Insulin Resistance and Myocardial Autophagy

描述（由申请方提供）：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。这些条件也独立增加心力衰竭的风险，虽然机制不完全清楚。这项建议的重点是了解自噬在胰岛素抵抗状态下心功能不全的病理生理学中的作用。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，心肌自噬增加与禁食和减少与再喂养和这种动态调节依赖于一个完整的胰岛素信号通路。事实上，体内或体外胰岛素信号传导的破坏迅速诱导心肌细胞内的自噬。我们还观察到，在胰岛素抵抗和T2DM的鼠和猪模型以及T2DM患者的心脏样本中，心肌自噬增加。在这些模型中，尽管Akt的胰岛素信号正常或增加，但基础和胰岛素介导的葡萄糖摄取减少。建议研究胰岛素信号调节心肌自噬的机制和胰岛素抵抗状态下心肌自噬增加的机制。心脏中增加的自噬可以是适应性的或适应不良的，并且在肥胖和T2DM背景下的临床意义尚不清楚。这些机制的问题将探讨在三个特定的目标，使用培养的细胞，并通过诱导T2DM的转基因小鼠改变胰岛素或自噬信号或改变葡萄糖摄取。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将确定在2型糖尿病（T2DM）饮食诱导的肥胖（DIO）模型中心肌自噬增加的机制。目的3将通过检验T2DM中增加的自噬是一种适应性反应以及减少自噬信号传导将加速线粒体和心脏功能障碍的假设，确定在2型糖尿病（T2DM）的DIO模型中改变的心肌自噬在糖尿病心肌病进展中的临床和功能意义。总之，这些研究将提供胰岛素信号转导对心肌自噬调节的全面分析，并确定T2DM中心肌自噬增加的意义和机制。他们还将阐明在T2DM中调节自噬对线粒体和心脏功能的影响。从这些研究中获得的知识将为自噬在糖尿病心功能不全的病理生理学中可能发挥的重要作用提供新的见解，并将产生翻译影响，因为许多用于糖尿病的治疗策略可能会深刻影响心脏中的自噬。

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.