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.

Public Health Relevance

The research in this VA Merit Review Award application is designed to discover mechanisms underlying circulating angiogenic cell (CAC) and vascular dysfunction in older veterans with impaired glucose tolerance (IGT) compared to those with normal glucose tolerance (NGT). Further, it will determine mechanisms by which chronic exercise training may improve CAC mobilization and function to improve vascular function in older veterans. This is especially relevant to veterans'health, as insulin resistance is highly prevalent among older veterans, and the associated vascular dysfunction and cardiovascular complications including coronary and peripheral arterial disease result in substantial VA health care costs. The identification of mechanisms affecting CAC and vascular dysfunction would have a significant impact on veterans'health, as these mechanisms can be targeted to improve treatment and potentially lead to a reduction in pharmaceutical and clinical costs related to insulin resistance in veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Endocriniology A (ENDA)
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Baltimore VA Medical Center
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Lutz, Andrew H; Blumenthal, Jacob B; Landers-Ramos, Rian Q et al. (2016) Exercise-induced endothelial progenitor cell mobilization is attenuated in impaired glucose tolerance and type 2 diabetes. J Appl Physiol (1985) 121:36-41