128-LB: Effects of Glucagon Receptor Antagonism (GRA) on Ketone Body Formation during Insulinopenia in Type 1 Diabetes (T1D)

Background: Diabetic ketoacidosis is a common and life-threatening complication of T1D. Glucagon stimulates ketogenesis via peripheral lipolysis and hepatic β-oxidation of free fatty acids (FFA). Blocking glucagon action may decrease ketone formation and reduce the risk of DKA. Methods: In this pilot study, 4 participants with T1D underwent 6 hours of insulin withdrawal before and after 4 weeks of monoclonal GRA treatment (REMD-477, 70mg weekly). Serial measurements of plasma glucose, FFA, and β-hydroxybutyrate (BHB) were collected to determine the efficacy of GRA therapy in reducing ketone formation in the setting of insulinopenia. Results: Pre- vs. post-treatment concentrations (mean ± SD; paired two-tailed t-test) after 6-hour insulin withdrawal were: Glucose (263 ± 63 vs. 235 ± 109 mg/dL; P = 0.53), FFA (1.37 ± 0.60 vs. 1.09 ± 0.77 mmol/L; P = 0.07), and BHB (1.30 ± 0.70 vs. 0.63 ± 0.54 mmol/L; P = 0.08). Glucagon concentrations increased (26.8 ± 9.9 vs. 454 ± 245 pg/mL; P = 0.04) with blockade of glucagon action. Frequent insulin draws confirmed insulinopenia. Conclusions: These preliminary results suggest that GRA treatment may reduce ketogenesis in the clinical setting in which DKA occurs (insulinopenia). These trends will be tested in a larger, randomized study. If confirmed, this would represent a novel therapy to reduce the risk of life-threatening DKA in T1D. Disclosure S.C. Boeder: Consultant; Self; Cecelia Health, Science 37. Research Support; Self; Dexcom, Inc. D.G. Ines: None. L. Carter: None. E.R. Giovannetti: None. D. Armstrong: None. P. Burke: None. J. Pettus: Consultant; Self; Diasome Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., MannKind Corporation, Novo Nordisk Inc., Sanofi. Funding National Institutes of Health (UL1TR001442, P30DK063491)