Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

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

  • Text
  • PDF
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

×

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
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2016 (12)

Title and authors Publication Year
ChREBP Regulates Fructose-Induced Glucose Production Independently of Insulin Signaling
Mi-sung Kim, Sarah Krawczyk, Ludivine Doridot, Alan J. Fowler, Jennifer Wang, Sunia Trauger, Hye-Lim Noh, Hee Joon Kang, John Meissen, Matthew Blatnik, Jason Kim, Michelle Lai, Mark Herman
Journal of Clinical Investigation 2016
Sequential cleavage of insulin receptor by calpain 2 and γ-secretase impairs insulin signalling
T Yuasa, K Amo-Shiinoki, S Ishikura, M Takahara, T Matsuoka, H Kaneto, A Kuroda, M Matsuhisa, S Hashida
Diabetologia 2016
Metabolomics reveals the protective of Dihydromyricetin on glucose homeostasis by enhancing insulin sensitivity
L Le, B Jiang, W Wan, W Zhai, L Xu, K Hu, P Xiao
Scientific Reports 2016
Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis
J Huo, Y Ma, JJ Liu, YS Ho, S Liu, LY Soh, S Chen, S Xu, W Han, A Hong, SC Lim, KP Lam
Cell Death and Disease 2016
Application of network construction to estimate functional changes to insulin receptor substrates?1 and?2 in Huh7 cells following infection with the hepatitis?C virus
J Liu, L Wang, W Wang, Y Li, X Jia, S Zhai, J Shi, S Dang
Molecular medicine reports 2016
NAMPT knockdown attenuates atherosclerosis and promotes reverse cholesterol transport in ApoE KO mice with high-fat-induced insulin resistance
S Li, C Wang, K Li, L Li, M Tian, J Xie, M Yang, Y Jia, J He, L Gao, G Boden, H Liu, G Yang
Scientific Reports 2016
Selective Insulin Resistance in the Kidney
S Horita, M Nakamura, M Suzuki, N Satoh, A Suzuki, G Seki
BioMed Research International 2016
Metabolic Benefit of Chronic Caloric Restriction and Activation of Hypothalamic AGRP/NPY Neurons in Male Mice Is Independent of Ghrelin
NH Rogers, H Walsh, O Alvarez-Garcia, S Park, B Gaylinn, MO Thorner, RG Smith
Endocrinology 2016
Novel hepatic microRNAs upregulated in human nonalcoholic fatty liver disease
J Soronen, H YkiJärvinen, Y Zhou, S Sädevirta, AP Sarin, M Leivonen, K Sevastianova, J Perttilä, PP Laurila, A Sigruener, G Schmitz, VM Olkkonen
Physiological Reports 2016
Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating the IRS-1/PI3K/Akt and AMPK/ACC2 signaling pathways
X Nie, H Chen, J Zhang, Y Zhang, J Yang, H Pan, W Song, F Murad, Y He, K Bian
Acta Pharmacologica Sinica 2016
Shift in Food Intake and Changes in Metabolic Regulation and Gene Expression during Simulated Night-Shift Work: A Rat Model
A Marti, P Meerlo, J Grønli, S Hasselt, J Mrdalj, S Pallesen, T Pedersen, T Henriksen, S Skrede
Nutrients 2016
IRS1 and IRS2: molecular characterization, tissue expression and transcriptional regulation by insulin in yellow catfish Pelteobagrus fulvidraco
MQ Zhuo, YX Pan, K Wu, YH Xu, LH Zhang, Z Luo
Fish Physiology and Biochemistry 2016

Advertisement

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 2
Posted by 1 X users
Mentioned by 1 peer review sites
144 readers on Mendeley
See more details