Journal
CIRCULATION
Volume 127, Issue 1, Pages 86-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.112.127514
Keywords
diabetes mellitus; endothelium; insulin resistance; nitric oxide
Funding
- National Heart, Lung, and Blood Institute [HL102299, HL109790]
- National Institutes of Health (NIH) [K12 HL083781, T32 HL007224, HL083801, HL081587, HL083269, HL75795]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [K12HL083781, P50HL083801, T32HL007224, P01HL081587, R01HL075795, R01HL083269, R21HL109790, R01HL102299] Funding Source: NIH RePORTER
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Background-Abnormal endothelial function promotes atherosclerotic vascular disease in diabetes. Experimental studies indicate that disruption of endothelial insulin signaling, through the activity of protein kinase C-beta (PKC beta) and nuclear factor kappa B, reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus. Methods and Results-We measured protein expression and insulin response in freshly isolated endothelial cells from patients with type 2 diabetes mellitus (n=40) and nondiabetic controls (n=36). Unexpectedly, we observed 1.7-fold higher basal endothelial nitric oxide synthase (eNOS) phosphorylation at serine 1177 in patients with diabetes mellitus (P=0.007) without a difference in total eNOS expression. Insulin stimulation increased eNOS phosphorylation in nondiabetic subjects but not in diabetic patients (P=0.003), consistent with endothelial insulin resistance. Nitrotyrosine levels were higher in diabetic patients, indicating endothelial oxidative stress. PKC beta expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=-0.541, P=0.02). Inhibition of PKC beta with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes mellitus. Endothelial nuclear factor kappa B activation was higher in diabetes mellitus and was reduced with PKC beta inhibition. Conclusions-We provide evidence for the presence of altered eNOS activation, reduced insulin action, and inflammatory activation in the endothelium of patients with diabetes mellitus. Our findings implicate PKC beta activity in endothelial insulin resistance. (Circulation. 2013;127:86-95.)
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