Acute effects of hyperglycemia on heart and skeletal muscle microvasculature

摘要 本修订申请提出了2项小型、单中心、机械临床试验。我们的总体 假设急性高血糖症和/或葡萄糖变异性（GV）对微血管 心脏（CM）和骨骼肌（SM）中的灌注，这可以部分解释 急性高血糖对急性冠状动脉综合征临床预后的负面影响而 慢性高血糖引起功能性和解剖性糖尿病微血管疾病， 高血糖可升高血浆内皮细胞（EC）应激“生物标志物”浓度， 急性高血糖症和GV的微血管后果（如果有的话）尚不清楚。微血管 灌注是向SM和CM输送营养和氧气的关键决定因素， 受到胰岛素抵抗的影响。利用我们在超声造影方面的丰富经验 (CEU)我们将在AIM 1中测试复杂代谢研究中微血管灌注的测量， 急性高血糖对CM和SM中基础和胰岛素介导的微血管灌注的影响 健康的人类在AIM 2中，我们将在基线时量化微血管灌注，以响应胰岛素 以及对T2 DM患者进餐的反应。我们将在T2 DM中进一步测试， SGLT-2抑制剂（vs安慰剂）降低GV和餐后高血糖波动，持续12 周增强CM微血管灌注，无论是在基线时，还是在急性 高胰岛素血症或膳食摄入。目标3将确定微血管的行为是否 在目的1和2中看到的，与大动脉对高血糖， 高胰岛素血症或膳食刺激或药物治疗，通过血流介导的扩张（FMD）测量，脉搏 波速度（PWV）、增强指数（AI）或缺血后血流速度（PIFV）。完成 这些研究将提供关于高血糖症，GV， T2 DM及T2 DM治疗对CM和SM微血管功能的影响。

Abstract This revised application proposes 2 small, single-center, mechanistic clinical trials. Our overarching hypothesis is that acute hyperglycemia and/or glucose variability (GV) negatively impact microvascular perfusion in cardiac (CM) and skeletal muscle (SM) and this could in part account for the strongly negative impact of acute hyperglycemia on clinical outcomes in acute coronary syndromes. While chronic hyperglycemia provokes functional and anatomic diabetic microvascular disease, and acute hyperglycemia can raise plasma endothelial cell (EC) stress “biomarkers” concentrations, the functional microvascular consequences, if any, of acute hyperglycemia and GV are unknown. Microvascular perfusion is a critical determinant of nutrient and oxygen delivery to SM and CM and is adversely affected by insulin resistance. Using our considerable experience with contrast enhanced ultrasound (CEU) measurement of microvascular perfusion in complex metabolic studies we will test in AIM 1 the effect of acute hyperglycemia on basal and insulin-mediated microvascular perfusion in CM and SM of healthy humans. In AIM 2 we will quantify microvascular perfusion at baseline, in response to insulin and in response to meal ingestion in patients with T2DM. We will further test in T2DM whether decreasing GV and post-prandial hyperglycemic excursions with an SGLT-2 inhibitor (vs placebo) for 12 weeks enhances CM microvascular perfusion, either at baseline, or in response to acute hyperinsulinemia or to meal ingestion. Aim 3 will identify whether the behavior of the microvasculature seen in Aims 1 and 2, is matched by the responses of large arteries to either hyperglycemic, hyperinsulinemic or meal stimuli or drug treatment, measured by flow-mediated dilation (FMD), pulse wave velocity (PWV), augmentation index (AI), or post-ischemic flow velocity (PIFV). Completion of these studies will provide unprecedented mechanistic information on the effects of hyperglycemia, GV, T2DM and T2DM treatment on CM and SM microvascular function.