1148-OR: Impaired Portal Glucose Sensing Is Restored by a Local, Low-Dose Dihydrotestosterone Implant to Normalize Insulin Dynamics and Glucose Homeostasis in a Porcine Model of Diabetes

Introduction and Objective: The hepatoportal glucose sensor, which converts portal glucose flux into metabolic signals that regulate systemic glucose homeostasis, is impaired in type 2 diabetes and not targeted by current glucose-lowering therapies. We have shown that portal sensing is restored by local administration of low-dose dihydrotestosterone (DHT) and have now evaluated the chronic impact of low-dose DHT on insulin sensitivity and clearance, and β-cell responsiveness in a large-animal model of diabetes Methods: In twelve minipigs, diabetes was induced using an obesogenic diet combined with streptozotocin (80 mg/kg IV). Six animals received an implant which delivered DHT (100 μg/day) close to the defective portal sensor, as identified by GLP-1 receptor PET imaging (DHT group), while six other animals received a sham implant (Sham group). Five months after implantation, all animals underwent a frequent sampling, oral glucose tolerance test (1.5 g glucose/kg body weight). Plasma glucose, insulin, and C-peptide concentrations were measured to evaluate whole-body insulin sensitivity, β-cell responsivity, disposition indices (DI), and hepatic insulin extraction using minimal models. Results: In the DHT group there was a marked improvement in insulin sensitivity (15.8 ± 2.90 DHT vs 9.2 ± 1.01 Sham dL/kg/min per µU/mL*1E-3, P0.01), with three-fold and six-fold increases in dynamic and static β-cell responsivity, respectively, leading to a ten-fold increase in total DI (0.807 ± 0.0028 DHT vs 0.036 ± 0.0035 Sham dL/kg/min 2 per pmol/L, P0.01), compared to the Sham group. Hepatic insulin extraction also increased in the DHT group, indicative of enhanced first-pass hepatic insulin uptake. Conclusion: In a porcine model of diabetes, restoration of portal glucose sensing using DHT improves insulin sensitivity, insulin clearance and β-cell function, markedly indicative of the importance of impaired portal glucose sensing as a therapeutic target. Disclosure C. Malbert: Research Support; Current; Paltech. M.R. Allouche: Stock/Shareholder; Current; Paltech. M. Horowitz: None. K.L. Jones: None.