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

Glucose-dependent insulinotropic polypeptide (GIP) promotes nutrient storage, but its vascular actions in skeletal muscle remain unclear. To determine whether GIP regulates muscle microvascular perfusion, a key determinant of substrate use, we examined GIP receptor (GIPR) expression in vascular endothelium and assessed GIP effects in vivo in chow-fed and high-fat diet (HFD)–fed rats. Overnight-fasted rats received 120-min infusions of saline or GIP, with or without concurrent insulin or glucagon-like peptide 1 (GLP-1). Immunofluorescence microscopy demonstrated clear GIPR expression in conduit, resistance, and microvascular vessel endothelium. GIP alone did not alter muscle microvascular perfusion in either group but completely abolished insulin- and GLP-1–induced microvascular recruitment. In cultured endothelial cells, GIP dose-dependently increased endothelin-1 (ET-1) secretion and suppressed insulin- or GLP-1–stimulated nitric oxide production. Transcriptomic profiling implicated activation of the GIP–angiotensin II type 1 receptor–ET-1 pathway. In conclusion, GIPR is widely expressed in vascular endothelium. While GIP does not independently recruit muscle microvasculature, it antagonizes insulin- and GLP-1–mediated vasodilation, identifying GIP as a conditional regulator of skeletal muscle perfusion and nutrient delivery, consistent with its physiological effect in directing nutrients toward storage depots. Article Highlights Skeletal muscle microvasculature is essential for nutrient delivery and metabolic regulation, but the vascular actions of glucose-dependent insulinotropic polypeptide (GIP) in muscle are unknown. We investigated whether GIP regulates skeletal muscle microvascular perfusion and interacts with insulin and GLP-1 signaling. GIP receptors are expressed in vascular endothelium, yet GIP alone does not increase muscle perfusion and instead antagonizes insulin- and GLP-1–mediated microvascular recruitment via possibly angiotensin II type 1 receptor–dependent endothelin-1/nitric oxide imbalance. GIP acts as a conditional regulator of skeletal muscle microvascular perfusion, revealing a novel mechanism of tissue-specific incretin regulation of nutrient partitioning.