Hepatic insulin resistance is a critical component in the development of type 2 diabetes mellitus. In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70–80% in livers of WT mice. The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor–4 α. Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. The alterations in the dual-knockdown mice were associated with defective Akt activation and Foxo1 phosphorylation. Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism.
Cullen M. Taniguchi, Kohjiro Ueki, C. Ronald Kahn
Title and authors | Publication | Year |
---|---|---|
IRS1 and IRS2 Signaling Is Essential for Hepatic Glucose Homeostasis and Systemic Growth
Xiaocheng Dong, Sunmin Park, Xueying Lin, Kyle Copps, Xianjin Yi, and Morris F. White |
Journal of Clinical Investigation | 2006 |
Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice
M Simmgen, C Knauf, M Lopez, AI Choudhury, M Charalambous, J Cantley, DC Bedford, M Claret, MA Iglesias, H Heffron, PD Cani, A Vidal-Puig, R Burcelin, DJ Withers |
Diabetologia | 2006 |
Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN
CM Taniguchi, TT Tran, T Kondo, J Luo, K Ueki, LC Cantley, CR Kahn |
Proceedings of the National Academy of Sciences | 2006 |
Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice
Y Zhang, FY Lee, G Barrera, H Lee, C Vales, FJ Gonzalez, TM Willson, PA Edwards |
Proceedings of the National Academy of Sciences | 2006 |
Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates
G Solinas, W Naugler, F Galimi, MS Lee, M Karin |
Proceedings of the National Academy of Sciences | 2006 |