1474-P: Testosterone Amplifies Glucose-Stimulated Insulin Secretion from Male ß-Cells via Soluble Adenylate Cyclase

• Published in: Diabetes (New York, N.Y.) Vol. 71; no. Supplement_1
• Main Authors: QADIR, MIRZA MUHAMMAD FAHD, XU, WEIWEI, NASTESKA, DANIELA, BHONDELEY, MANIKA, MOTA DE SA, PAULA, EVANS, CHARLES R., BUCK, JOCHEN, LEVIN, LONNY, BURANT, CHARLES, HODSON, DAVID, MAUVAIS-JARVIS, FRANCK
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.06.2022
• Subjects: Acetazolamide; Acidification; Adenylate cyclase; Allosteric properties; Androgen receptors; Beta cells; Bicarbonates; Bioenergetics; Carbon dioxide; Cell culture; Cyclic AMP; Diabetes; Dihydrotestosterone; Electron microscopy; Endosomes; Exocytosis; Glucose; Glucose metabolism; Glycolysis; Hydrogen; Hyperglycemia; Insulin; Insulin secretion; Metabolomics; Mitochondria; Secretion; Testosterone; Tricarboxylic acid cycle
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db22-1474-P

Male mice with elimination of the androgen receptor (AR) in islet β cells (βARKO) exhibit blunted glucose-stimulated insulin secretion (GSIS) , leading to hypoinsulinemia and hyperglycemia. We showed that dihydrotestosterone (DHT) activation of an extranuclear AR in β cells potentiates GSIS by amplifying the insulinotropic action of islet-derived and exogenous GLP-1 via GLP-1R in mouse and human islets. Using electron microscopy, we observe that DHT increases the size of granules and the frequency of multivesicular granules, suggesting that DHT promotes multivesicular exocytosis. Using live β cell models expressing organelle-specific cAMP sensors and novel allosteric inhibitors in human islets, we show that DHT enhances the ability of GLP-1 to produce cAMP at the plasma membrane and endosomes and enhances islet GSIS via the bicarbonate (HCO3 -) sensor, soluble adenylate cyclase (sAC) . The end-products of glucose metabolism in the TCA cycle are CO2 and H2O, which is followed by rapid conversion of CO2 to HCO3 - and H+ by carbonic anhydrase (CA) . Therefore, CO2 production is translated to HCO3 - and specifically sensed by sAC. Bioenergetics analysis of DHT-stimulated respiration in mouse islets using a Seahorse Analyser revealed that DHT decreases glycolytic acidification and increases mitochondrial acidification (H+ efflux rate) , suggesting that DHT increases mitochondrial production of CO2 followed by conversion to HCO3 - and H+, allowing HCO3 - to stimulate sAC. We discuss experiments of single-cell transcriptomics, proteomics and metabolomics dissecting the impact of DHT on human islets glycolysis and mitochondrial CO2 production. Consistent with DHT increasing production of CO2 followed by conversion to HCO3 - by CA and activation of sAC, in cultured human male islets, the CA inhibitor acetazolamide blunted DHT-enhancement of GSIS. Together these experiments provide novel insights into the role of DHT action via an extranuclear AR in enhancing GSIS. Disclosure M.Qadir: None. D.Hodson: Other Relationship; Celtarys Research. F.Mauvais-jarvis: Consultant; Mithra Pharmaceutical. W.Xu: None. D.Nasteska: None. M.Bhondeley: None. P.Mota de sa: None. C.R.Evans: None. J.Buck: None. L.Levin: None. C.Burant: None. Funding National Institutes of Health (DK107444 and DK074970) U.S. Department of Veterans Affairs Merit Award (BX003725)