Exercise training, CACs, and vascular function in older veterans with IGT

患有 IGT 的老年退伍军人的运动训练、CAC 和血管功能

• 批准号: 8768272
• 负责人: Steven J Prior
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768272
• 关键词: Acute; Aerobic Exercise; Affect; Age; Analysis of Variance; Angiogenic Factor; Attenuated; Award; Biological Assay; Blood Vessels; Blood capillaries; Blood flow; Blood specimen; Body Composition; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Cell Count; Cell physiology; Cells; Chronic; Clinical; Coronary; Development; Diabetes Mellitus; Elderly; Enrollment; Euglycemic Clamping; Exercise; Exercise stress test; Functional disorder; Glucose Clamp; Goals; Growth Factor; Health; Health Care Costs; Healthcare; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Intervention; Kidney Diseases; Lead; Maintenance; Measures; Medical; Microvascular Dysfunction; Modeling; NADPH Oxidase; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Oxidative Stress; Peripheral arterial disease; Pharmacologic Substance; Quality of life; Regression Analysis; Research; Research Proposals; Retinal Diseases; Risk; Sampling; Serum; Skeletal Muscle; Stromal Cell-Derived Factor 1; Superoxides; Testing; Therapeutic; Training; Translating; Translational Research; Tube; Tumor Necrosis Factor-alpha; Vascular Diseases; Vascular Endothelial Growth Factors; Veterans; angiogenesis; brachial artery; capillary; cardiovascular disorder risk; clinical care; clinically relevant; cost; cytokine; density; design; fitness; glucose tolerance; impaired glucose tolerance; improved; in vivo; indexing; innovation; insulin sensitivity; lymphotoxin beta; novel; patient oriented; prevent; public health relevance; response; sedentary; sex

DESCRIPTION (provided by applicant): Overweight, older Veterans with impaired glucose tolerance (IGT) are at increased risk for type 2 diabetes and its macro- and microvascular complications. Impaired circulating angiogenic cell (CAC) mobilization and reduced CAC function may contribute to the development of vascular complications in IGT because CACs participate in angiogenesis and vascular maintenance. This study tests the hypothesis that 6-month aerobic exercise (AEX) training will improve CAC mobilization and function in older Veterans with IGT by increasing angiogenic growth factor levels and reducing inflammation and CAC oxidative stress, and that the improvements in CACs will translate to better vascular function and insulin sensitivity. This will be tested in older Veterans with IGT and normal glucose tolerance (NGT) through two aims. Aim 1: Determine the effects of AEX training on CAC mobilization and function in age and BMI- matched older Veterans with IGT and NGT. A) We will assess circulating and skeletal muscle angiogenic growth factor levels (VEGF and SDF-1) and CAC mobilization in response to an acute bout of exercise to determine whether these are reduced in subjects with IGT vs. NGT, and whether these increase after AEX training in both groups. B) We will measure ex vivo CAC tube formation using serum and freshly-isolated CACs from older subjects with IGT and NGT to determine whether inflammatory cytokines (¿circulating CRP, IL-6 and TNF¿) and/or oxidative stress in CACs (¿superoxide, ¿Nox2, and ¿SOD-1) impair CAC tube formation in IGT vs. NGT, and whether 6-month AEX+WL increases CAC tube formation in both groups. Aim 2: Determine whether AEX training-induced effects on CAC mobilization and function translate to in vivo vascular function and insulin sensitivity in older Veterans by measuring skeletal muscle capillary density, brachial artery endothelial reactivity, microvascular blood flow, and insulin sensitivity before and after 6-month AEX training. We will enroll 32 sedentary, overweight-obese (BMI 25-35kg/m2) older (50-75 years) Veterans with IGT and 32 sex-, age-, and BMI-matched Veterans with NGT who will undergo 6-month AEX training. Before and after the intervention, subjects will undergo a) acute exercise tests to assess CAC mobilization and angiogenic growth factor levels, b) blood sampling to assess CAC function, c) skeletal muscle sampling to measure capillary density and angiogenic growth factor expression, d) vascular testing to assess endothelial vasoreactivity and microvascular blood flow, e) hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, and f) cardiorespiratory fitness testing and determination of body composition. ANOVA models will be used to determine abnormalities in CAC mobilization and function in IGT vs. NGT at baseline, as well as changes with AEX training in both groups. Regression analyses will determine whether changes in CAC mobilization and function are associated with improvements in skeletal muscle capillary density and endothelial vasoreactivity, and whether improvements in vascular outcomes are associated with increases in insulin sensitivity. This patient-oriented translational research proposal uses innovative approaches to study mechanisms regulating CAC mobilization and function in older subjects with IGT and NGT, and translate these findings to clinically-relevant measures of vascular function and insulin sensitivity. Currently, the macro- and microvascular complications (e.g., retinopathy, nephropathy and neuropathy) of insulin resistance result in substantial VA health care costs and significantly impair the quality of life of older Veterans. We are optimistic that tis study will provide VA with therapeutic and programmatic directions to improve vascular health in insulin resistant older Veterans. This may reduce the progression of IGT to type 2 diabetes and its associated vascular complications, lower medical costs related to treatment of these cardiovascular disease complications, and improve the health of our Nation's Veterans.

