Insulin's actions on vascular tissues: Physiological effects and pathophysiological contributions to vascular complications of diabetes

Figures

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  Figure 1. An overview of insulin's various actions on the vascular wall. Insulin receptors mediate insulin transport across the endothelial barrier via receptor-mediated transcytosis. In the endothelium, insulin activates either the PI3K/Akt pathway (through IRS) or the MAPK/Erk pathway and regulates the expression of HO-1, VEGF, and VCAM-1. In vascular smooth muscle cells, the PI3K/Akt pathway eventually leads to NO activation and muscular relaxation, while the MAPK/Erk pathway leads to ET-1 activation and consequently muscular contraction as well as cellular proliferation and migration. In vascular pericytes, insulin can also exert anti-apoptotic actions by inhibiting caspases and FOXO and increasing HO-1. IRS, insulin receptor substrate; HO-1, heme oxygenase; VEGF, vascular endothelial growth factor; VCAM-1, vascular cell adhesion molecule-1; NO, nitric oxide; ET-1, endothelin-1; ETBR, endothelin receptor type B; HAS2, hyaluronan synthase 2.

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  Figure 2. Selective insulin resistance in vascular endothelial cells (EC). Selective insulin resistance in EC is induced by angiotensin II, elevated FFA, high glucose levels, and proinflammatory cytokines from diabetes and insulin resistance. These stimulate PKC isoforms and other stress kinases to inhibit only the IRS/PI3K/Akt pathway through phosphorylation of IRS1/2. In contrast, insulin's stimulation of the SOS/Grb2/MAPK pathway is enhanced in diabetes and insulin resistance. The selective loss of insulin's actions via the IRS/PI3K/Akt pathway causes the reduction in insulin's anti-atherosclerotic action and contributes to the acceleration of atherosclerosis and other cardiovascular pathologies in diabetes and insulin resistance. FFA, free fatty acid; PKC, protein kinase C; IRS1/2, insulin receptor substrate 1/2; PTEN, phosphatase and tensin homolog; ETBR, endothelin receptor type B; ROS, reactive oxygen species.

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  Figure 3. Signaling of homozygous insulin receptor (IR/IR), IGF-1 receptor (IGF1R/IGF1R), and hybrid IR/IGF1R in vascular smooth muscle cells (VSMC). Physiological levels of insulin only bind to homo IR/IR, which enhance VSMC proliferation and exacerbate injury-induced intimal hyperplasia and atherosclerotic plaque stability by activating insulin signaling and upregulating Has2. In hyperinsulinemic conditions, insulin can bind to IR/IGF1R and homo IGF1R/IGF1R, enhance proliferation and migration, and accelerate restenosis. However, insulin resistance or hypoglycemia decreases restenosis and plaque stability. IGF-1, which mainly binds to IGF1R/IGF1R, does not alter restenosis but can increase plaque stability by enhancing VSMC proliferation, migration, and secretion of the extracellular matrix. HAS2, hyaluronan synthase 2.