254-LB: EndoC-ßH5 Human Beta Cells—A Unique “Thaw and Go” Model for Accelerating Diabetes Research with Highly Functional and Ready-to-Use Human Beta Cells

Abstract

In 2021, 537 million adults were living with diabetes worldwide (90% T2D) , a number that is predicted to rise to 643 million by 2030. The need for physiologically relevant human cellular models to study human beta cell function, insulin secretion and diabetes is thus greater than ever. To date, human pancreatic islets present many drawbacks related to lack of availability and reproducibility that limit their use. While animal models remain far from human reality. Newly developed EndoC-βH5® cells represent an extremely promising tool both for drug discovery and disease modeling. They take the best out of native cells from which they were derived, with high sensitivity to physiological concentrations of glucose and robust response to insulin secretagogues. They also leave the rest, thanks to direct availability as frozen stocks, ready-to-use format, batch-to-batch reproducibility and maintaining stable function for weeks. Specifically, EndoC-βH5® is a pure population of insulin expressing cells (100% INS/92.3% PDX1/90% NKX6.1) . Insulin content is close to that of native pancreatic beta cells (> 5µg/million cells) . EndoC-βH5® cells dose dependently respond to physiological concentrations of glucose (highest potentiation of insulin secretion between 2.8 and 8 mM glucose) with elevated absolute insulin secretion values (hundreds of ng/hr/106 cells) similar to native islets. Furthermore, they dose dependently respond to GLP1R agonists, GIPR agonist, and dual agonist Tirzepatide® with reproducible EC50 and increased insulin secretion >3-fold over high glucose. In addition, Endoc-BH5® cells can be assayed in 384-well plates paving the way for HTS and have been validated as 3D spheroids with extremely robust functional data. Finally, expression of diabetes related genes can be modified to produce relevant disease models. Overall, EndoC-βH5® represent a novel human pancreatic beta cell solution with very high potential for developing human diabetes models, unraveling diabetes mechanisms in human cells and developing antidiabetic drugs. Disclosure H. Olleik: None. B. Blanchi: None.