TARGETING INSULIN RESISTANCE TO IMPROVE ABNORMAL CARDIOVASCULAR CONTROL IN DIABETES

项目概要/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。 由于这种对体力消耗的过度BP反应增加了发生 不利的心血管事件，阐明负责的机制在临床上是重要的。行使 升压反射（EPR，起源于骨骼肌的反射）在心血管调节中起着关键作用 系统在运行中。来自运动肌肉的感觉信号是通过机械激活产生的。 敏感（肌肉机械反射）和化学敏感（肌肉代谢反射）传入神经元。虽然 已经表明，肌肉代谢反射功能在T2 DM患者中增强，但仍有待阐明 肌肉机械反射是否也发生了改变。慢性高胰岛素血症与外周血 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 瞬时受体电位香草酸受体1（TRPV 1）在肌肉中的伤害性离子通道功能 已知对代谢反射功能有显着贡献，这表明高胰岛素血症可能是外周的 增强T2 DM患者的EPR功能。相反，慢性高胰岛素血症导致胰岛素转运受损 中枢神经系统，降低大脑中胰岛素信号通路的活性。因此，在本发明中， 外周和中枢胰岛素处理的变化可能有助于产生异常的EPR活性， 2型糖尿病。该提案的总体目标是确定BP升高的潜在机制 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反射的改变 功能显著有助于T2 DM患者循环控制异常的演变， 因为外周胰岛素抵抗增强了T2 DM中的EPR活性。我们进一步假设， 通过阻断化学敏感性肌肉受体改善T2 DM患者对运动的BP反应 外周或增加胰岛素的中枢递送。因此，我们建议在体内和体外研究， 糖尿病动物以综合确定：a）T2 DM中运动血压升高是否由下列因素介导 过度活跃的肌肉机械反射以及代谢反射（具体目标1）; B）外周胰岛素是否 导致肌肉高胰岛素血症的抵抗导致T2 DM中EPR增加， 通过拮抗TRPV 1和机械敏感受体而改善（具体目的2）;和c）是否 导致脑低胰岛素血症的中枢胰岛素抵抗导致T2 DM患者的EPR增加， 可以通过增加胰岛素的中心递送来改善（具体目标3）。拟议的研究是 创新之处在于它们保持了通过鉴定胰岛素来改变当前临床实践范例的潜力 作为预防和治疗糖尿病心血管控制异常的关键目标。 最终，我们的工作成果可能导致更有效的战略，以减轻全球的 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.