OR09-5 Importance of Islet Intracrinology for Glucose-Stimulated Insulin Secretion (GSIS) in the Male

The importance of androgens and estrogens in preventing adiposity and insulin resistance in the male is well characterized (1, 2), but less is known about the role of androgens and estrogens in β cell function and insulin secretion. Both the androgen receptor (AR) and estrogen receptors (ERs) are present in β cells, and we showed that AR and ERs are important for pancreatic β cell health and function in the male (3, 4). In males, testosterone (T) is the main circulating source of active androgen acting on AR (dihydrotestosterone, DHT) and estrogen acting on ERs (estradiol, E2) following conversion by 5α-reductase (5α-R) and aromatase (Ar) respectively. However, whether 5α-R and Ar are expressed and active in β cells is unknown. Using qPCR and immunohistochemistry, we show that mRNA and proteins for 5α-R and Ar are expressed in male islets and β cells. In male mouse islets, T treatment enhances GSIS compared to vehicle. The effect of T is partially blocked by the 5α-R inhibitors, finasteride (FNS) and dutasteride (DTS) demonstrating that T is converted to DHT by 5α-R to enhance GSIS. Further, the insulinotropic effect of T is totally blocked by co-treatment with FNS, DTS and the Ar inhibitor, anastrozole, demonstrating that T is also converted to E2 by Ar to enhance GSIS. We detected DHT by tandem mass spectrometry in the incubations from male mouse islets with T treatment. DHT was not detectable in any of the incubations with T and 5α-R inhibitor treatment. Our study reveals the presence of functional 5α-R and Ar in male pancreatic islet β cells and identifies a novel paradigm of islet intracrinology with local conversion of T into DHT and E2, the actions of which enhance GSIS. References: (1) Khaw et al., Ann Epidemiol. 1992 Sep. 2(5): 675-82. (2) Pitteloud et al., Diabetes Care. 2005 Jul. 28(7): 1636-42. (3) Navarro et al., Cell Metab. 2016 May; 23(5):837-51. (4) Tiano et al., Nat Rev Endocrinol. 2012 Feb. 8(6):342-51.