To understand the relationship between hypertension and insulin resistance and the effects of nutritional supplements to improve or worsen these conditions, we are studying insulin signal transduction pathways related to nitric oxide (NO) production in vascular endothelium. Human forearm blood flow studies suggest that physiological concentrations of insulin cause vasodilation of small vessels via the production of NO in endothelial cells. Furthermore, the degree of insulin sensitivity exhibited for this response is positively correlated with insulin sensitivity for glucose uptake. Thus, insulin resistance may contribute to the pathogenesis of hypertension under some conditions. We used an NO electrode to directly measure NO at nanomolar concentrations to characterize the insulin response of human umbilical vein endothelial cells (HUVEC) in primary culture. In addition, we developed a novel method for transiently transfecting endothelial cells in primary culture and selecting the transfected cells using a fluorescently activated cell sorter. Recently, we also developed a method to directly visualize NO production in single living cells using an NO-specific fluorescent dye DAF-2. By overexpressing wild-type, constitutively active, or dominant inhibitory forms of various signaling molecules, we have now elucidated a complete biochemical pathway from the insulin receptor to phosphorylation of IRS-1, leading to binding and activation of PI 3-kinase, activation of PDK-1, phosphorylation and activation of Akt that then directly phosphorylates eNOS resulting in activation of eNOS and increased NO production. Moreover, we have ruled out an important role for Ras in insulin-stimulated proudction of NO. We have also used the NO-specific fluorescent dye DAF-2 to visualize production of NO in single cells and dissect the mechanisms whereby insulin regulates activity of endothelial nitric oxide synthase. We found that insulin stimulates activation of eNOS by a calcium independent mechanism involving phosphorylation of eNOS by Akt. We have recently initiated studies to investigate the role of nutritional supplements DHEA and epigallocatechin gallate (EGCG, an antioxidant in green tea) to activate endothelial nitric oxide synthase and modulate or augment insulin-stimulated production of NO. In this context, we are attempting to identify a cell surface membrane receptors for DHEA and EGCG that may mediate some of these effects. In addition, we have identified a novel biological action of adiponectin to stimulate production of NO in endothelium and we are attempting to elucidate the signal transduction pathways related to this.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Intramural Research (Z01)
Project #
1Z01AT000001-04
Application #
7129169
Study Section
(DIAB)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Complementary & Alternative Medicine
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Nacci, Carmela; Tarquinio, Mariela; De Benedictis, Leonarda et al. (2009) Endothelial dysfunction in mice with streptozotocin-induced type 1 diabetes is opposed by compensatory overexpression of cyclooxygenase-2 in the vasculature. Endocrinology 150:849-61
Koh, Kwang Kon; Quon, Michael J; Han, Seung Hwan et al. (2009) Additive beneficial effects of atorvastatin combined with amlodipine in patients with mild-to-moderate hypertension. Int J Cardiol :
Potenza, Maria A; Gagliardi, Sara; De Benedictis, Leonarda et al. (2009) Treatment of spontaneously hypertensive rats with rosiglitazone ameliorates cardiovascular pathophysiology via antioxidant mechanisms in the vasculature. Am J Physiol Endocrinol Metab 297:E685-94
Koh, Kwang Kon; Oh, Pyung Chun; Quon, Michael J (2009) Does reversal of oxidative stress and inflammation provide vascular protection? Cardiovasc Res 81:649-59
Koh, Kwang Kon; Quon, Michael J; Han, Seung Hwan et al. (2008) Simvastatin improves flow-mediated dilation but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients. Diabetes Care 31:776-82
Koh, Kwang Kon; Quon, Michael J; Rosenson, Robert S et al. (2008) Vascular and metabolic effects of treatment of combined hyperlipidemia: focus on statins and fibrates. Int J Cardiol 124:149-59
Koh, Kwang Kon; Quon, Michael J (2008) Combination therapy for treatment or prevention of atherosclerosis. Hypertension 52:e18;author reply e19
Koh, Kwang Kon; Park, Sang Min; Quon, Michael J (2008) Leptin and cardiovascular disease: response to therapeutic interventions. Circulation 117:3238-49
Tesauro, Manfredi; Schinzari, Francesca; Rovella, Valentina et al. (2008) Tumor necrosis factor-alpha antagonism improves vasodilation during hyperinsulinemia in metabolic syndrome. Diabetes Care 31:1439-41
Koh, Kwang Kon; Quon, Michael J; Waclawiw, Myron A (2008) Are statins effective for simultaneously treating dyslipidemias and hypertension? Atherosclerosis 196:1-8

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