Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
Mol Cell Endocrinol. 2013 Sep 25;378(1-2):59-69. doi: 10.1016/j.mce.2012.05.017. Epub 2012 Jun 7.
Metabolic actions of insulin to promote glucose disposal are augmented by nitric oxide (NO)-dependent increases in microvascular blood flow to skeletal muscle. The balance between NO-dependent vasodilator actions and endothelin-1-dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K)--and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. Angiotensin II acting on AT₂ receptor increases capillary blood flow to increase insulin-mediated glucose disposal. In contrast, AT₁ receptor activation leads to reduced NO bioavailability, impaired insulin signaling, vasoconstriction, and insulin resistance. Insulin-resistant states are characterized by dysregulated local renin-angiotensin-aldosterone system (RAAS). Under insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Similarly, excess AT₁ receptor activity in the microvasculature may selectively impair vasodilation while simultaneously potentiating the vasoconstrictor actions of insulin. Therapeutic interventions that target pathway-selective impairment in insulin signaling and the imbalance in AT₁ and AT₂ receptor signaling in microvascular endothelium may simultaneously ameliorate endothelial dysfunction and insulin resistance. In the present review, we discuss molecular mechanisms in the endothelium underlying microvascular and metabolic actions of insulin and Angiotensin II, the mechanistic basis for microvascular endothelial dysfunction and insulin resistance in RAAS dysregulated clinical states, and the rationale for therapeutic strategies that restore the balance in vasodilator and constrictor actions of insulin and Angiotensin II in the microvasculature.
胰岛素促进葡萄糖摄取的代谢作用通过一氧化氮 (NO) 依赖性增加骨骼肌微血管血流得到增强。胰岛素的 NO 依赖性血管舒张作用和内皮素-1 依赖性血管收缩作用之间的平衡分别受血管内皮细胞中磷脂酰肌醇 3-激酶依赖性 (PI3K) 和丝裂原活化蛋白激酶 (MAPK) 依赖性信号转导的调节。血管紧张素 II 通过 AT₂ 受体作用于增加毛细血管血流以增加胰岛素介导的葡萄糖摄取。相反，AT₁ 受体的激活导致 NO 生物利用度降低、胰岛素信号受损、血管收缩和胰岛素抵抗。胰岛素抵抗状态的特征是局部肾素-血管紧张素-醛固酮系统 (RAAS) 失调。在胰岛素抵抗状态下，PI3K 依赖性信号通路的特异性损伤可能导致 NO 和内皮素-1 的产生之间的失衡，导致血流量减少，从而加重胰岛素抵抗。同样，微血管中 AT₁ 受体活性的过度增加可能选择性地损害血管舒张，同时增强胰岛素的血管收缩作用。针对胰岛素信号通路和 AT₁ 和 AT₂ 受体信号通路在微血管内皮细胞中选择性损伤的治疗干预可能同时改善内皮功能障碍和胰岛素抵抗。在本综述中，我们讨论了胰岛素和血管紧张素 II 的微血管和代谢作用的内皮细胞中的分子机制、RAAS 失调的临床状态中小血管内皮功能障碍和胰岛素抵抗的机制基础，以及恢复血管舒张和血管紧张素 II 的血管收缩作用在微血管中的平衡的治疗策略的合理性。
