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Tumor Necrosis Factor-α Induces Insulin Resistance in Endothelial Cells via a p38 Mitogen-Activated Protein Kinase-Dependent Pathway
| Content Provider | Paperity |
|---|---|
| Author | Barrett, Eugene J. Liu, Zhenqi Cao, Wenhong Li, Guolian Barrett, Matthew O. |
| Abstract | Chronic inflammation contributes to vascular insulin resistance and endothelial dysfunction. Systemic infusion of TNF-α abrogates insulin’s action to enhance skeletal muscle microvascular perfusion. In skeletal muscle TNF-α induces insulin resistance via the p38 MAPK pathway. To examine whether p38 MAPK also regulates TNF-α-induced vascular insulin resistance, bovine aortic endothelial cells (bAECs) were incubated ± TNF-α (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-α increased p38 MAPK phosphorylation, potently stimulated IRS-1 serine phosphorylation, and blunted insulin-stimulated IRS-1 tyrosine and Akt phosphorylation and eNOS activity. TNF-α 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-α-treated bAECs without affecting TNF-α-induced ERK1/2 and AMPK phosphorylation. We conclude that in cultured bAECs, TNF-α 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-α’s actions by p38 MAPK suggests that p38 MAPK plays a key role in TNF-α-mediated vascular insulin resistance and may contribute to the generalized endothelial dysfunction seen in type 2 diabetes mellitus and the cardiometabolic syndrome. |
| Starting Page | 3356 |
| Ending Page | 3363 |
| File Format | HTM / HTML |
| ISSN | 00137227 |
| DOI | 10.1210/en.2006-1441 |
| Issue Number | 7 |
| Journal | Endocrinology |
| Volume Number | 148 |
| e-ISSN | 19457170 |
| Language | English |
| Publisher | Oxford University Press |
| Publisher Date | 2007-07-01 |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
| Subject | Endocrinology |
