| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 16, 2005
Accepted on March 22, 2006
Laboratory of Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands, Tel: +31-20-5667062, Fax: +31-20-6977192, E mail: m.lowenberg@amc.uva.nl; Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands.; Department of Cell Biology, University of Groningen, A. Deussinglaan 1, NL-9713 AV Groningen, The Netherlands
* To whom correspondence should be addressed. E-mail: m.lowenberg{at}amc.uva.nl.
Glucocorticoids (GCs) are powerful immunosuppressive agents that control genomic effects through GC receptor-dependent transcriptional changes. A common complication of GC therapy is insulin resistance, but the underlying molecular mechanism remains obscure. Evidence is increasing for rapid genomic-independent GC action on cellular physiology. We here generate a comprehensive description of nongenomic GC effects on insulin signaling using peptide arrays containing 1176 different kinase consensus substrates. Reduced kinase activities of the insulin receptor and several downstream insulin receptor signaling intermediates (i.e. p70S6k, AMPK, GSK-3 and Fyn) were detected in adipocytes and T lymphocytes due to short-term treatment with dexamethasone, a synthetic fluorinated GC. Western blot analysis confirmed suppressed phosphorylation of the insulin receptor and a series of downstream insulin receptor targets (i.e. IRS-1, p70S6k, PKB, PDK, Fyn and GSK-3) following dexamethasone treatment. Dexamethasone inhibited insulin signaling through a GC receptor-dependent (RU486-sensitive) and transcription-independent (actinomycin D-insensitive) mechanism. Overall, we here postulate a molecular mechanism for GC-induced insulin resistance based on nongenomic GC receptor-dependent inhibition of insulin signaling.
This article has been cited by other articles:
 |
|
 |
|
  L. L. Gathercole, I. J. Bujalska, P. M. Stewart, and J. W. Tomlinson Glucocorticoid Modulation of Insulin Signaling in Human Subcutaneous Adipose Tissue J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4332 - 4339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Rogoff, J. W. Ryder, K. Black, Z. Yan, S. C. Burgess, D. R. McMillan, and P. C. White Abnormalities of Glucose Homeostasis and the Hypothalamic-Pituitary-Adrenal Axis in Mice Lacking Hexose-6-Phosphate Dehydrogenase Endocrinology, October 1, 2007; 148(10): 5072 - 5080. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. de Borst, S. H. Diks, J. Bolbrinker, M. W. Schellings, M. B. A. van Dalen, M. P. Peppelenbosch, R. Kreutz, Y. M. Pinto, G. Navis, and H. van Goor Profiling of the renal kinome: a novel tool to identify protein kinases involved in angiotensin II-dependent hypertensive renal damage Am J Physiol Renal Physiol, July 1, 2007; 293(1): F428 - F437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Qi and B. Rodrigues Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E654 - E667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W.P.M. van Baal, S. H. Diks, R. J.A. Wanders, A. M. Rygiel, F. Milano, J. Joore, J. J.G.H.M. Bergman, M. P. Peppelenbosch, and K. K. Krishnadath Comparison of Kinome Profiles of Barrett's Esophagus with Normal Squamous Esophagus and Normal Gastric Cardia Cancer Res., December 15, 2006; 66(24): 11605 - 11612. [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 |
