Acute effects of hyperglycemia on heart and skeletal muscle microvasculature

高血糖对心脏和骨骼肌微血管系统的急性影响

• 批准号: 10330026
• 负责人: EUGENE Joseph BARRETT
• 金额: $ 73.74万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330026
• 关键词: 3-nitrotyrosine; Acute; Address; Affect; Anatomy; Animal Model; Arteries; Behavior; Biological Markers; Blood Vessels; Blood flow; Cardiac; Cell model; Cellular Stress; Chronic; Clinical; Clinical Trials; Complex; Complications of Diabetes Mellitus; Diabetes Mellitus; Endothelial Cells; Endothelium; Exercise; Future; Glucose; Hour; Human; Hyperglycemia; Hyperinsulinism; IL6 gene; Imaging Techniques; Impairment; Inflammation; Infusion procedures; Ingestion; Injury; Insulin; Insulin Resistance; Intervention; Knowledge; Lipids; Measurement; Measures; Mediating; Metabolic syndrome; Microvascular Dysfunction; Myocardium; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Observational Study; Oral; Outcome; Oxidative Stress; Oxygen; Patients; Perfusion; Pharmacotherapy; Physiologic pulse; Placebos; Plasma; Production; Prognosis; Resistance; Role; Skeletal Muscle; Stimulus; Stress; Testing; Tissues; Ultrasonography; Vasodilation; acute coronary syndrome; adiponectin; arteriole; basal insulin; brachial artery; circulating biomarkers; contrast enhanced; diabetic; euglycemia; experience; glucagon-like peptide 1; improved; indexing; inhibitor; inhibitor therapy; metabolic abnormality assessment; mortality; response; ultrasound; vasoconstriction

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.

抽象的 本修订后的申请提出了 2 项小型、单中心、机制性临床试验。 假设是急性高血糖和/或葡萄糖变异性 (GV) 对微血管产生负面影响 心脏（CM）和骨骼肌（SM）的灌注，这可以部分解释强烈的 急性高血糖对急性冠脉综合征临床结果的负面影响。 慢性高血糖会引发功能性和解剖性糖尿病微血管疾病，以及急性高血糖 高血糖可以提高血浆内皮细胞（EC）应激“生物标志物”浓度，功能性 急性高血糖和 GV 的微血管后果（如果有）尚不清楚。 灌注是向 SM 和 CM 输送营养和氧气的关键决定因素，并且对 利用我们在超声造影方面的丰富经验。 (CEU) 复杂代谢研究中微血管灌注的测量，我们将在 AIM 1 中测试 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 在 AIM 2 中，我们将量化基线时对胰岛素的反应的微血管灌注。 针对 T2DM 患者的膳食摄入情况，我们将进一步测试 T2DM 是否会出现这种情况。 使用 SGLT-2 抑制剂（与安慰剂相比）可降低 GV 和餐后高血糖波动 12 次 数周可增强 CM 微血管灌注，无论是在基线还是对急性反应 目标 3 将确定高胰岛素血症或膳食摄入是否有微血管行为。 目标 1 和 2 中看到的，与大动脉对高血糖的反应相匹配， 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）、脉搏来测量 波速 (PWV)、增强指数 (AI) 或缺血后血流速度 (PIFV)。 这些研究将提供有关高血糖影响的前所未有的机制信息， T2DM 和 T2DM 治疗对 CM 和 SM 微血管功能的影响。

项目成果

Microvascular Dysfunction in Diabetes Mellitus and Cardiometabolic Disease.

糖尿病和心脏代谢疾病中的微血管功能障碍。

• DOI: 10.1210/endrev/bnaa025
• 发表时间: 2020-10-30
• 期刊: Endocrine reviews
• 影响因子: 20.3
• 作者: W. Horton;E. Barrett
• 通讯作者: E. Barrett

Metformin's Impact on the Microvascular Response to Insulin.

二甲双胍对胰岛素微血管反应的影响。

• 发表时间: 2022-10-11
• 影响因子: 4.8
• 作者: Love, Kaitlin M;Barrett, Eugene J;Horton, William B
• 通讯作者: Horton, William B

Insulin-induced vasoconstriction is prevalent in muscle microvasculature of otherwise healthy persons with type 1 diabetes.

胰岛素诱导的血管收缩在其他健康的 1 型糖尿病患者的肌肉微血管系统中普遍存在。

• 发表时间: 2023-05-01
• 作者: Jahn, Linda A;Hartline, Lee M;Kleiner, Amanda J;Horton, William B;Hasan, Farhad;Wai Kit Tan, Alvin;Liu, Zhenqi;Barrett, Eugene J
• 通讯作者: Barrett, Eugene J

Early Microvascular Dysfunction: Is the Vasa Vasorum a "Missing Link" in Insulin Resistance and Atherosclerosis.

早期微血管功能障碍：血管滋养管是胰岛素抵抗和动脉粥样硬化的“缺失环节”吗？

• 发表时间: 2021-07-15
• 影响因子: 5.6
• 作者: Owusu, Jeanette;Barrett, Eugene
• 通讯作者: Barrett, Eugene

Predictors of arterial stiffness in adolescents and adults with type 1 diabetes: a cross-sectional study.

患有 1 型糖尿病的青少年和成人动脉硬化的预测因素：一项横断面研究。

• 发表时间: 2022-01
• 影响因子: 4.1
• 作者: Love, Kaitlin M;Horton, William B;Patrie, James T;Jahn, Linda A;Hartline, Lee M;Barrett, Eugene J
• 通讯作者: Barrett, Eugene J