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Dynamic Functional Relay between Insulin Receptor Substrate 1 and 2 in Hepatic Insulin Signaling during Fasting and Feeding
Open accessAbstract
Insulin receptor substrate (Irs) mediates metabolic actions of insulin. Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding.
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“Irs1 is an insulin receptor substrate and when lost, leads to suppressed lipogenesis due to reduced insulin signaling20-22.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [21]
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Metadata
- Authors
- Kubota, N., Kubota, T., Itoh, S., Kumagai, H., Kozono, H., Takamoto, I., Mineyama, T., Ogata, H., Tokuyama, K., Ohsugi, M., Sasako, T., Moroi, M., Sugi, K., Kakuta, S., Iwakura, Y., Noda, T., Ohnishi, S., Nagai, R., Tobe, K., Terauchi, Y., Ueki, K., & Kadowaki, T.
- Affiliations
- National Institute of Health and Nutrition (JP)
- Toho University (JP)
- Kowa (Japan) (JP)
- The University of Tokyo (JP)
- University of Tsukuba (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- Japanese Foundation For Cancer Research (JP)
- University of Toyama (JP)
- Yokohama City University (JP)
- Corresponding author
- Kadowaki, Takashi
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 8
- Issue
- 1
- Pages
- 49-64
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W1969750989
- Cited by
- 244
- References
- 37
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 15 · 2023: 11 · 2022: 6 · 2021: 18 · 2020: 9 · 2019: 8 · 2018: 17 · 2017: 10 · 2016: 10 · 2015: 7 · 2014: 15 · 2013: 24 · 2012: 15
- FWCI
- 8.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (16209030, 18209033, 19591037)
- Core Research for Evolutional Science and Technology
- Japan Science and Technology Corporation
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- IRS-1, insulin receptor substrate 2, hepatic insulin signaling, glucose homeostasis, fasting, refeeding, insulin resistance, liver-specific knockout mice
- MeSH terms
- Animals, Eating, Fasting, Glucose, Homeostasis, Insulin, Insulin Resistance, Liver, Phosphoproteins, Signal Transduction, Phosphatidylinositol 3-Kinases, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Insulin Receptor Substrate Proteins
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