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Citations to this article

Insulin signaling is required for insulin’s direct and indirect action on hepatic glucose production
Simon J. Fisher, C. Ronald Kahn
Simon J. Fisher, C. Ronald Kahn
Published February 15, 2003
Citation Information: J Clin Invest. 2003;111(4):463-468. https://doi.org/10.1172/JCI16426.
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Article Metabolism Article has an altmetric score of 5

Insulin signaling is required for insulin’s direct and indirect action on hepatic glucose production

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Abstract

We and others have suggested that insulin predominantly acts indirectly to inhibit hepatic glucose production (HGP) via suppression of gluconeogenic precursors, FFAs, and glucagon. To test that hypothesis, we performed high-dose hyperinsulinemic-euglycemic clamps using [3-3H]-glucose in liver-specific insulin receptor knockout (LIRKO) mice, LIRKO mice treated with streptozotocin (LIRKO+STZ), and controls. In LIRKO mice, fasted glucose was normal, but insulin levels were elevated tenfold. STZ treatment reduced insulinemia by 60% with resulting hyperglycemia. Interestingly, basal HGP was similar in all three groups. During the clamp, HGP was suppressed by 82 ± 17% in controls, but was not suppressed in either LIRKO or LIRKO+STZ mice. Glucose infusion and utilization were impaired (∼50%) in LIRKO and LIRKO+STZ mice versus controls. Insulin suppressed FFAs similarly in all groups (∼46%). Glucagon was not significantly suppressed during the clamp. Thus, in LIRKO mice, (a) high-dose insulin fails to suppress HGP indicating that both direct and indirect effects of insulin require an intact insulin-signaling pathway in the liver; (b) primary hepatic insulin resistance leads to hyperinsulinemia and secondary extrahepatic insulin resistance; and (c) lowering insulin levels with STZ tended to improve extrahepatic insulin sensitivity but failed to reveal the previously postulated indirect role of insulin in suppressing HGP.

Authors

Simon J. Fisher, C. Ronald Kahn

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Total citations by year

Year: 2024 2023 2022 2021 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 Total
Citations: 2 2 3 6 1 5 6 6 5 4 3 2 7 4 4 1 1 7 4 1 2 76
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 2006 (7)

Title and authors Publication Year
Insulin’s Direct Effects on the Liver Dominate the Control of Hepatic Glucose Production
Dale S. Edgerton, Margaret Lautz, Melanie Scott, Carrie A. Everett, Kathryn M. Stettler, Doss W. Neal, Chang A. Chu, Alan D. Cherrington
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
The Genetic Basis of Type 2 Diabetes
SK Das, SC Elbein
Cellscience 2006
Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism
S Qu, J Altomonte, G Perdomo, J He, Y Fan, A Kamagate, M Meseck, HH Dong
Endocrinology 2006
Central nervous system and control of endogenous glucose production
G Demuro, S Obici
Current Diabetes Reports 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
Insulin’s effect on the liver: “Direct or indirect?” continues to be the question
J Girard
Journal of Clinical Investigation 2006

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