We hypothesize that insulin acts on endothelial cells in 2 ways to enhance its delivery (and that of glucose) to skeletal muscle. One action is to recruit microvascular elements (capillaries) in muscle to increase the surface area available for insulin and glucose to enter skeletal muscle interstitium. A second action is to bind to its receptor on the capillary endothelium and via a receptor-mediated pathway cross the endothelium to the interstitium. We further hypothesize that insulin-resistance (e.g. type 2 diabetes and obesity) inhibits both of these vascular actions and this impairs overall insulin-mediated glucose disposal. Inasmuch as exercise also recruits muscle microvasculature, we further propose that even very modest exercise will enhance insulin and glucose delivery to muscle interstitium and improve muscle insulin sensitivity and glucose uptake. Establishment of 4 methods by our laboratory now allows critical testing of these hypotheses in humans: 1) the human forearm method;2) contrast enhanced ultrasound (CEU) to measure microvascular recruitment;3) a high sensitivity, precise immunoassay for insulin;and 4) immunohistochemical, confocal microscopic measurement of insulin, insulin receptor and insulin signaling proteins. We will study healthy as well as obese and type 2 diabetic volunteers to quantify the rate of insulin uptake by human forearm skeletal muscle. We will define whether insulin and glucose uptake are impaired by obesity or diabetes or by experimental manipulations which limit microvascular recruitment (nitric oxide synthase inhibition or intralipid infusion). We will as well ascertain whether exercise restores microvascular recruitment and insulin and glucose uptake by skeletal muscle in diabetic and obese volunteers. Together these measurements will allow a quantitative determination of the role of the endothelium in insulin delivery to muscle cells and the impact of altered insulin delivery on overall glucose homeostasis within skeletal muscle. Inasmuch as obesity and type 2 diabetes are expanding public health problems, defining the effects of altered insulin delivery produced by endothelial insulin resistance on glucose homeostasis will introduce the opportunity for novel interventions (either pharmacologic or behavioral) to mitigate a rising epidemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK073759-04
Application #
7644522
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (90))
Program Officer
Laughlin, Maren R
Project Start
2006-09-15
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$295,537
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Gray, Sarah M; Aylor, Kevin W; Barrett, Eugene J (2017) Unravelling the regulation of insulin transport across the brain endothelial cell. Diabetologia 60:1512-1521
Jahn, Linda A; Hartline, Lee; Rao, Nagashree et al. (2016) Insulin Enhances Endothelial Function Throughout the Arterial Tree in Healthy But Not Metabolic Syndrome Subjects. J Clin Endocrinol Metab 101:1198-206
Wang, Hong; Wang, Aileen X; Aylor, Kevin et al. (2015) Caveolin-1 phosphorylation regulates vascular endothelial insulin uptake and is impaired by insulin resistance in rats. Diabetologia 58:1344-53
Eggleston, Emma M; Jahn, Linda A; Barrett, Eugene J (2013) Early microvascular recruitment modulates subsequent insulin-mediated skeletal muscle glucose metabolism during lipid infusion. Diabetes Care 36:104-10
Anderson, Amy; Barrett, Eugene J (2013) Severe hypernatremia from a urea-induced diuresis due to body protein wasting in an insulin-resistant type 2 diabetic patient. J Clin Endocrinol Metab 98:1800-2
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
Barrett, Eugene J; Eringa, Etto C (2012) The vascular contribution to insulin resistance: promise, proof, and pitfalls. Diabetes 61:3063-5
Barrett, Eugene J; Rattigan, Stephen (2012) Muscle perfusion: its measurement and role in metabolic regulation. Diabetes 61:2661-8
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
Chai, Weidong; Liu, Jia; Jahn, Linda A et al. (2011) Salsalate attenuates free fatty acid-induced microvascular and metabolic insulin resistance in humans. Diabetes Care 34:1634-8

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