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Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.
Open accessAbstract
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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“For example, liver-specific insulin receptor knockout (LIRKO) mice develop insulin resistance, glucose intolerance, impaired insulin suppression of hepatic glucose production, and altered patterns of hepatic gene expression (208).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [208]
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Metadata
- 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
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 6
- Issue
- 1
- Pages
- 87-97
- ISSN
- 1097-2765 (ISSN-L)
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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