1588-P: Translatable Modeling of Glucagon Actions in Human iPSC-Derived Hepatocytes Uniquely Predicts Differential Clinical Responses to Glucagon Analog Agonist Molecules

Abstract

As the development of clinically efficacious glucagon receptor (GCGR) agonists for the treatment of metabolic diseases evolves, the challenge to identify physiologically relevant preclinical models that predict glucagon receptor actions in humans becomes ever more important. While many hepatocyte models are available, most fail to recapitulate fundamental metabolic regulatory responses to key physiologic stimuli including integration of glucagon and insulin actions that govern hepatic carbohydrate or lipid metabolism. We developed and optimized a human induced pluripotent stem cell (iPSC)-derived hepatocyte model to mimic physiologic insulin and glucagon signaling and counter-regulation of metabolic pathways. We leveraged the model to evaluate functional responses of different glucagon receptor agonist molecules to regulate carbohydrate and lipid metabolism. Unlike assays conducted in several other cell line and primary isolated hepatocyte systems, hepatic glucose output assays in the human IPSC hepatocyte model demonstrated substantial potency differences between two novel soluble glucagon analog agonists. These findings predicted differential dose-dependent blood glucose excursions in response to these agonists when administered in a single ascending dose study in healthy human volunteers. Modeling physiologic integration of insulin and glucagon signaling in a clinically translatable human iPSC hepatocyte model can advance understanding of the regulation of nutrient metabolism by glucagon receptor agonists in humans and support the development of novel therapeutic approaches to address metabolic disorders, including type 2 diabetes, obesity, and nonalcoholic fatty liver disease. Disclosure W.Roell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. A.Regmi: Employee; Eli Lilly and Company. C.T.Benson: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.S.Moyers: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J.Alsina-fernandez: Employee; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.