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The oxazolidinedione CP-92,768-2 partially protects insulin receptor substrate-1 from dexamethasone down-regulation in 3T3-L1 adipocytes.

Abstract
Oxazolidinediones are a class of oral antidiabetic agents that are closely related structurally and pharmacologically to thiazolidinediones. The thiazolidinediones have been shown to partially reverse the loss in insulin-responsive glucose uptake caused by chronic treatment with dexamethasone. This study was conducted to determine certain aspects of the mechanism of thiazolidinedione and oxazolidinedione action. We selected the oxazolidinedione CP-92,768-2 (5-[2-[(5-methyl2-phenyl-4-oxazolyl)methyl]5-benzofuranyl methyl]2,4- oxazolidinedione) to determine whether these agents could reverse the dexamethasone-induced down-regulation of IRS-1, the insulin receptor substrate-1. In 3T3-L1 adipocytes, dexamethasone treatment resulted in down-regulation of IRS-1 to 60% of control values. Simultaneous treatment with CP-92,768-2 significantly increased IRS-1 to 78% of the control value (EC50, < 10 nM), although it did not completely reverse the dexamethasone effect at any concentration tested. CP-92,768-2 alone did not have any effect on IRS-1. CP-92,768-2 did not affect the stability of IRS-1 protein in the presence or absence of dexamethasone, as measured by [35S]methionine pulse-chase labeling. Dexamethasone decreased messenger RNA (mRNA) for IRS-1 after 24 h of treatment to 40% of the control value. CP-92,768-2 partially reversed this decrease in IRS-1 mRNA to 65% of the control value after 24 h of treatment, but had no effect on IRS-1 mRNA in the absence of dexamethasone. Dexamethasone down-regulated the insulin stimulation of [3H]thymidine incorporation to 68% of the control value. Dexamethasone in the presence of CP-92,768-2 down-regulated insulin stimulation of thymidine incorporation by only 9%. Dexamethasone also down-regulated the expression of phosphoenolpyruvate carboxykinase (PEPCK) protein by 50%. CP-92,768-2 partially protected PEPCK from the dexamethasone down-regulation. Conversely, the up-regulation of expression of PEPCK and IRS-1 produced by dexamethasone in KRC-7 hepatoma cells was not affected by CP-92,768-2. One contribution of oxazolidinediones to an increase in insulin responsiveness in the presence of glucocorticoids may be the up-regulation of IRS-1 in adipose cells.
AuthorsM A Turnbow, L K Smith, C W Garner
JournalEndocrinology (Endocrinology) Vol. 136 Issue 4 Pg. 1450-8 (Apr 1995) ISSN: 0013-7227 [Print] United States
PMID7895655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Benzofurans
  • CP 92768-2
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Oxazoles
  • Oxazolidinones
  • Phosphoproteins
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Mifepristone
  • Dexamethasone
  • Phosphoenolpyruvate Carboxykinase (GTP)
Topics
  • 3T3 Cells
  • Adipocytes (metabolism)
  • Animals
  • Benzofurans (pharmacology)
  • Dexamethasone (pharmacology)
  • Down-Regulation
  • Gene Expression Regulation (drug effects)
  • Insulin (pharmacology)
  • Insulin Receptor Substrate Proteins
  • Mice
  • Mifepristone (pharmacology)
  • Oxazoles (pharmacology)
  • Oxazolidinones
  • Phosphoenolpyruvate Carboxykinase (GTP) (metabolism)
  • Phosphoproteins (genetics, metabolism)
  • RNA, Messenger (metabolism)
  • Receptors, Glucocorticoid (metabolism)

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