Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure.
Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure.
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胰岛素受体底物信号传导控制心脏能量代谢和心力衰竭。
DOI：
10.1530/joe-16-0679
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发表时间：
2017-06
影响因子：
4
通讯作者：
Guo, Shaodong
中科院分区：
文献类型：
--
作者：
Guo, Cathy A.;Guo, Shaodong
心脏是一个胰岛素依赖性和能量消耗器官，其中胰岛素和营养信号整合到心脏代谢、生长和存活的调节中。心力衰竭与胰岛素抵抗密切相关，心力衰竭患者会出现心脏能量不足、结构和功能障碍。慢性病理状况，例如肥胖和2型糖尿病，涉及通过重塑代谢途径、调节心脏能量和损害心肌收缩力来促进心力衰竭的多种机制。最近的研究表明，胰岛素受体底物-1, -2 (IRS-1, -2) 是胰岛素和胰岛素样生长因子-1 (IGF-1) 信号传导的主要介质，负责心肌能量、结构、功能和机体存活。重要的是，胰岛素受体底物 (IRS) 在磷脂酰肌醇 3 依赖性激酶 (PI-3K) 的激活中发挥重要作用，PI-3K 控制 Akt 和 Foxo1 信号级联，调节线粒体功能、心脏能量代谢和肾素-血管紧张素系统。通过内分泌系统，心脏中的胰岛素抵抗导致信号级联中的这一分支失调，从而促进心力衰竭，为糖尿病性心肌病提供了一种新机制。因此，针对IRS→PI-3K→Foxo1信号级联和相关通路的这一分支可能为控制代谢和心血管疾病的治疗和营养开发提供基本策略。在这篇综述中，我们重点关注心脏中的胰岛素信号传导和抵抗，以及能量学在心脏代谢、结构和功能中发挥的作用。
The heart is an insulin-dependent and energy consuming organ in which insulin and nutritional signaling integrates to the regulation of cardiac metabolism, growth, and survival. Heart failure is highly associated with insulin resistance and heart failure patients suffer from the cardiac energy deficiency, structural and functional dysfunction. Chronic pathological conditions, such as obesity and type 2 diabetes mellitus, involve various mechanisms in promoting heart failure by remodeling metabolic pathways, modulating cardiac energetics, and impairing cardiac contractility. Recent studies demonstrated that insulin receptor substrate-1, −2 (IRS-1, −2) are major mediators of both insulin and insulin-like growth factor-1 (IGF-1) signaling responsible for myocardial energetics, structure, function, and organismal survival. Importantly, the insulin receptor substrates (IRS) play an important role in activation of the phosphatidylinositide-3 dependent kinase (PI-3K) that controls Akt and Foxo1 signaling cascade, regulating the mitochondrial function, cardiac energy metabolism, and the renin-angiotensin system. Dysregulation of this branch in signaling cascades by insulin resistance in the heart through the endocrine system promotes heart failure, providing a novel mechanism for diabetic cardiomyopathy. Therefore, targeting this branch of IRS→PI-3K→Foxo1 signaling cascade and associated pathways may provide a fundamental strategy for the therapeutic and nutritional development in control of metabolic and cardiovascular diseases. In this review, we focus on insulin signaling and resistance in the heart and the role energetics play in cardiac metabolism, structure and function.