The role of blood vessels, endothelial cells, and vascular pericytes in insulin secretion and peripheral insulin action

Abstract

The pathogenesis of type 2 diabetes is intimately intertwined with the vasculature. Insulin must efficiently enter the bloodstream from pancreatic beta-cells, circulate throughout the body, and efficiently exit the bloodstream to reach target tissues and mediate its effects. Defects in the vasculature of pancreatic islets can lead to diabetic phenotypes. Similarly, insulin resistance is accompanied by defects in the vasculature of skeletal muscle, which ultimately reduce the ability of insulin and nutrients to reach myocytes. An underappreciated participant in these processes is the vascular pericyte. Pericytes, the smooth muscle-like cells lining the outsides of blood vessels throughout the body, have not been directly implicated in insulin secretion or peripheral insulin delivery. Here, we review the role of the vasculature in insulin secretion, islet function, and peripheral insulin delivery, and highlight a potential role for the vascular pericyte in these processes.

Figure 1

Transendothelial transport of insulin and glucose to muscle interstitium. A, In the normal state, insulin and glucose must travel from the blood stream across endothelial cells and potentially pericytes to reach the muscle interstitium and activate insulin signaling in myocytes. The basal flow rate is depicted by the horizontal arrow. B, Insulin induces vasodilation of muscle vasculature, which is thought to increase nutritive blood flow, which increases transport of insulin and glucose to the muscle interstitium. C, In insulin-resistant situations, insulin exerts only vasoconstriction signals, which decreases nutritive flow, leading to reduced glucose and insulin transendothelial transport. D, Loss of pericytes is thought to increase muscle vessel permeability and transendothelial transport. A color version of this figure is available as Supplemental Figure 1.

Figure 2

Insulin-induced vasodilation and vasoconstriction signaling in endothelial cells and pericytes. A, Insulin signaling in endothelial cells results in increased NO production and secretion, which stimulates the dephosphorylation of myosin in pericytes and vSMCs and results in vasorelaxation. B, Conversely, insulin also stimulates endothelin-1 production, which stimulates myosin phosphorylation and results in vasoconstriction. DAG, Diacylglycerol; IR, insulin receptor; IP₃, insositol tris-phosphate; P, phosphate; PLC, phospholipase C, ETA/ETB, endothelin receptor.