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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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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
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Citations to this article in year 2023 (2)

Title and authors Publication Year
Glucosamine Improves Non-Alcoholic Fatty Liver Disease Induced by High-Fat and High-Sugar Diet through Regulating Intestinal Barrier Function, Liver Inflammation, and Lipid Metabolism
Li F, Zhang Z, Bai Y, Che Q, Cao H, Guo J, Su Z
Molecules (Basel, Switzerland) 2023
Partners in diabetes epidemic: A global perspective
Wang H, Akbari-Alavijeh S, Parhar RS, Gaugler R, Hashmi S
World journal of diabetes 2023

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