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Protein kinase C-? contributes to impaired endothelial insulin signaling in humans with diabetes mellitus.

ABSTRACT: 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-? (PKC?) and nuclear factor ?B, reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus.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? expression was higher in diabetic patients and was associated with lower flow-mediated dilation (r=-0.541, P=0.02). Inhibition of PKC? with LY379196 reduced basal eNOS phosphorylation and improved insulin-mediated eNOS activation in patients with diabetes mellitus. Endothelial nuclear factor ?B activation was higher in diabetes mellitus and was reduced with PKC? inhibition.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? activity in endothelial insulin resistance.

SUBMITTER: Tabit CE

PROVIDER: S-EPMC3572725 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Protein kinase C-β contributes to impaired endothelial insulin signaling in humans with diabetes mellitus.

Tabit Corey E CE Shenouda Sherene M SM Holbrook Monica M Fetterman Jessica L JL Kiani Soroosh S Frame Alissa A AA Kluge Matthew A MA Held Aaron A Dohadwala Mustali M MM Gokce Noyan N Farb Melissa G MG Rosenzweig James J Ruderman Neil N Vita Joseph A JA Hamburg Naomi M NM

Circulation 20121130 1

<h4>Background</h4>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-β (PKCβ) and nuclear factor κB, reduces nitric oxide availability. We sought to establish whether similar mechanisms operate in the endothelium in human diabetes mellitus.<h4>Methods and results</h4>We measured protein expression and insulin response in freshly isolated endo ...[more]

PMID: 23204109

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Protein kinase C-? contributes to impaired endothelial insulin signaling in humans with diabetes mellitus.

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Protein kinase C-β contributes to impaired endothelial insulin signaling in humans with diabetes mellitus.

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