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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 2013 (8)

Title and authors Publication Year
Deficiency of a Glycogen Synthase-associated Protein, Epm2aip1, Causes Decreased Glycogen Synthesis and Hepatic Insulin Resistance
J Turnbull, E Tiberia, S Pereira, X Zhao, N Pencea, AL Wheeler, WQ Yu, A Ivovic, T Naranian, N Israelian, A Draginov, M Piliguian, PW Frankland, P Wang, CA Ackerley, A Giacca, BA Minassian
The Journal of biological chemistry 2013
Bofutsushosan, a Japanese herbal (Kampo) medicine, attenuates progression of nonalcoholic steatohepatitis in mice
M Ono, M Ogasawara, A Hirose, S Mogami, N Ootake, K Aritake, T Higuchi, N Okamoto, S Sakamoto, M Yamamoto, Y Urade, T Saibara, JA Oben
Journal of Gastroenterology 2013
Role for sterol regulatory element binding protein-1c activation in mediating skeletal muscle insulin resistance via repression of rat insulin receptor substrate-1 transcription
Y Bi, W Wu, J Shi, H Liang, W Yin, Y Chen, S Tang, S Cao, M Cai, S Shen, Q Gao, J Weng, D Zhu
Diabetologia 2013
Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes
CM Taniguchi, EC Finger, AJ Krieg, C Wu, AN Diep, EL LaGory, K Wei, LM McGinnis, J Yuan, CJ Kuo, AJ Giaccia
2013
Insulin-receptor substrate-2 (irs-2) is required for maintaining glucokinase and glucokinase regulatory protein expression in mouse liver
I Roncero, E Alvarez, C Acosta, C Sanz, P Barrio, V Hurtado-Carneiro, D Burks, E Blázquez
PloS one 2013
Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β
R Song, X Wang, Y Mao, H Li, Z Li, W Xu, R Wang, T Guo, L Jin, X Zhang, Y Zhang, N Zhou, R Hu, J Jia, Z Lei, DM Irwin, G Niu, H Tan
Gene 2013
Effect of IRS4 levels on PI 3-kinase signalling
G Hoxhaj, K Dissanayake, C MacKintosh
PloS one 2013
PREP1 deficiency downregulates hepatic lipogenesis and attenuates steatohepatitis in mice
F Oriente, S Cabaro, A Liotti, M Longo, L Parrillo, TB Pagano, GA Raciti, D Penkov, O Paciello, C Miele, P Formisano, F Blasi, F Beguinot
Diabetologia 2013

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