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

Testosterone (T) affects beta-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 5 alpha-reductase (5 alpha-R) or to the active estrogen 17 beta-estradiol (E2) via the aromatase enzyme. Using male and female human pancreas sections, we show that the 5 alpha-R type 1 isoform (SRD5A1) and aromatase are expressed in male and female beta-cells. We show that cultured male and female human islets exposed to T produce DHT and downstream metabolites. In these islets, exposure to the 5 alpha-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 5 alpha-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.