2470-P: Optimizing Diazoxide to Study Hyperinsulinemia and De Novo Lipogenesis in MASLD

Introduction and Objective: Hyperinsulinemia is generally regarded as a surrogate marker of insulin resistance, but high insulin levels may drive the development of metabolic dysfunction-associated steatotic liver disease (MASLD) by continuing to stimulate hepatic de novo lipogenesis (DNL) despite systemic insulin resistance. One strategy to understand the pathogenic role of hyperinsulinemia is to directly reduce high insulin levels in people with insulin resistance. Methods: We conducted a randomized, double-blind pilot & feasibility trial (NCT05729282) to optimize use of diazoxide, an oral insulin anti-secretagogue, as a tool for mechanistic study of human hyperinsulinemia. Adults with body mass index 27-50 kg/m2 and clinical insulin resistance (fasting hyperinsulinemia ≥13 µU/mL plus either prediabetes or HOMA-IR score ≥2.73) were randomized to take either placebo, diazoxide 1 mg/kg, or diazoxide 2 mg/kg (n=6 per arm) twice daily for 14 days along with deuterated water for hepatic DNL measurement. Fasting blood samples were obtained at baseline and after 1, 7, and 14 days of treatment to measure glucose, insulin, C-peptide, and lipid parameters including DNL. Results: We found the optimal diazoxide regimen for balancing insulin lowering with glycemic and symptomatic tolerability to be 2 mg/kg twice daily for 7 days. This regimen significantly reduced fasting insulin by 37 ± 25% from baseline (mean ± S.D., p=0.012 vs. placebo) while slightly raising fasting glucose by 17 ± 10 mg/dL (p=0.07 vs. placebo). Hepatic DNL trended 47% lower in subjects treated with diazoxide and directly correlated with post-treatment insulin levels. Conclusion: We expect our findings to promote further clinical investigation of human hyperinsulinemia using diazoxide, including in our ongoing study of the impact of hyperinsulinemia reduction on DNL in patients with MASLD. Disclosure J.R. Cook: None. Z. Sone: None. N. Bedeir: None. L. Sacchetta: None. I. Nagnur: None. L.C. Jones: None. L. Bordone: None. M. Owen-Michaane: Research Support; Current; CorMedix. J. Wattacheril: Research Support; Current; Regeneron Pharmaceuticals Inc. Advisory Panel; Ended; AstraZeneca. Advisory Panel; Current; GlaxoSmithKline plc. Research Support; Ended; Galectin Therapeutics. H. Ginsberg: None. B. Laferrère: Consultant; Ended; Azurity. M.K. Hellerstein: Research Support; Current; Lilly, Merck & Co., Inc. Funding National Institutes of Health (K12DK133995, K23DK140614, UL1TR001873), Columbia University Department of Medicine, University of California Rausser College of Natural Resources