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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

基本信息

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
项目类别：
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

项目摘要

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.

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基础和胰岛素介导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中进一步测试是否 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。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Insulin increases central aortic stiffness in response to hyperglycemia in healthy humans: A randomized four-arm study.

DOI：
10.1177/14791641211011009
发表时间：
2021-03
期刊：
Diabetes & vascular disease research
影响因子：
2.4
作者：
Horton WB;Jahn LA;Hartline LM;Aylor KW;Patrie JT;Barrett EJ
通讯作者：
Barrett EJ

Nitric oxide-dependent micro- and macrovascular dysfunction occurs early in adolescents with type 1 diabetes.

一氧化氮依赖性的微血管功能障碍发生在1型糖尿病的青少年早期。

DOI：
10.1152/ajpendo.00267.2021
发表时间：
2022-02-01
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
0
作者：
Jahn LA;Logan B;Love KM;Horton WB;Eichner NZ;Hartline LM;Weltman AL;Barrett EJ
通讯作者：
Barrett EJ

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。

DOI：
10.1152/ajpendo.00242.2022
发表时间：
2023
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
0
作者：
Jahn,LindaA;Hartline,LeeM;Kleiner,AmandaJ;Horton,WilliamB;Hasan,Farhad;WaiKitTan,Alvin;Liu,Zhenqi;Barrett,EugeneJ
通讯作者：
Barrett,EugeneJ

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