Liver-derived systemic factors drive β cell hyperplasia in insulin-resistant states
Open accessAbstract
Integrative organ crosstalk regulates key aspects of energy homeostasis, and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that crosstalk between the liver and pancreatic islets modulates β cell growth in response to insulin resistance, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, as well as in vitro islet culture approaches, we demonstrate that humoral, nonneural, non-cell-autonomous factor(s) induces β cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β cell growth factor(s) in insulin-resistant states.
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In the ACCORD, VADT, ORIGIN, and ADVANCE trials, intensive glucose lowering did not reduce cardiovascular events.
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- Authors
- El Ouaamari, A., Kawamori, D., Dirice, E., Liew, C. W., Shadrach, J. L., Hu, J., Katsuta, H., Hollister-Lock, J., Qian, W.-J., Wagers, A. J., & Kulkarni, R. N.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- Kulkarni, Rohit N.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 3
- Issue
- 2
- Pages
- 401-410
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3655439
- OpenAlex
- W1985508368
- Cited by
- 136
- References
- 42
- Citations by year
- 2025: 6 · 2024: 6 · 2023: 2 · 2022: 8 · 2021: 8 · 2020: 9 · 2019: 6 · 2018: 11 · 2017: 11 · 2016: 14 · 2015: 19 · 2014: 23 · 2013: 13
- FWCI
- 22.69
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-03-28)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1dp2od004345-01)
- Japan Society for the Promotion of Science (23591309)
- National Institute of Diabetes and Digestive and Kidney Diseases (5 P30 DK36836-20, R00DK090210, R01DK074795, P30DK036836, R01DK067536)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- beta-cell hyperplasia, insulin resistance, beta-cell proliferation, parabiosis, islet transplantation, islet culture, obesity, diabetes mellitus, energy homeostasis
- MeSH terms
- Animals, Cells, Cultured, Humans, Hyperplasia, Insulin Resistance, Islets of Langerhans, Mice, Inbred C57BL, Receptor, Insulin, Islets of Langerhans Transplantation, Culture Media, Conditioned, Mice, Knockout, Hepatocytes, Intercellular Signaling Peptides and Proteins, Cell Proliferation, Insulin-Secreting Cells, Mice
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