Insulin Resistance and Myocardial Autophagy

描述（由申请人提供）：心血管疾病是肥胖、胰岛素抵抗和2型糖尿病（T2DM）患者发病和死亡的主要原因。这些情况也会独立增加心力衰竭的风险，尽管机制尚不完全清楚。本建议的重点是了解自噬在胰岛素抵抗状态心功能障碍的病理生理中的作用。自噬是一个受多种上游信号通路调控的动态过程。我们的初步研究表明，心肌自噬随着禁食而增加，随着再喂养而减少，这种动态调节依赖于完整的胰岛素信号通路。事实上，体内或体外胰岛素信号的破坏可迅速诱导心肌细胞自噬。我们还观察到，胰岛素抵抗和2型糖尿病小鼠和猪模型以及2型糖尿病患者心脏样本的心肌自噬增加。在这些模型中，尽管胰岛素对Akt的信号正常或增加，但基础和胰岛素介导的葡萄糖摄取减少。研究建议确定胰岛素信号调节心肌自噬的机制以及胰岛素抵抗状态下心肌自噬增加的机制。心脏自噬增加可能是适应性的，也可能是不适应性的，其在肥胖和2型糖尿病中的临床意义尚不清楚。这些机制问题将在三个特定目的中进行探讨，通过培养细胞和在胰岛素或自噬信号或葡萄糖摄取改变的转基因小鼠中诱导2型糖尿病。目的1将确定胰岛素信号调节心肌自噬的分子机制。目的2将确定2型糖尿病（T2DM）饮食性肥胖（DIO）模型中心肌自噬增加的机制。在2型糖尿病（T2DM） DIO模型中，心肌自噬改变在糖尿病心肌病进展中的临床和功能意义，通过验证T2DM中自噬增加是一种适应性反应的假设，以及自噬信号的减少会加速线粒体和心功能障碍。综上所述，这些研究将全面分析胰岛素信号对心肌自噬的调节，并确定T2DM患者心肌自噬增加的意义和机制。他们还将阐明调节自噬对T2DM患者线粒体和心功能的影响。从这些研究中获得的知识将为自噬在糖尿病心功能障碍的病理生理学中可能发挥的重要作用提供新的见解，并且考虑到许多用于糖尿病的治疗策略可能深刻影响心脏的自噬，将具有转化影响。

DESCRIPTION (provided by applicant): Cardiovascular disease is the major cause of morbidity and mortality in humans with obesity, insulin resistance and type 2 diabetes (T2DM). These conditions also independently increase the risk of heart failure, although mechanisms are incompletely understood. The focus of this proposal is to understand the role of autophagy in the pathophysiology of cardiac dysfunction in insulin resistant states. Autophagy is a dynamic process that is regulated by various upstream signaling pathways. Our preliminary studies indicate that myocardial autophagy is increased with fasting and reduced with re-feeding and this dynamic regulation is dependent upon an intact insulin signaling pathway. Indeed, disruption of insulin signaling in vivo or in vitro rapidly induces autophagy within cardiomyocytes. We have also observed that myocardial autophagy is increased in murine and pig models of insulin resistance and T2DM and in heart samples from humans with T2DM. In these models basal and insulin-mediated glucose uptake is reduced, despite normal or increased insulin signaling to Akt. Studies are proposed to determine the mechanisms by which insulin signaling regulates myocardial autophagy and mechanisms responsible for increased myocardial autophagy in insulin resistant states. Increased autophagy in the heart can be adaptive or maladaptive and the clinical significance in the context of obesity and T2DM are unknown. These mechanistic questions will be explored in three specific aims using cultured cells and by inducing T2DM in genetically modified mice with altered insulin or autophagic signaling or altered glucose uptake. Aim 1 will determine the molecular mechanisms by which insulin signaling regulates myocardial autophagy. Aim 2 will determine the mechanism for increased myocardial autophagy in the diet-induced obesity (DIO) model of type 2 diabetes (T2DM). Aim 3 will determine the clinical and functional significance of altered myocardial autophagy in the progression of diabetic cardiomyopathy in the DIO model of type 2 diabetes (T2DM) by testing the hypothesis that increased autophagy in T2DM is an adaptive response and that reducing autophagic signaling will accelerate mitochondrial and cardiac dysfunction. Taken together, these studies will provide a comprehensive analysis of the regulation of myocardial autophagy by insulin signaling and determine the significance of and the mechanisms for increased myocardial autophagy in T2DM. They will also elucidate the consequence of modulating autophagy on mitochondrial and cardiac function in T2DM. The knowledge gained from these studies will shed novel insights into the important role that autophagy may play in the pathophysiology of cardiac dysfunction in diabetes and will have translational impact given that many therapeutic strategies in use for diabetes may profoundly impact autophagy in the heart. PUBLIC HEALTH RELEVANCE: The global increase in the prevalence of obesity, insulin resistance and type 2 diabetes is predicted to lead to an increase in cardiovascular morbidity, including heart failure. The mechanisms linking insulin resistance to heart failure are multifactorial. Although increased coronary ischemia, and ventricular hypertrophy play important roles, there is growing evidence for a role for intrinsic defects within cardiomyocytes that include altered mitochondrial function, altered calcium signaling and lipotoxicity. The current proposal will evaluate the significance if increased autophagy, which is a novel mechanism that may contribute to the pathophysiology of cardiac dysfunction in insulin resistant states. It is not known if this increase is autophagy represents an adaptation that maintains cardiac function or if it is deleterious. Because many diabetes therapies may alter myocardial autophagy, it is important to understand the impact of these therapies on cardiac autophagy. Recent evidence of adverse cardiovascular consequences of some diabetes therapeutics has prompted the FDA to require evidence for improved cardiovascular outcomes in addition to improved metabolic control as a pre-requisite for the approval of any new diabetes therapy. Moreover, the impact of tight glycemic control on cardiovascular outcomes in type 2 diabetes is mixed. Therefore, studies that will elucidate the molecular mechanisms linking diabetes-associated metabolic disturbances with cardiac dysfunction, and the way that these mechanisms could be altered by diabetes therapies are timely and important.