Androgen Excess in Pancreatic β Cells and Neurons Predisposes Female Mice to Type 2 Diabetes
Open accessAbstract
Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed to chronic androgen excess using dihydrotestosterone (DHT) exhibit hyperinsulinemia and insulin resistance associated with secondary pancreatic β cell failure, leading to hyperglycemia. These abnormalities are not observed in mice lacking the androgen receptor (AR) in β cells and partially in neurons of the mediobasal hypothalamus (MBH) as well as in mice lacking AR selectively in neurons. Accordingly, i.c.v. infusion of DHT produces hyperinsulinemia and insulin resistance in female WT mice. We observe that acute DHT produces insulin hypersecretion in response to glucose in cultured female mouse and human pancreatic islets in an AR-dependent manner via a cAMP- and mTOR-dependent pathway. Acute DHT exposure increases mitochondrial respiration and oxygen consumption in female cultured islets. As a result, chronic DHT exposure in vivo promotes islet oxidative damage and susceptibility to additional stress induced by streptozotocin via AR in β cells. This study suggests that excess androgen predisposes female mice to T2D following AR activation in neurons, producing peripheral insulin resistance, and in pancreatic β cells, promoting insulin hypersecretion, oxidative injury, and secondary β cell failure.
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Androgens may promote insulin resistance by acting on the central nervous system.
“That observation suggests that androgens may also promote IR by acting on the central nervous system [52].”
From The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome (2022) · cites this paper as [52]
Activation of androgen receptors by dihydrotestosterone in the brains of mice led to the development of insulin resistance, whereas rodents deprived of these receptors did not develop this disorder.
“Studies on mice have shown that activation of androgen receptors by dihydrotestosterone in the brains of the tested animals led to the development of IR, whereas rodents deprived of these receptors did not develop this type of disorder.”
From The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome (2022) · cites this paper as [52]
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- Authors
- Navarro, G., Allard, C., Morford, J. J., Xu, W., Liu, S., Molinas, A. J. R., Butcher, S. M., Fine, N. H. F., Blandino-Rosano, M., Sure, V. N., Yu, S., Zhang, R., Münzberg, H., Jacobson, D. A., Katakam, P. V., Hodson, D. J., Bernal-Mizrachi, E., Zsombok, A., & Mauvais-Jarvis, F.
- Affiliations
- Northwestern University (US)
- Department of Medicine, Section of Endocrinology and Metabolism, and
- Tulane University (US)
- University of Birmingham (GB)
- University of Miami (US)
- Pennington Biomedical Research Center (US)
- Vanderbilt University (US)
- Department of Internal Medicine, Division Endocrinology, Metabolism and Diabetes, Miller School of Medicine, University of Miami, Miami, Florida, USA.
- ORCID
- Venue
- JCI Insight
- Published
- 2018-06-21
- Volume
- 3
- Issue
- 12
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC6124401
- OpenAlex
- W2809002075
- Cited by
- 80
- References
- 52
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 11 · 2023: 9 · 2022: 3 · 2021: 20 · 2020: 9 · 2019: 5 · 2018: 3
- FWCI
- 9.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- NIDDK (DK074970,DK107444)
- NICHD (HD044405)
- U.S. Department of Veterans Affairs (BX003725)
- Topics
- Health Sciences › Medicine › Surgery › 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
- hyperandrogenism, type 2 diabetes, dihydrotestosterone, androgen receptor, pancreatic beta cells, insulin resistance, hyperinsulinemia, insulin hypersecretion, beta-cell failure, mediobasal hypothalamus, cAMP signaling, mTOR signaling, mitochondrial respiration, oxidative stress, islet damage, streptozotocin, sex differences, Western diet
- MeSH terms
- Androgens, Animals, Diabetes Mellitus, Type 2, Female, Glucose, Humans, Hyperinsulinism, Hypothalamus, Insulin Resistance, Mice, Inbred C57BL, Mitochondria, Neurons, Receptors, Androgen, Dihydrotestosterone, Streptozocin, Mice, Knockout, Insulin-Secreting Cells, Mice, Diet, Western
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