Cited by 1,296Metabolism, Diabetes, and CancerPancreatic function and diabetesLiver physiology and pathology

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Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.

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Michael, M.Dodson, Kulkarni, Rohit N., Postic, Catherine, Previs, Steven F., Shulman, Gerald I., Magnuson, Mark A., Kahn, C.Ronald·2000·Molecular Cell

DOI 10.1016/s1097-2765(05)00015-8

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Abstract

The liver plays a central role in the control of glucose homeostasis and is subject to complex regulation by substrates, insulin, and other hormones. To investigate the effect of the loss of direct insulin action in liver, we have used the Cre-loxP system to inactivate the insulin receptor gene in hepatocytes. Liver-specific insulin receptor knockout (LIRKO) mice exhibit dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations are paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the LIRKO liver exhibits morphological and functional changes, and the metabolic phenotype becomes less severe. Thus, insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function.

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Authors: Michael, M. D., Kulkarni, R. N., Postic, C., Previs, S. F., Shulman, G. I., Magnuson, M. A., & Kahn, C. R.
Affiliations: Joslin Diabetes Center (US)
Vanderbilt University (US)
Yale University (US)
Corresponding author: Kahn, C.Ronald
ORCID: Michael, M.Dodson
Kulkarni, Rohit N.
Postic, Catherine
Shulman, Gerald I.
Magnuson, Mark A.
Kahn, C.Ronald
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2000-07
Volume: 6
Issue: 1
Pages: 87-97
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/s1097-2765(05)00015-8
OpenAlex: W2118688616
Cited by: 1,296
References: 82
Citations by year: 2026: 12 · 2025: 24 · 2024: 47 · 2023: 37 · 2022: 45 · 2021: 56 · 2020: 46 · 2019: 60 · 2018: 64 · 2017: 66 · 2016: 60 · 2015: 73 · 2014: 61 · 2013: 64 · 2012: 68
FWCI: 13.76
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 4764 d)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
Funders: School of Medicine, Vanderbilt University
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK031036, P01DK042502, R01DK040936, F32DK009825)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords: insulin resistance, insulin signaling, hepatocytes, insulin receptor, liver-specific knockout, glucose homeostasis, hepatic glucose production, hyperinsulinemia, insulin secretion, insulin clearance, hepatic gene expression, aging, liver dysfunction
MeSH terms: Aging, Animals, Glucose, Homeostasis, Insulin, Insulin Resistance, Liver, Mice, Inbred C57BL, Microscopy, Electron, Receptor, Insulin, Signal Transduction, Mice, Knockout, Mice

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Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.

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