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J. Biol. Chem., Vol. 277, Issue 26, 23301-23307, June 28, 2002
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From the The ability of insulin to suppress
gluconeogenesis in type II diabetes mellitus is impaired; however, the
cellular mechanisms for this insulin resistance remain poorly
understood. To address this question, we generated transgenic (TG) mice
overexpressing the phosphoenolpyruvate carboxykinase (PEPCK) gene under
control of its own promoter. TG mice had increased basal hepatic
glucose production (HGP), but normal levels of plasma free fatty acids (FFAs) and whole-body glucose disposal during a
hyperinsulinemic-euglycemic clamp compared with wild-type controls. The
steady-state levels of PEPCK and glucose-6-phosphatase mRNAs were
elevated in livers of TG mice and were resistant to down-regulation by
insulin. Conversely, GLUT2 and glucokinase mRNA levels were
appropriately regulated by insulin, suggesting that insulin resistance
is selective to gluconeogenic gene expression. Insulin-stimulated
phosphorylation of the insulin receptor, insulin receptor substrate
(IRS)-1, and associated phosphatidylinositol 3-kinase were normal in TG
mice, whereas IRS-2 protein and phosphorylation were down-regulated compared with control mice. These results establish that a modest (2-fold) increase in PEPCK gene expression in vivo is
sufficient to increase HGP without affecting FFA concentrations.
Furthermore, these results demonstrate that PEPCK overexpression
results in a metabolic pattern that increases glucose-6-phosphatase
mRNA and results in a selective decrease in IRS-2 protein,
decreased phosphatidylinositol 3-kinase activity, and reduced ability
of insulin to suppress gluconeogenic gene expression. However, acute suppression of HGP and glycolytic gene expression remained intact, suggesting that FFA and/or IRS-1 signaling, in addition to reduced IRS-2, plays an important role in downstream insulin signal
transduction pathways involved in control of gluconeogenesis and
progression to type II diabetes mellitus.
Phosphoenolpyruvate Carboxykinase Overexpression Selectively
Attenuates Insulin Signaling and Hepatic Insulin Sensitivity in
Transgenic Mice*
,,,,,¶
Department of Nutrition, Case Western
Reserve University School of Medicine, Cleveland, Ohio 44106-4935 and the § Edison Animal Biotechnology Center, Ohio
University, Athens, Ohio 45107
*
This work was supported by National Institutes of Health
Grant DK59767.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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