权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pan-arterial insulin resistance - a target for clinical intervention

全动脉胰岛素抵抗——临床干预的目标

基本信息

批准号：
8204372
负责人：
EUGENE Joseph BARRETT
金额：
$ 38.5万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204372
关键词：
Address Adult Age Angiotensin II Type 1 Receptor Blockers Antihypertensive Agents Arteries Atherosclerosis Biological Markers Blinded Blood Pressure Blood Vessels Blood capillaries Cardiovascular Diseases Clinical Clinical Trials Congestive Heart Failure Cross-Over Studies Data Diet Disease Outcome Elasticity Euglycemic Clamping Evaluation Event Exercise Fatty acid glycerol esters Figs - dietary Functional disorder Glucose Glucose Clamp Health Hour Hyperglycemia Hyperinsulinism Hypertension Individual Insulin Insulin Resistance Intervention Left Ventricular Hypertrophy Measures Mechanics Mediating Metabolic Metabolic syndrome Metformin Methods Mineralocorticoid Receptor Morbidity - disease rate Muscle Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Outcome Patients Physiologic pulse Placebos Population Property Randomized Receptor, Angiotensin, Type 1 Relaxation Resistance Risk Risk Factors Selection for Treatments Stimulus Stroke Systolic Pressure Testing Tissues Training Trees Ultrasonography Vascular Diseases arterial stiffness arteriole base blind capillary cardiovascular disorder risk clinical effect design diet and exercise high risk improved indexing insulin sensitivity mortality novel response saturated fat trial comparing

项目摘要

DESCRIPTION (provided by applicant): Dysfunction throughout the arterial vasculature is responsible for significant morbidity/mortality in patients with type 2 diabetes (DM 2) and metabolic syndrome (MS). The arterial vasculature in healthy subjects responds to insulin and this response is impaired with insulin resistance (IR). Available noninvasive methods allow comprehensive evaluation of insulin action at each of 3 levels of arterial vasculature, including conduit, resistance, and microvascular vessels. Here we propose to use measures of pan-arterial vascular function and insulin sensitivity to address several fundamental questions related to the impact of insulin resistance on vascular function. Our general hypothesis is that IR, either induced experimentally or as occurs with MS and DM 2, impairs vascular function at all levels of the arterial vasculature. We further hypothesize that treatments previously shown to improve vascular outcomes will effectively improve this pan-arterial dysfunction. If these hypotheses prove correct, they may provide: A) a functional mechanism to explain the linkage between IR and cardiovascular diseases (CVD); B) a rationale for the previously observed salutory clinical effects of metformin, type 1 angiotensin II receptor (AT1R) blockers, mineralocorticoid receptor (MR) blockers and diet/exercise on CVD and; C) a basis to suggest that early assessment of pan-arterial function affords a platform to improve candidate treatment selection for later clinical trials. In Aim 1, we will measure pan-arterial vascular function and insulin responsiveness in healthy subjects and assess the effect of a single high-fat meal on insulin's vascular and metabolic actions. In Aim 2, in subjects with MS, we will again measure pan-arterial vascular function and insulin sensitivity before and following 12 weeks treatment with a placebo or metformin with or without a diet low in saturated fat combined with exercise training in a randomized 2 X 2 design. In Aim 3, in metformin-treated DM 2 subjects, we will characterize pan-arterial vascular function and vascular insulin sensitivity before and following 12 weeks treatment with an AT1R blocker, a MR blocker or a placebo in a blinded, crossover study. PUBLIC HEALTH RELEVANCE: As CVD remains the major cause of morbidity/mortality in DM2 and MS in the post-statin and post- antihypertensives era and as arterial dysfunction independently predicts CVD, elucidation of the linkage between IR, arterial dysfunction, and CVD is vital. By examining insulin's action on 3 levels of the arterial vasculature in healthy individuals and patients with MS or DMS 2, we can improve both our understanding of the mechanisms of vascular IR and our ability to efficiently test potential new therapies.