Acute effects of hyperglycemia on heart and skeletal muscle microvasculature

摘要 这项修订后的申请提出了两项小型、单中心、机械性的临床试验。我们最重要的是 假设急性高血糖和/或葡萄糖变异性(GV)对微血管产生负面影响 心肌(CM)和骨骼肌(SM)的灌流，这在一定程度上可以解释 急性高血糖对急性冠脉综合征患者临床结局的负面影响。而当 慢性高血糖引起功能性和解剖性糖尿病微血管病变，并急性 高血糖可提高血浆内皮细胞应激“生物标记物”浓度，功能性 急性高血糖和GV的微血管后果(如果有的话)尚不清楚。微血管 灌流是向SM和CM输送营养和氧气的关键决定因素，相反 受胰岛素抵抗的影响。利用我们在声学造影方面的丰富经验 我们将在AIM 1中测试复杂代谢研究中的微血管血流灌注(CEU)测量 急性高血糖对大鼠心肌和SM基础及胰岛素介导的微血管灌流的影响 健康的人类。在AIM 2中，我们将量化基线时的微血管血流灌注，以响应胰岛素 以及对T2 DM患者进食的反应。我们将在T2 DM中进一步测试是否 使用SGLT-2抑制剂(与安慰剂相比)减少GV和餐后高血糖漂移12天 无论是在基线状态下，还是在急性发作时，几周都能增强CM微血管的血流灌注 高胰岛素血症或进食。目标3将确定微血管系统的行为是否 在目标1和目标2中所见，与大动脉对高血糖的反应相匹配， 高胰岛素血症或饮食刺激或药物治疗，通过血流介导的扩张(FMD)、脉搏测量 波速(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、GV、 T2 DM和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.