Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes

Guadalupe Navarro, Camille Allard, Jamie J. Morford, Weiwei Xu, Suhuan Liu, Adrien Jr Molinas, Sierra M. Butcher, Nicholas Hf Fine, Manuel Blandino-Rosano, Venkata N. Sure, Sangho Yu, Rui Zhang, Heike Münzberg, David A. Jacobson, Prasad V. Katakam, David J. Hodson, Ernesto Bernal-Mizrachi, Andrea Zsombok, Franck Mauvais-Jarvis

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournalJCI Insight
Volume3
Issue number12
DOIs
StatePublished - Jun 21 2018

Keywords

  • Beta cells
  • Diabetes
  • Endocrinology
  • Metabolism
  • Sex hormones

ASJC Scopus subject areas

  • Medicine(all)

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    Navarro, G., Allard, C., Morford, J. J., Xu, W., Liu, S., Molinas, A. J., Butcher, S. M., Fine, N. H., 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. (2018). Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes. JCI Insight, 3(12). https://doi.org/10.1172/jci.insight.98607