Restoring vasodilator actions of insulin in patients with type 2 diabetes

项目摘要/摘要 在2型糖尿病(T2D)中，胰岛素刺激的骨骼肌血流明显迟钝， 显著限制葡萄糖摄取，从而导致葡萄糖动态平衡受损。一个详细的 对血管舒张剂作用缺陷的诱发因素和机制的认识 胰岛素对于开发旨在改善血糖控制和治疗的治疗策略至关重要 预防心血管疾病。根据我们之前的工作和最新的初步数据，我们 认为在高血糖的T2D患者中，蛋白激酶C(PKC)的激活驱动 内皮素-1(ET-1)及其在胰岛素诱导的扩张中的损害。此外，我们假设 增加血管对切应力的暴露，与体力活动有关，可以减轻这些有毒分子 高血糖对血管内皮细胞的影响并显著改善胰岛素诱导的血管扩张 T2D。具体地说，我们将测试最重要的假设，即内皮细胞PKC激活介导 T2D患者ET-1上调和胰岛素诱导的扩张功能受损，这一缺陷可能是 修正了增加的体力活动和剪切力。在目标1和目标2中，体外功能研究将 在肥胖的T2D和肥胖的非T2D患者的隔离内脏阻力动脉上进行手术 Roux-en-Y胃旁路手术。通过功能增益和损耗实验，我们将检验其作用 蛋白激酶C活化在T2D患者胰岛素诱导的动脉扩张受损中的作用 高血糖和剪切力在调节胰岛素诱导的扩张中的作用。在目标3中，我们将执行一项临床 T2D患者步行增加和剪切力对胰岛素刺激影响的研究 腿部血液流动。特别是，我们将检验这样一个假设，即增加8周的步行会减少血管 PKC激活和ET-1的产生，从而导致胰岛素刺激的腿部血流量的改善。腿 在高胰岛素-正常血糖钳夹期间，将通过多普勒超声评估血流。骨骼 将进行肌肉活组织检查以确定血管表型。此外，我们将确定是否 使用非运动刺激增加腿部血管切应力(即8周的腿部加热干预) 重述了增加步行对血管有益的影响。靶向PKC激活和ET-1， 从药理上或通过增加切应力，可能是纠正血管胰岛素的关键 T2D患者的代谢和心血管结局的抵抗和最终改善。 事实上，我们的研究团队正准备在一个领域推动心血管和糖尿病的研究 目前很少受到关注，尽管它很重要，而且显然需要进行调查。

PROJECT SUMMARY/ABSTRACT In type 2 diabetes (T2D), insulin-stimulated blood flow to skeletal muscle is markedly blunted which significantly limits glucose uptake, thus contributing to impaired glucose homeostasis. A detailed understanding of the precipitating factors and mechanisms underlying the defects in vasodilator actions of insulin is critical for the development of therapeutic strategies aimed at improving glycemic control and protecting against cardiovascular disease. Based on our prior work and most recent preliminary data, we propose that in hyperglycemic T2D patients, protein kinase C (PKC) activation drives the upregulation of endothelin-1 (ET-1) and consequent impairment in insulin-induced dilation. Furthermore, we hypothesize that increased vascular exposure to shear stress, associated with physical activity, mitigates these toxic molecular effects of hyperglycemia on endothelial cells and lead to substantial improvements in insulin-induced dilation in T2D. Specifically, we will test the overarching hypothesis that endothelial PKC activation mediates the upregulation of ET-1 and impairment in insulin-induced dilation in patients with T2D, a defect that can be corrected with increased physical activity and shear stress. In Aims 1 and 2, ex vivo functional studies will be performed in isolated visceral resistance arteries from obese T2D and obese non-T2D patients undergoing Roux-en-Y gastric bypass surgery. Through gain- and loss-of-function experiments, we will examine the role of PKC activation in mediating impaired insulin-induced dilation in arteries from T2D patients as well as the role of hyperglycemia and shear stress in modulating insulin-induced dilation. In Aim 3, we will perform a clinical study in patients with T2D to determine the effects of increased walking and shear stress on insulin-stimulated leg blood flow. In particular, we will test the hypothesis that increased walking for 8 weeks decreases vascular PKC activation and ET-1 production, thus leading to an improvement in insulin-stimulated leg blood flow. Leg blood flow via Doppler ultrasound will be assessed during a hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies will be performed for vascular phenotypic characterization. Furthermore, we will determine if increased leg vascular shear stress using a non-exercise stimulus (i.e., leg heating intervention for 8 weeks) recapitulates the beneficial vascular effects of increased walking. Targeting PKC activation and ET-1, pharmacologically or through an increase in shear stress, may be key for correction of vascular insulin resistance and ultimately improvement of metabolic and cardiovascular outcomes in patients with T2D. Indeed, our research team is poised to move cardiovascular and diabetes research forward in an area currently receiving little attention, despite its importance and clear need for investigation.