help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on April 19, 2007
Endocrinology, doi:10.1210/en.2006-1441
A more recent version of this article appeared on July 1, 2007
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
148/7/3356    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Li, G.
Right arrow Articles by Liu, Z.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, G.
Right arrow Articles by Liu, Z.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH

Submitted on October 27, 2006
Accepted on April 11, 2007

TNF-{alpha} induces insulin resistance in endothelial cells via a p38 MAPK-dependent pathway

Guolian Li, Eugene J. Barrett, Matthew O. Barrett, Wenhong Cao, and Zhenqi Liu*

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908; Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709

* To whom correspondence should be addressed. E-mail: zl3e{at}virginia.edu.

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 mitogen-activated protein kinase (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 hr in the presence or absence of SB203580 (p38 MAPK specific inhibitor, 10 µM) after serum starvation for 10 hr. For the last 30 min, cells were treated ± 1 nM insulin, and IRS-1, Akt, eNOS, p38 MAPK, ERK1/2, JNK and 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 PI3-kinase/Akt/eNOS pathway via a p38 MAPK-dependent mechanism and enhances ERK1/2 and AMPK phosphorylation independent of 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.
Key words: endothelial cells • insulin resistance • inflammation • mitogen-activated protein kinase




This article has been cited by other articles:


Home page
 J. Physiol.Home page
M. J. Zhu, B. Han, J. Tong, C. Ma, J. M. Kimzey, K. R. Underwood, Y. Xiao, B. W. Hess, S. P. Ford, P. W. Nathanielsz, et al.
AMP-activated protein kinase signalling pathways are down regulated and skeletal muscle development impaired in fetuses of obese, over-nourished sheep
J. Physiol., May 15, 2008; 586(10): 2651 - 2664.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. Li, J.-P. del Rincon, L. A. Jahn, Y. Wu, B. Gaylinn, M. O. Thorner, and Z. Liu
Growth Hormone Exerts Acute Vascular Effects Independent of Systemic or Muscle Insulin-like Growth Factor I
J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1379 - 1385.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
H. Wang, A. X. Wang, Z. Liu, and E. J. Barrett
Insulin Signaling Stimulates Insulin Transport by Bovine Aortic Endothelial Cells
Diabetes, March 1, 2008; 57(3): 540 - 547.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
W. Chai, Y. Wu, G. Li, W. Cao, Z. Yang, and Z. Liu
Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury
Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E183 - E189.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
Z. Liu
Insulin at physiological concentrations increases microvascular perfusion in human myocardium
Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1250 - E1255.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
J. Ye, Z. Gao, J. Yin, and Q. He
Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice
Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E1118 - E1128.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2007 by The Endocrine Society