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Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo
Open accessAbstract
Insulin signalling and nutrient levels coordinate the metabolic response to feeding in the liver. Insulin signals in hepatocytes to activate Akt, which inhibits Foxo1 suppressing hepatic glucose production (HGP) and allowing the transition to the postprandial state. Here we provide genetic evidence that insulin regulates HGP by both direct and indirect hepatic mechanisms. Liver-specific ablation of the IR (L-Insulin Receptor KO) induces glucose intolerance, insulin resistance and prevents the appropriate transcriptional response to feeding. Liver-specific deletion of Foxo1 (L-IRFoxo1DKO) rescues glucose tolerance and allows for normal suppression of HGP and gluconeogenic gene expression in response to insulin, despite lack of autonomous liver insulin signalling. These data indicate that in the absence of Foxo1, insulin signals via an intermediary extrahepatic tissue to regulate liver glucose production. Importantly, a hepatic mechanism distinct from the IR–Akt–Foxo1 axis exists to regulate glucose production. Insulin and the transcription factor FoxO1 are key regulators of hepatic glucose metabolism. Here, Titchenell et al. provide evidence for the existence of an insulin-dependent extrahepatic pathway that is fully capable of regulating hepatic glucose production in the absence of hepatic FoxO1.
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“Intact hepatic insulin signaling is, however, dispensable for the postprandial repression of hepatic glucose production in the absence of hepatic FoxO1 32, 33, highlighting the importance of hypothalamic insulin signaling in the control of liver glucose metabolism 34.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [33]
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Metadata
- Authors
- Titchenell, P. M., Chu, Q., Monks, B. R., & Birnbaum, M. J.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Birnbaum, Morris J.
- Venue
- Nature Communications
- Published
- 2015-05-12
- Volume
- 6
- Issue
- 1
- Pages
- 7078-7078
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4429930
- OpenAlex
- W240175869
- Cited by
- 169
- References
- 43
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 11 · 2023: 14 · 2022: 18 · 2021: 15 · 2020: 15 · 2019: 11 · 2018: 19 · 2017: 24 · 2016: 14 · 2015: 8
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056886, F32DK101175)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- hepatic glucose production, FOXO1, insulin receptor, Akt, gluconeogenesis, impaired glucose tolerance, insulin resistance, liver-specific knockout, postprandial glucose metabolism, hepatic glucose metabolism
- MeSH terms
- Forkhead Box Protein O1, Animals, Gene Expression Regulation, Gluconeogenesis, Glucose, Glucose Tolerance Test, Insulin Resistance, Liver, Male, Receptor, Insulin, RNA, Messenger, Signal Transduction, Mice, Knockout, Mice, Forkhead Transcription Factors
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