Backup mandate Research Council: Uncovering the role of iron metabolism in beta cell differentiation, maturation, and function.

Diabetes is a pandemic metabolic disorder. Current therapy strives for glycemic control but fails to tackle the underlying beta cell defect. Transplantation of pancreatic islets has shown that cell therapy can result in insulin independence, but donor islets are scarce. Stem cell- derived beta cells (SC-beta) may offer a reliable cell source for cell replacement. Improved understanding of beta cell differentiation, maturation and function, however, is needed to generate functional SC-beta cells. Beta cells specifically express high levels of the transferrin receptor (TFRC), which mediates cellular iron uptake from transferrin, compared to alpha and delta cells – the main endocrine cell types in pancreatic islets. It is currently unclear why this is the case and whether it is relevant for beta cell biology. In my proposal, I aim to uncover the role of iron metabolism in beta cell differentiation, maturation, and function. We will characterize changes in iron metabolism over time in the main endocrine islet cell types and disclose if in beta cells these changes relate to metabolic and signaling shifts key for maturation. We will study how iron deficiency affects beta cell development using novel mouse lines and cutting- edge technologies with the aim of improving protocols to generate
SC-beta. This work will improve our understanding of diabetes pathophysiology by disclosing new intricacies of beta cell development and hopefully contribute to the development of a cell- based cure.