IRON-BETA · IRON-BETA - Unraveling the iron metabolism of pancreatic β-cells

Iron is a critical cofactor for proteins and enzymes involved in oxygen and energy metabolism, functions that are especially vital in pancreatic β-cells. In these cells, iron is indispensable for mitochondrial respiration, the process that powers insulin production. However, disruptions in iron homeostasis - whether through deficiency or overload - have been linked to β-cell dysfunction, yet the underlying mechanisms remain poorly understood. With IRON-BETA, I seek to unravel how iron metabolism regulates β-cell identity, function, and survival, under both normal and stressed conditions, such as type 2 diabetes (T2D) and early post-transplant ischemia. Using cutting-edge techniques and models, including multiplex single-cell RNA-Seq, super-resolution microscopy, ICP-mass spectrometry, novel genetic mouse models, and iPSC-islet cell differentiation, I, together with my team, will comprehensively explore the role of iron in β-cell biology. We will map iron distribution in islet cells, particularly β-cells, to understand its impact on their function and overall islet health. We will investigate how fluctuations in iron availability contribute to β-cell dysfunction in T2D, with the aim of identifying novel therapeutic targets. Additionally, we will optimize iron supply during the maturation of iPSC-derived β-cells to enhance their functional capacity for cell-based therapy. Finally, we will explore the interplay between iron and oxygen homeostasis in β-cell grafts, focusing on hypoxia-inducible factor 1-alpha (HIF-1α) signaling—a crucial regulatory pathway that integrates both iron levels and oxygen availability. By evaluating how iron deficiency and hypoxia impact β-cell survival and graft success during islet transplantation, we aim to improve transplantation outcomes and advance therapeutic strategies. By addressing these critical gaps in understanding iron homeostasis, IRON-BETA will open new avenues for treating T2D and advance β-cell replacement therapies for T1D.