DESCRIPTION (provided by applicant): Overweight, older Veterans with impaired glucose tolerance (IGT) are at increased risk for type 2 diabetes and its macro- and microvascular complications. Impaired circulating angiogenic cell (CAC) mobilization and reduced CAC function may contribute to the development of vascular complications in IGT because CACs participate in angiogenesis and vascular maintenance. This study tests the hypothesis that 6-month aerobic exercise (AEX) training will improve CAC mobilization and function in older Veterans with IGT by increasing angiogenic growth factor levels and reducing inflammation and CAC oxidative stress, and that the improvements in CACs will translate to better vascular function and insulin sensitivity. This will be tested in older Veterans with IGT and normal glucose tolerance (NGT) through two aims. Aim 1: Determine the effects of AEX training on CAC mobilization and function in age and BMI- matched older Veterans with IGT and NGT. A) We will assess circulating and skeletal muscle angiogenic growth factor levels (VEGF and SDF-1) and CAC mobilization in response to an acute bout of exercise to determine whether these are reduced in subjects with IGT vs. NGT, and whether these increase after AEX training in both groups. B) We will measure ex vivo CAC tube formation using serum and freshly-isolated CACs from older subjects with IGT and NGT to determine whether inflammatory cytokines (¿circulating CRP, IL-6 and TNF¿) and/or oxidative stress in CACs (¿superoxide, ¿Nox2, and ¿SOD-1) impair CAC tube formation in IGT vs. NGT, and whether 6-month AEX+WL increases CAC tube formation in both groups. Aim 2: Determine whether AEX training-induced effects on CAC mobilization and function translate to in vivo vascular function and insulin sensitivity in older Veterans by measuring skeletal muscle capillary density, brachial artery endothelial reactivity, microvascular blood flow, and insulin sensitivity before and after 6-month AEX training. We will enroll 32 sedentary, overweight-obese (BMI 25-35kg/m2) older (50-75 years) Veterans with IGT and 32 sex-, age-, and BMI-matched Veterans with NGT who will undergo 6-month AEX training. Before and after the intervention, subjects will undergo a) acute exercise tests to assess CAC mobilization and angiogenic growth factor levels, b) blood sampling to assess CAC function, c) skeletal muscle sampling to measure capillary density and angiogenic growth factor expression, d) vascular testing to assess endothelial vasoreactivity and microvascular blood flow, e) hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, and f) cardiorespiratory fitness testing and determination of body composition. ANOVA models will be used to determine abnormalities in CAC mobilization and function in IGT vs. NGT at baseline, as well as changes with AEX training in both groups. Regression analyses will determine whether changes in CAC mobilization and function are associated with improvements in skeletal muscle capillary density and endothelial vasoreactivity, and whether improvements in vascular outcomes are associated with increases in insulin sensitivity. This patient-oriented translational research proposal uses innovative approaches to study mechanisms regulating CAC mobilization and function in older subjects with IGT and NGT, and translate these findings to clinically-relevant measures of vascular function and insulin sensitivity. Currently, the macro- and microvascular complications (e.g., retinopathy, nephropathy and neuropathy) of insulin resistance result in substantial VA health care costs and significantly impair the quality of life of older Veterans. We are optimistic that tis study will provide VA with therapeutic and programmatic directions to improve vascular health in insulin resistant older Veterans. This may reduce the progression of IGT to type 2 diabetes and its associated vascular complications, lower medical costs related to treatment of these cardiovascular disease complications, and improve the health of our Nation's Veterans.