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.