First published November 1, 2016 - More info
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
Original citation: J Clin Invest. 2005;115(3):718–727. doi:10.1172/JCI23187.
Citation for this retraction: J Clin Invest. 2016;126(11):4387. doi:10.1172/JCI90689.
At the request of the corresponding author, the JCI is retracting this article. The authors were recently made aware of duplicated bands in Figures 1B, 3C, and 4C. After an extensive internal review, it was discovered that these duplications were introduced during figure assembly. The authors have stated that experimental data generated in the lab from the same time period support the original conclusions of the study and that other studies have subsequently confirmed and extended the primary conclusions of the manuscript. However, in the interest of maintaining accuracy in the published scientific literature and because the initial figures were not up to the standards of the JCI, the authors wish to retract this article. The authors apologize for these errors.