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Intracrine testosterone activation in human pancreatic β cells stimulates insulin secretion.

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posted on 14.09.2020 by Ada Admin, Weiwei Xu, Lina Schiffer, M.M. Fahd Qadir, Yanqing Zhang, James Hawley, Paula Mota De Sa, Brian G Keevil, Hongju Wu, Wiebke Arlt, Franck Mauvais-Jarvis
Testosterone (T) affects β cell function in men and women. T is a pro-hormone that undergoes intracrine conversion in target tissues to the potent androgen dihydrotestosterone (DHT) via the enzyme 5α-reductase (5α-R), or to the active estrogen 17β-estradiol (E2) via the aromatase enzyme. Using male and female human pancreas sections, we show that the 5α-R type1 isoform (SRD5A1) and aromatase are expressed in male and female β cells. We show that cultured male and female human islets exposed to T produce DHT and downstream metabolites. In these islets, exposure to the 5α-R inhibitors finasteride and dutasteride inhibited T conversion into DHT. We did not detect T conversion into E2 from female islets. However, we detected T conversion into E2 in islets from one out of four male donors. In this donor, exposure to the aromatase inhibitor anastrozole inhibited E2 production. Notably, in cultured male and female islets, T enhanced glucose-stimulated insulin secretion (GSIS). In these islets, exposure to 5α-R inhibitors or the aromatase inhibitor both inhibited T enhancement of GSIS. In conclusion, male and female human islets convert T into DHT and E2 via the intracrine activities of SRD5A1 and aromatase. This process is necessary for T enhancement of GSIS.

Funding

This work was supported by grants from the National Institutes of Health (DK074970 and DK107444 to F.M.J., DK107412 to H.W.), a U.S. Department of Veterans Affairs Merit Review Award (BX003725) to F.M.J., a Wellcome Trust Investigator Award (209492/Z/17/Z) to W.A., and the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham (Grant BRC-1215-20009).

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