(A) GSIS measured in static incubation in islets from mice fed a WD for 8 weeks and treated with vehicle (V) or DHT (10 nM) for 48 hours ex vivo. (B) Islet insulin content from A. Results represent 10 islets/condition in triplicate from n ≥ 3 independent experiments. (C) Glucose-stimulated insulin secretion (GSIS) measured after static incubation in islets from female human donors. (D) Islet insulin content from C. Islets were treated V, DHT (10 nM), and or flutamide (Flut, 10 μM) in vitro for 48 hours. Results represent 5 islets per condition of n = 6 independent experiments. (E) Basal and GSIS at the indicated glucose concentrations during a perifusion in WT female islets (vehicle, ethanol; DHT, 10 nM). Islets were isolated from mice at 14 weeks and perifused in batches of 60 per group. (F) Intracellular Ca²⁺ influx and corresponding AUC from the indicated glucose concentrations in isolated female mouse islets (n = 397 cells for V, n = 360 cells for DHT). (G) 10 nM DHT- and 10 nM Ex-stimulated cAMP concentrations monitored in female mouse islets infected with adenovirus harboring the FRET probe Epac2 camps, with corresponding AUC and representative live cell imaging. Scale bar: 20 μm. (H) GSIS measured in static incubation in islets from WT female mice fed chow or WD, treated with V, DHT (10 nM), rapamycin (RAPA, 10 nM), or DHT+RAPA for 48 hours (n = 12–14 batches of 10 islets/condition, 4 independent experiments). (I) GSIS measured in static incubation in islets from female WT and KD-mTOR mice, treated as in A. Results represent 10 islets per condition of n = 4 independent experiments. (J) WT female mice were exposed to WD for 4 weeks followed by 4 weeks of treatment with V, DHT, or DHT+RAPA (0.5 mg/kg/d; n = 7–8/group). Results represent the mean ± SEM, with dot plots of fasting and fed serum insulin as well as fasting and fed blood glucose. **P < 0.01, ***P < 0.001, 1-way ANOVA.