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Tumor Necrosis Factor- Induces Insulin Resistance in Endothelial Cells via a p38 Mitogen-Activated Protein Kinase-Dependent Pathway

Division of Endocrinology and Metabolism (G.L., E.J.B., M.O.B., Z.L.), Department of Internal Medicine, University of Virginia Health System, Charlottesville, Virginia 22908; and Endocrine Biology Program (W.C.), The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Zhenqi Liu, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, P.O. Box 801410, Charlottesville, Virginia 22908-1410. E-mail: zl3e{at}virginia.edu.

Chronic inflammation contributes to vascular insulin resistance and endothelial dysfunction. Systemic infusion of TNF- abrogates insulin’s action to enhance skeletal muscle microvascular perfusion. In skeletal muscle TNF- induces insulin resistance via the p38 MAPK pathway. To examine whether p38 MAPK also regulates TNF--induced vascular insulin resistance, bovine aortic endothelial cells (bAECs) were incubated ± TNF- (5 ng/ml) for 6 h in the presence or absence of SB203580 (p38 MAPK specific inhibitor, 10 µM) after serum starvation for 10 h. For the last 30 min, cells were treated ± 1 nM insulin, and insulin receptor substrate (IRS)-1, Akt, endothelial nitric oxide synthase (eNOS), p38 MAPK, ERK1/2, c-Jun N-terminal kinase, and AMP-activated protein kinase (AMPK) phosphorylation, and eNOS activity were measured. TNF- increased p38 MAPK phosphorylation, potently stimulated IRS-1 serine phosphorylation, and blunted insulin-stimulated IRS-1 tyrosine and Akt phosphorylation and eNOS activity. TNF- also potently stimulated the phosphorylation of ERK1/2 and AMPK. Treatment with SB203580 decreased p38 MAPK phosphorylation back to the baseline and restored insulin sensitivity of IRS-1 tyrosine and Akt phosphorylation and eNOS activity in TNF--treated bAECs without affecting TNF--induced ERK1/2 and AMPK phosphorylation. We conclude that in cultured bAECs, TNF- induces insulin resistance in the phosphatidylinositol 3-kinase/Akt/eNOS pathway via a p38 MAPK-dependent mechanism and enhances ERK1/2 and AMPK phosphorylation independent of the p38 MAPK pathway. This differential modulation of TNF-’s actions by p38 MAPK suggests that p38 MAPK plays a key role in TNF--mediated vascular insulin resistance and may contribute to the generalized endothelial dysfunction seen in type 2 diabetes mellitus and the cardiometabolic syndrome.

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