Endothelial progenitor cell (EPC) dysfunction may contribute to vascular dysfunction in type 2 diabetes (T2DM) and aging because EPCs are progenitor cells that participate in vascular growth and repair. EPCs may be dysregulated in older age and T2DM by reduced mobilization from bone marrow and impaired function once in the circulation. My preliminary data suggest that aerobic exercise training may increase EPC and vascular function in T2DM, but that the effects may be reduced in older age. This study tests the hypothesis that reduced EPC mobilization and function adversely affect vascular function in T2DM, and that and that there are age-associated differences in the effects of AEX training on EPC mobilization and function in T2DM, which will affect AEX-induced changes in angiogenesis and endothelial vasoreactivity. This will be accomplished by specific aims that 1) Determine the effects of 6-month aerobic exercise training on EPC number and EPC mobilization factor expression in older subjects with T2DM compared middle-aged T2DM subjects and normal controls;and 2) Determine the effects of 6-month aerobic exercise training on mechanisms regulating EPC function and migration in older subjects with T2DM compared middle-aged T2DM subjects and normal controls. I will study sedentary, overweight/obese (BMI >25 kg/m2), middle-aged (50-65 yrs) and older (65-80 yrs) adults with T2DM and an age- and BMI- matched group of healthy controls. All subjects will be studied before and after 6-months of aerobic exercise training. An acute bout of exercise will be used to assess EPC mobilization at each time point to determine whether EPC mobilization is reduced in older vs. middle-aged T2DM subjects and normal controls, and also whether aerobic exercise training improves EPC mobilization. In the same subjects, ex vivo EPC tube formation, migration, and gene expression will be measured to determine whether specific markers of EPC function are reduced in middle-aged and older T2DM compared to controls and are improved with exercise training. Endothelial vasoreactivity and skeletal muscle capillarization will be measured to determine whether increases in EPC mobilization and function are associated with improved vascular function in T2DM and whether this differs between older and middle-aged T2DM subjects. This mentored, patient-oriented translational research study will provide me with the training to determine mechanisms of EPC dysfunction at the molecular and cellular level, and translate those findings to tissue (skeletal muscle capillarization) and the whole body level (endothelial vasoreactivity). Results of this study will enhance our understanding of EPC and vascular dysfunction and may lead to therapeutic and pharmacologic strategies to reduce vascular dysfunction in T2DM. This Paul B. Beeson Patient-Oriented Career Development Award will allow me to transition to an independent research career and become a leader in translational research in vascular biology in aging and diabetes.

Public Health Relevance

The research project in this K23 BCDA is designed to discover mechanisms underlying endothelial progenitor cell (EPC) and vascular dysfunction in type 2 diabetes and aging. Further, it will determine whether exercise training-induced increases in EPC mobilization contribute to improved vascular function in middle-aged and older adults with type 2 diabetes. The identification of the mechanisms of EPC and vascular dysfunction would have a significant impact on the millions of older Americans with T2DM, as these mechanisms can be targeted for drug discovery or other therapeutic interventions to reduce risk for cardiovascular complications.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23AG040775-01A1
Application #
8368174
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6 (M1))
Program Officer
Joseph, Lyndon
Project Start
2012-08-15
Project End
2015-08-31
Budget Start
2012-08-15
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$182,211
Indirect Cost
$13,497
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Prior, Steven J; Blumenthal, Jacob B; Katzel, Leslie I et al. (2014) Increased skeletal muscle capillarization after aerobic exercise training and weight loss improves insulin sensitivity in adults with IGT. Diabetes Care 37:1469-75
Prior, Steven J; Ryan, Alice S; Stevenson, Troy G et al. (2014) Metabolic inflexibility during submaximal aerobic exercise is associated with glucose intolerance in obese older adults. Obesity (Silver Spring) 22:451-7
Landers-Ramos, Rian Q; Jenkins, Nathan T; Spangenburg, Espen E et al. (2014) Circulating angiogenic and inflammatory cytokine responses to acute aerobic exercise in trained and sedentary young men. Eur J Appl Physiol 114:1377-84
Prior, Steven J; Ryan, Alice S (2013) Low clonogenic potential of circulating angiogenic cells is associated with lower density of capillaries in skeletal muscle in patients with impaired glucose tolerance. Diabetes Metab Res Rev 29:319-25
Brandauer, Josef; Landers-Ramos, Rian Q; Jenkins, Nathan T et al. (2013) Effects of prior acute exercise on circulating cytokine concentration responses to a high-fat meal. Physiol Rep 1:e00040