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agonists) but not PPAR
agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes1
The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Goteborg University, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden
2Correspondence: The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Guldhetsgatan, Gothenburg S-413 45 Goteborg, Sweden. E-mail. ulf.smith{at}medic.gu.se
Thiazolidinediones (TZD) improve insulin sensitivity in human as well as
in different animal models of insulin resistance and Type 2 diabetes.
However, no clear link to the insulin signaling events has been
identified. Using differentiated 3T3-L1 adipocytes, we found that TZD
rapidly and markedly increased IRS-2 gene expression. This effect was
specific for PPAR
agonists and was not seen with PPAR
agonists.
It was rapidly induced (within 4 h) and maintained throughout the
observation period of 48 h. It was also concentration dependent
(EC50 
50 nM) and not inhibited by cycloheximide,
suggesting a direct effect on the IRS-2 promoter. There was no evidence
that TZD altered IRS-2 mRNA stability, supporting that the increased
mRNA levels were due to an increased gene transcription. IRS-2 protein
expression was increased 30% after 48 h and 50% after
96 h. No effects of TZD were seen on IRS-1, PKB/Akt, or GLUT4 gene
expression. TZD also increased IRS-2 mRNA levels in cultured human
adipose tissue. These data show the first direct link between TZD and a
critical molecule in insulin’s signaling cascade in both 3T3-L1 and
human adipocytes, and indicate a novel mode of action of these
compounds.—Smith, U., Gogg, S., Johansson, A., Olausson, T., Rotter,
V., Svalstedt, B. Thiazolidinediones (PPAR agonists) but not PPAR
agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes.
Key Words: insulin signaling • insulin action • gene transcription • IRS-2 • PPAR
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