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Abstract
Insulin resistance is a hallmark of metabolic syndrome, including type 2 diabetes mellitus and obesity which are characterized by endothelial dysfunction. The endothelial dysfunction leads to erectile dysfunction (ED). Thus, understanding of insulin resistance is mandatory for urologists to understand a pathophysiology of ED. There are two distinct features of insulin signal transduction pathway. One is phosphatidylinositol 3-ki- nase-dependent pathway which regulates glucose uptake in skeletal muscle and nitric oxide (NO) production and vasodilation in vascular endo- thelium. In cavernous smooth muscles, insulin also induces the endothe- lium-dependent relaxation, however it may emanate from the direct inhibition of ᄂ-type Ca2+ channels by prostacyclin in addition to NO production. The other one is mitogen-activated protein (MAP)-kinase pathway which regulates growth and mitogenesis and controls secretion of endo- thelin-1 in vascular endothelium. Stimulation of sympathetic activity by insulin may also contribute to hemodynamic regulation. A shift in balance between vasoconstrictor and vasodilator actions of insulin may be an important factor in the vascular pathophysology of insulin resistance, leading to ED. Hyperglycemia, elevated free fatty acid levels, and proin- flammatory states share mechanisms between insulin resistance and endothelial dysfunction. There is evidence to suggest that testosterone is an important regulator of insulin sensitivity in men and hypotestoste- ronemia may have a role in the pathogenesis of insulin-resistant states. (Korean J Urol 2006;47:917-927)
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Fig. 1.
General feature of insulin signal transduction pathways. PI 3-kinase branch of insulin signaling regulates GLUT4 translocation and vasodilation in vascular endothelium. MAP-kinase branch of insulin signaling generally regulates growth and mitogenesis and controls secretion of ET-1 in vascular endothelium.91 PI: phosphatidylinositol, GLUT: glucose transporter, MAP: mitogen-activated protein, ET: endothelin.
Fig. 2.
Pathway specific insulin resistance creates imbalance between prohypertensive and antihypertensive vascular actions of insulin exacerbated by compensatory hyperinsulinemia.92 SNS: sympathetic nervous system, ET: endothelin, NO: nitric oxide.
Fig. 3.
Effects of NS-398 (10yM) and U-51605 (ΙΟμΜ) on the insulin-induced relaxations (n=8). NS-398 produced no remarkable changes, but U-51605 almost completely inhibits the insulin- induced relaxation.18 ∗p<0.05.
Fig. 4.
ᄂ-type calcium channel activities recorded in whole cell patch clamp mode (n=8). ᄂ-type Ca2+ currents are unaffected by insulin (ΙΟμΜ) treatment but prostacyclin (lOyM) treatment significantly reduces the L-type Ca2+ currents. ∗p<0.05.
Fig. 5.
Left, Parallel PI 3-kinase-dependent insulin-signaling pathways in metabolic and vascular tissues synergistically couple metabolic and vascular physiology under healthy conditions. IR: insulin receptor. Right, Parallel impairment in insulin-signaling pathways under pathological conditions contributes to synergistic coupling of insulin resistance and endothelial dysfunction. PI: phosphatidylinositol, eNOS: endothelial nitric oxide synthase, PDK: phosphoinositide-dependent kinase, GLUT: glucose transporter.
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