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Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus
Open accessAbstract
We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity.
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“mice with neuron-specific deletion of either the insulin receptor (IR) or insulin receptor-substrate-2 (IRS-2) are characterized by mild obesity and insulin resistance (27, 97, 105).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [97]
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Metadata
- Authors
- Kubota, N., Terauchi, Y., Tobe, K., Yano, W., Suzuki, R., Ueki, K., Takamoto, I., Satoh, H., Maki, T., Kubota, T., Moroi, M., Okada-Iwabu, M., Ezaki, O., Nagai, R., Ueta, Y., Kadowaki, T., & Noda, T.
- Affiliations
- The University of Tokyo (JP)
- Japan Science and Technology Agency (JP)
- Toho University (JP)
- National Institute of Health and Nutrition (JP)
- University of Occupational and Environmental Health Japan (JP)
- Tohoku University (JP)
- Corresponding author
- Kadowaki, Takashi
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2004-10-01
- Volume
- 114
- Issue
- 7
- Pages
- 917-927
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC518663
- OpenAlex
- W2140622624
- Cited by
- 239
- References
- 39
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 6 · 2019: 9 · 2018: 9 · 2017: 8 · 2016: 6 · 2015: 13 · 2014: 15 · 2013: 14 · 2012: 11
- FWCI
- 17.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Kowa Company
- Ministry of Education, Culture, Sports, Science and Technology
- Kanae Foundation for the Promotion of Medical Science
- Japan Society for the Promotion of Science (10NP0201)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- insulin receptor substrate 2, pancreatic beta cells, hypothalamus, arcuate nucleus, leptin resistance, obesity, beta-cell mass, beta-cell proliferation, insulin secretion, impaired glucose tolerance, hepatic insulin resistance, type 2 diabetes, insulin sensitivity
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, Blood Glucose, Body Weight, Cell Division, Diet, Female, Hyperlipidemias, Insulin, Insulin Resistance, Islets of Langerhans, Male, Mice, Inbred C57BL, Obesity, Phosphoproteins, RNA, Messenger, Tissue Distribution, Transcription Factors, Signal Transduction, Glucose Intolerance, Mice, Knockout, Leptin, Caloric Restriction, Intracellular Signaling Peptides and Proteins, Mice, Insulin Receptor Substrate Proteins
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