madman
Super Moderator
Abstract
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.
Introduction
Accumulated evidence suggests that the gonadal steroid testosterone (T) is necessary for proper glucose-stimulated insulin secretion (GSIS) in men and promotes insulin hypersecretion and β cell dysfunction in women with androgen excess (1-4). Accordingly, the active metabolite of T, dihydrotestosterone (DHT), enhances GSIS in cultured islets from male human donors (3). Male mice lacking the androgen receptor (AR) selectively in β cells (βARKO) exhibit impaired GSIS, leading to glucose intolerance, and develop diabetes (3). In addition, exposure of cultured islets from female human donors to DHT promotes insulin hypersecretion (4). In a female mouse model of chronic androgen excess, DHT promotes hyperinsulinemia associated with secondary pancreatic β cell dysfunction via action on AR in β cells (4).
In healthy men and hyperandrogenic women, T is the main circulating gonadal androgen. T is a weak androgen and a pro-hormone that undergoes local conversion in target tissues to either DHT via the action of one of the 5α-reductase (5α-R) isoforms (5), or 17β-estradiol (E2) via the action of the enzyme aromatase, to activate AR or estrogen receptor(ER)s, respectively (5, 6). Notably, activation of ERs by E2 in male and female human β cells enhances insulin synthesis, GSIS, and promotes survival from multiple metabolic injuries (7-11). Therefore, circulating T could have a clinically relevant impact on β cell function in healthy men and hyperandrogenic women via conversion to DHT and/or E2 within pancreatic islets. However, the extent to which 5α-R isoforms and the aromatase are present in human islets from both sexes and able to convert T to DHT and E2 to directly affect β cell function is unknown.
Here, we have used pancreas sections and cultured islets from male and female human donors to study the expression of the three 5α-R isoforms and the aromatase, quantify the conversion of T to DHT and E2 and assess the functional significance of intracrine conversion of T in pancreatic islets on GSIS.
In conclusion, using highly selective and specific tandem mass spectrometry assays we show for the first time that human pancreatic islets can locally activate androgens and estrogens from circulating T and that this activity is localized to β cells. We show that these local steroid metabolic pathways drive GSIS, thereby establishing an intracrine mode of sex steroid action in β cells.
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.
Introduction
Accumulated evidence suggests that the gonadal steroid testosterone (T) is necessary for proper glucose-stimulated insulin secretion (GSIS) in men and promotes insulin hypersecretion and β cell dysfunction in women with androgen excess (1-4). Accordingly, the active metabolite of T, dihydrotestosterone (DHT), enhances GSIS in cultured islets from male human donors (3). Male mice lacking the androgen receptor (AR) selectively in β cells (βARKO) exhibit impaired GSIS, leading to glucose intolerance, and develop diabetes (3). In addition, exposure of cultured islets from female human donors to DHT promotes insulin hypersecretion (4). In a female mouse model of chronic androgen excess, DHT promotes hyperinsulinemia associated with secondary pancreatic β cell dysfunction via action on AR in β cells (4).
In healthy men and hyperandrogenic women, T is the main circulating gonadal androgen. T is a weak androgen and a pro-hormone that undergoes local conversion in target tissues to either DHT via the action of one of the 5α-reductase (5α-R) isoforms (5), or 17β-estradiol (E2) via the action of the enzyme aromatase, to activate AR or estrogen receptor(ER)s, respectively (5, 6). Notably, activation of ERs by E2 in male and female human β cells enhances insulin synthesis, GSIS, and promotes survival from multiple metabolic injuries (7-11). Therefore, circulating T could have a clinically relevant impact on β cell function in healthy men and hyperandrogenic women via conversion to DHT and/or E2 within pancreatic islets. However, the extent to which 5α-R isoforms and the aromatase are present in human islets from both sexes and able to convert T to DHT and E2 to directly affect β cell function is unknown.
Here, we have used pancreas sections and cultured islets from male and female human donors to study the expression of the three 5α-R isoforms and the aromatase, quantify the conversion of T to DHT and E2 and assess the functional significance of intracrine conversion of T in pancreatic islets on GSIS.
In conclusion, using highly selective and specific tandem mass spectrometry assays we show for the first time that human pancreatic islets can locally activate androgens and estrogens from circulating T and that this activity is localized to β cells. We show that these local steroid metabolic pathways drive GSIS, thereby establishing an intracrine mode of sex steroid action in β cells.
Last edited:
