TARGETING INSULIN RESISTANCE TO IMPROVE ABNORMAL CARDIOVASCULAR CONTROL IN DIABETES

项目摘要/摘要 在2型糖尿病(T2 DM)患者中，运动会导致血压(BP)过度升高。 由于如此夸大的BP对体力消耗的反应增加了发生 不良心血管事件的发生，阐明其发生机制具有重要的临床意义。演练 升压反射(EPR)是一种起源于骨骼肌的反射，在心血管调节中起着关键作用。 系统在运动过程中。来自锻炼肌肉的感觉信号是通过机械地激活 敏感(肌肉机械反射)和化学敏感(肌肉代谢反射)传入神经元。尽管它 已有研究表明，T2 DM患者的肌肉代谢反射功能增强，这一点尚待阐明 肌肉机械反射是否也发生了改变。外周相关性慢性高胰岛素血症 胰岛素抵抗是2型糖尿病的病理生理特征之一。胰岛素直接影响 肌肉瞬时受体电位香草酸受体1的伤害性离子通道功能 已知对代谢反射功能有显著贡献，这表明高胰岛素血症可能在外周 增强2型糖尿病患者的EPR功能。相反，慢性高胰岛素血症会导致胰岛素转运障碍。 对中枢神经系统的作用，降低大脑中胰岛素信号通路的活性。因此， 外周和中枢胰岛素处理的变化可能有助于产生异常的EPR活动 T2 DM。这项提议的全球目标是确定BP升高背后的机制 2型糖尿病患者的运动反应。我们假设肌肉机械反射和代谢性反射的改变 功能在T2 DM和中枢异常循环控制的演变中起重要作用 外周胰岛素抵抗使T2 DM患者EPR活性增强。我们进一步假设，增强的 阻断化学敏感的肌肉受体可改善T2 DM患者的运动血压反应 外周或集中增加胰岛素的输送。因此，我们建议在体内和体外进行研究 糖尿病动物综合确定：a)T2 DM患者运动血压升高是否由 过度活跃的肌肉机械反射和代谢性反射(特定目标1)；b)外周胰岛素 抵抗导致肌肉高胰岛素血症导致T2 DM患者EPR的夸大，这可能是 通过拮抗TRPV1和机械敏感受体(特定目标2)而改善；以及c)是否 中枢性胰岛素抵抗导致脑低胰岛素血症是T2 DM患者EPR增加的原因 可以通过增加胰岛素的中枢递送来改善(特定目标3)。建议进行的研究包括 创新之处在于，它们保持了通过识别胰岛素来改变当前临床实践范例的潜力 抵抗是防治糖尿病心血管控制异常的关键靶点。 归根结底，我们的工作结果可能导致制定更有效的战略，以减轻 糖尿病相关的心血管疾病。

Project Summary/Abstract In patients with type 2 diabetes mellitus (T2DM), exercise elicits an excessive increase in blood pressure (BP). Since such an exaggerated BP response to physical exertion increases the risk for the development of an unfavorable cardiovascular event, elucidating the mechanisms responsible is clinically important. The exercise pressor reflex (EPR, a reflex originating in skeletal muscle) plays a pivotal role in regulating the cardiovascular system during exercise. Sensory signals from exercising muscle are generated by activation of mechanically sensitive (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) afferent neurons. Although it has been shown that muscle metaboreflex function is augmented in T2DM patients, it remains to be elucidated whether the muscle mechanoreflex is altered as well. Chronic hyperinsulinemia associated with peripheral insulin resistance is one of the pathophysiological characteristics of T2DM. Insulin directly influences the nociceptive ion channel function of the transient receptor potential vanilloid receptor 1 (TRPV1) in muscle known to contribute significantly to metaboreflex function, suggesting that hyperinsulinemia may peripherally augment EPR function in T2DM. In contrast, chronic hyperinsulinemia results in impairment of insulin transport to the central nervous system, decreasing the activity of the insulin signaling pathway in the brain. Thus, peripheral and central changes in insulin handling may contribute to the generation of abnormal EPR activity in T2DM. The global objective of this proposal is to determine the mechanisms underlying the heightened BP response to exercise in T2DM. We hypothesize that alterations in muscle mechanoreflex and metaboreflex function significantly contribute to the evolution of abnormal circulatory control in T2DM and that central as well as peripheral insulin resistance potentiates EPR activity in T2DM. We further hypothesize that the enhanced BP response to exercise in T2DM is ameliorated by blocking chemically sensitive muscle receptors peripherally or increasing the delivery of insulin centrally. Therefore, we propose in vivo and in vitro studies in diabetic animals to integratively determine: a) whether the heightened exercise BP in T2DM is mediated by an overactive muscle mechanoreflex as well as metaboreflex (specific aim 1); b) whether peripheral insulin resistance leading to muscle hyperinsulinemia contributes to the exaggerated EPR in T2DM which can be ameliorated by antagonizing TRPV1 and mechanically sensitive receptors (specific aim 2); and c) whether central insulin resistance leading to brain hypoinsulinemia contributes to the exaggerated EPR in T2DM which can be ameliorated by increasing central delivery of insulin (specific aim 3). The proposed studies are innovative in that they maintain the potential to shift current clinical practice paradigms by identifying insulin resistance as a key target for the prevention and treatment of abnormal cardiovascular control in diabetes. Ultimately, the results of our work could lead to more effective strategies for reducing the global burden of diabetes-associated cardiovascular disease.