Type 2 diabetes, obesity, and hypertension are highly prevalent in Western society and increasingly prevalent in the developing world. Abundant clinical and basic research suggests that insulin resistance (IR) underlies each of these disorders and emerges in response to the environmental stresses of Western diet and diminished physical activity. However, the precise linkage between these environmental changes and these diverse clinical disorders is only marginally understood. Others have reported that insulin delivery to muscle is the rate limiting step for its metabolic action in vivo. Our laboratory has been testing the hypothesis that vascular IR plays an important pathogenetic role in the development metabolic IR. Specifically, we have provided abundant data (supported by this grant) that skeletal muscle microvasculature is exquisitely sensitive to physiologic concentrations of insulin which act to expand the microvascular pool perfused. We have also reported that insulin is transported across the endothelial cell (EC) by a regulated process which is activated by insulin. In this manner, insulin can facilitate its own delivery and that of glucose and other nutrients to muscle. IR inhibits these vascular actions of insulin. In studies proposed here we will probe the linkage between environmental factors (elevated plasma free fatty acid concentrations, high fat diet, acute and chronic exercise) and vascular and metabolic insulin resistance. We will utilize techniques developed in our laboratory to assess the functional actions of insulin on the microvasculature, its biochemical signaling, and the role of oxidative stress and inflammation within the vasculature on insulin actions. This will be done addressing 3 specific aims :
Aim 1 -will test whether FFA promote an inflammatory response in the EC, the vascular smooth muscle cell or both in rat vasculature and thereby diminish muscle insulin delivery;
Aim 2 -will test whether enhancing nitric oxide availability or blocking either the AT1 or endothelin A receptor will diminish/prevent FFA-induced microvascular inflammation and dysfunction, and whether exercise training may have a similar effect;
and Aim 3 - will test whether different dietary lipids [saturated, omega-3, and omega-6 polyunsaturated fatty acids (PUFA)] will differentially affect muscle microvascular insulin responsiveness, delivery of 125I-insulin to skeletal muscle, muscle insulin sensitivity, and vascular inflammation. By addressing the origins of muscle microvascular dysfunction in IR should allow us to develop strategies to limit or reverse vascular IR and thereby improve metabolic IR.

Public Health Relevance

Insulin resistance (IR) underlies multiple, prevalent, serious diseases. Muscle is a major insulin target tissue and insulin movement from the plasma to muscle interstitium is rate limiting for insulin's metabolic action and IR slows this. Using novel methods developed in our laboratory we will test whether vascular inflammation and increased production of reactive oxygen species induced by pro- inflammatory lipids play a critical role in producing skeletal muscle vascular and consequent metabolic IR and if this can be reversed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057878-13
Application #
8444474
Study Section
Special Emphasis Panel (ZRG1-EMNR-B (02))
Program Officer
Jones, Teresa L Z
Project Start
2000-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2013
Total Cost
$308,225
Indirect Cost
$108,079
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Wang, Hong; Wang, Aileen X; Aylor, Kevin et al. (2013) Nitric oxide directly promotes vascular endothelial insulin transport. Diabetes 62:4030-42
Barrett, Eugene J; Liu, Zhenqi (2013) The endothelial cell: an "early responder" in the development of insulin resistance. Rev Endocr Metab Disord 14:21-7
Wang, Hong; Wang, Aileen X; Barrett, Eugene J (2012) Insulin-induced endothelial cell cortical actin filament remodeling: a requirement for trans-endothelial insulin transport. Mol Endocrinol 26:1327-38
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Majumdar, S; Genders, A J; Inyard, A C et al. (2012) Insulin entry into muscle involves a saturable process in the vascular endothelium. Diabetologia 55:450-6

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