Intracrine Testosterone Activation in Human Pancreatic β-Cells Stimulates Insulin Secretion

Diabetes. 2020 Nov;69(11):2392-2399. doi: 10.2337/db20-0228. Epub 2020 Aug 27.


Testosterone (T) affects β-cell function in men and women. T is a prohormone 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 type 1 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 two out of four male donors. In these donors, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism*
  • Aromatase / genetics
  • Aromatase / metabolism*
  • Cells, Cultured
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Insulin / metabolism*
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Male
  • Testosterone / pharmacology*


  • Insulin
  • Testosterone
  • Aromatase
  • CYP19A1 protein, human
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase

Associated data

  • figshare/10.2337/figshare.12841109