Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA; Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, USA.
Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
Metabolism. 2021 Jun;119:154766. doi: 10.1016/j.metabol.2021.154766. Epub 2021 Mar 22.
The cardiometabolic syndrome (CMS) and obesity are typically characterized by a state of metabolic insulin resistance. As global and US rates of obesity increase there is an acceleration of the incidence and prevalence of insulin resistance along with associated cardiovascular disease (CVD). Under physiological conditions insulin regulates glucose homeostasis by enhancing glucose disposal in insulin sensitive tissues while also regulating delivery of nutrients through its vasodilation actions on small feed arteries. Specifically, insulin-mediated production of nitric oxide (NO) from the vascular endothelium leads to increased blood flow enhancing disposal of glucose. Typically, insulin resistance is considered as a decrease in sensitivity or responsiveness to the metabolic actions of insulin including insulin-mediated glucose disposal. However, a decreased sensitivity to the normal vascular actions of insulin, especially diminished nitric oxide production, plays an additional important role in the development of CVD in states of insulin resistance. One mechanism by which insulin resistance and attendant hyperinsulinemia promote CVD is via increases in vascular stiffness. Although obesity and insulin resistance are known to be associated with substantial increases in the prevalence of vascular fibrosis and stiffness the mechanisms and mediators that underlie vascular stiffening in insulin resistant states are complex and have only recently begun to be addressed. Current evidence supports the role of increased plasma levels of aldosterone and insulin and attendant reductions in bioavailable NO in the pathogenesis of impaired vascular relaxation and vascular stiffness in the CMS and obesity. Aldosterone and insulin both increase the activity of serum and glucocorticoid kinase 1 (SGK-1) which in turn is a major regulator of vascular and renal sodium (Na channel activity.The importance of SGK-1 in the pathogenesis of the CMS is highlighted by observations that gain of function mutations in SGK-1 in humans promotes hypertension, insulin resistance and obesity. In endothelial cells, an increase in Na flux contributes to remodeling of the cytoskeleton, reduced NO bioavailability and vascular stiffening. Thus, endothelial SGK-1 may represent a point of convergence for insulin and aldosterone signaling in arterial stiffness associated with obesity and the CMS. This review examines our contemporary understanding of the link between insulin resistance and increased vascular stiffness with emphasis placed on a role for enhanced SGK-1 signaling as a key node in this pathological process.
代谢综合征（CMS）和肥胖通常以代谢性胰岛素抵抗为特征。随着全球和美国肥胖率的上升，胰岛素抵抗的发生率和患病率加速上升，同时伴有心血管疾病（CVD）。在生理条件下，胰岛素通过增强胰岛素敏感组织中葡萄糖的摄取来调节葡萄糖稳态，同时通过对小动脉的血管舒张作用来调节营养物质的输送。具体而言，胰岛素介导的血管内皮一氧化氮（NO）的产生导致血流增加，从而增强葡萄糖的摄取。通常，胰岛素抵抗被认为是对胰岛素的代谢作用的敏感性或反应性降低，包括胰岛素介导的葡萄糖摄取。然而，对胰岛素正常血管作用的敏感性降低，特别是一氧化氮产生减少，在胰岛素抵抗状态下 CVD 的发展中发挥着额外的重要作用。胰岛素抵抗和伴随的高胰岛素血症促进 CVD 的一种机制是通过增加血管僵硬度。尽管肥胖和胰岛素抵抗与血管纤维化和僵硬程度的显著增加相关，但在胰岛素抵抗状态下血管僵硬的机制和介质非常复杂，并且最近才开始得到解决。目前的证据支持血浆醛固酮和胰岛素水平升高以及生物可利用的一氧化氮减少在 CMS 和肥胖症中血管舒张和血管僵硬受损的发病机制中的作用。醛固酮和胰岛素都增加血清和糖皮质激素激酶 1（SGK-1）的活性，而 SGK-1 反过来又是血管和肾脏钠（Na）通道活性的主要调节剂。在 CMS 发病机制中 SGK-1 的重要性突出表现在人类 SGK-1 的功能获得性突变促进高血压、胰岛素抵抗和肥胖。在内皮细胞中，Na 通量的增加导致细胞骨架重塑、NO 生物利用度降低和血管僵硬。因此，内皮细胞 SGK-1 可能代表与肥胖和 CMS 相关的动脉僵硬中胰岛素和醛固酮信号的交汇点。本综述检查了我们对胰岛素抵抗与血管僵硬增加之间联系的现代理解，重点介绍了增强的 SGK-1 信号作为这一病理过程关键节点的作用。
