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Role of Microvascular insulin resistance and cardiorespiratory fitness in diabetes

微血管胰岛素抵抗和心肺健康在糖尿病中的作用

基本信息

批准号：
10371154
负责人：
ZHENQI LIU
金额：
$ 71.19万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371154
关键词：
Address Adult Attenuated Blood Vessels Cardiac Cardiovascular system Clinical assessments Colorado Complications of Diabetes Mellitus Data Development Diabetes Mellitus Evaluation Exercise Functional disorder Goals Health Impairment Insulin Insulin Resistance Intervention Kinetics Knowledge Life Style Longevity Measures Mediating Microvascular Dysfunction Morbidity - disease rate Muscle Muscle Development Muscle Mitochondria Muscle function Myocardium Non-Insulin-Dependent Diabetes Mellitus Outcome Oxygen Oxygen Consumption Performance Perfusion Persons Physical Fitness Physical activity Physiological Premature Mortality Publishing Reporting Research Research Methodology Rest Role Sex Differences Site Skeletal Muscle Testing Therapeutic Effect Training Universities Virginia Woman Workload Youth cardiorespiratory fitness clinically significant exercise capacity exercise training experimental study functional disability functional status heart function impaired capacity improved in vivo innovation insight insulin regulation men mortality non-diabetic novel pharmacologic remediation response sex disparity skeletal success survival prediction therapeutic target uptake

项目摘要

Project Summary The goal of this two-site proposal is to determine whether and by what means insulin resistance, in the form of impaired insulin regulation of microvascular perfusion, leads to decreased functional exercise capacity (FEC) in type 2 diabetes (T2D). Data from our two research teams suggest that the cardiac and skeletal muscle microvascular dysfunction present in people with T2D contributes to limitations in cardiac and skeletal muscle oxygenation and function associated with impaired function exercise capacity (a major predictor of CV and all- cause mortality). Insulin action is a potent predictor of the FEC impairment in T2D. The exact relationship between insulin action, cardiac and muscle dysfunction, cardiac and skeletal muscle perfusion and decreased FEC in T2D remains unclear. Here we propose to address this gap in knowledge by defining the roles of impaired insulin-mediated cardiac and skeletal muscle perfusion and exercise performance in people with T2D. Hypothesis: Decreased insulin-mediated muscle perfusion found in T2D contributes to the development of cardiac and skeletal muscle dysfunction and subsequent impairment in exercise capacity. We further hypothesize that exercise training attenuates insulin resistance and restores insulin-mediated perfusion to the skeletal and cardiac muscle, leading to improved exercise performance. Specific Aim 1: To test the hypothesis that impairment in insulin-mediated cardiac perfusion limits exercise performance through its effect on cardiac function in people with T2D. We will examine the relationship between insulin- mediated cardiac perfusion, other measures of cardiac function, and VO2 peak at rest and with exercise in subjects with and without T2D. Given that there is a sex disparity in diabetes outcomes and exercise impairment with a lack of mechanistic insights on sex differences, we will analyze all parameters for differences by sex on an exploratory basis in the three aims. Specific Aim 2: To test the hypothesis that impaired insulin-mediated skeletal muscle perfusion limits exercise performance through its effect on oxidative capacity in people with T2D. We will examine the relationship between insulin-mediated skeletal muscle perfusion; muscle oxygenation, skeletal muscle mitochondrial function and in vivo skeletal muscle oxidative flux; and VO2 peak in subjects with and without T2D. Specific Aim 3: To test the hypothesis that the improvement in FEC subsequent to exercise training operates via action on cardiac and muscle function in T2D. These experiments will test whether the improvements in VO2peak observed with exercise training correlate with improvements in insulin-mediated perfusion, cardiac and skeletal muscle function and the impact of T2D on these changes. Understanding the role of microvascular disease in the diabetes-mediated exercise impairment may offer novel targets for intervention to improve exercise capacity, functional status and longevity in people with diabetes. Together, our two groups will employ complementary theoretical backgrounds and research methods in a synergistic approach to address the innovative hypothesis posed to improve health in T2D.