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Citations to this article

Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism
Cullen M. Taniguchi, … , Kohjiro Ueki, C. Ronald Kahn
Cullen M. Taniguchi, … , Kohjiro Ueki, C. Ronald Kahn
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):718-727. https://doi.org/10.1172/JCI23187.
View: Text | PDF | Corrigendum | Retraction
Article Metabolism Article has an altmetric score of 14

Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism

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Abstract

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.

Authors

Cullen M. Taniguchi, Kohjiro Ueki, C. Ronald Kahn

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Total citations by year

Year: 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 Total
Citations: 2 1 2 3 3 6 4 12 5 3 8 8 5 12 10 6 4 5 1 100
Citation information
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Citations to this article in year 2011 (5)

Title and authors Publication Year
MicroRNAs in metabolism and metabolic diseases
V Rottiers, SH Najafi-Shoushtari, F Kristo, S Gurumurthy, L Zhong, Y Li, DE Cohen, RE Gerszten, N Bardeesy, R Mostoslavsky, AM Näär
Cold Spring Harbor Symposia on Quantitative Biology 2011
Pathophysiology of insulin resistance and steatosis in patients with chronic viral hepatitis
M Basaranoglu, G Basaranoglu
World journal of gastroenterology : WJG 2011
Constitutive expression of short hairpin RNA in vivo triggers buildup of mature hairpin molecules
M Ahn, SR Witting, R Ruiz, R Saxena, N Morral
Human Gene Therapy 2011
A Hepatocyte Growth Factor Receptor (Met)–Insulin Receptor hybrid governs hepatic glucose metabolism
A Fafalios, J Ma, X Tan, J Stoops, J Luo, MC Defrances, R Zarnegar
Nature Medicine 2011
The Worker Honeybee Fat Body Proteome Is Extensively Remodeled Preceding a Major Life-History Transition
QW Chan, NS Mutti, LJ Foster, SD Kocher, GV Amdam, F Wolschin, OS Shirihai
PloS one 2011

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