Tumor necrosis factor-alpha induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway

Endocrinology. 2007 Jul;148(7):3356-63. doi: 10.1210/en.2006-1441. Epub 2007 Apr 19.

Abstract

Chronic inflammation contributes to vascular insulin resistance and endothelial dysfunction. Systemic infusion of TNF-alpha abrogates insulin's action to enhance skeletal muscle microvascular perfusion. In skeletal muscle TNF-alpha induces insulin resistance via the p38 MAPK pathway. To examine whether p38 MAPK also regulates TNF-alpha-induced vascular insulin resistance, bovine aortic endothelial cells (bAECs) were incubated+/-TNF-alpha (5 ng/ml) for 6 h in the presence or absence of SB203580 (p38 MAPK specific inhibitor, 10 microM) 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-alpha increased p38 MAPK phosphorylation, potently stimulated IRS-1 serine phosphorylation, and blunted insulin-stimulated IRS-1 tyrosine and Akt phosphorylation and eNOS activity. TNF-alpha 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-alpha-treated bAECs without affecting TNF-alpha-induced ERK1/2 and AMPK phosphorylation. We conclude that in cultured bAECs, TNF-alpha 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-alpha's actions by p38 MAPK suggests that p38 MAPK plays a key role in TNF-alpha-mediated vascular insulin resistance and may contribute to the generalized endothelial dysfunction seen in type 2 diabetes mellitus and the cardiometabolic syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Cattle
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Enzyme Activation / drug effects
  • Immunoblotting
  • Immunoprecipitation
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Multienzyme Complexes / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects*
  • Time Factors
  • Tumor Necrosis Factor-alpha / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Insulin
  • Insulin Receptor Substrate Proteins
  • Multienzyme Complexes
  • Phosphoproteins
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase Type III
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases