muscle, GIP incubation for 24 h does-dependently increased ET-1 and inhibited GLP-1 (1 ng/mL)-induced nitric oxide (NO) production. We conclude that microvascular endothelium is a direct target of GIP action, and GIP modulates insulin’s and GLP-1’s vascular actions partly through the ET-1 and NO signaling pathways.