RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function – published online 14/05/2024

Hazem Ibrahim, Diego Balboa, Jonna Saarimaki‑Vire, Hossam Montaser, Oleg Dyachok, Per‑Eric Lund, Muhmmad Omar‑Hmeadi, Jouni Kvist, Om P. Dwivedi, Väinö Lithovius, Tom Barsby, Vikash Chandra, Solja Eurola, Jarkko Ustinov, Tiinamaija Tuomi, Päivi J. Miettinen, Sebastian Barg, Anders Tengholm, Timo Otonkoski

Regulatory factor X 6 (RFX6) is crucial for the development of pancreatic beta cells. In this issue (https://doi.org/10.1007/s00125-024-06163-y), Ibrahim et al show that a pathogenic variant in the RFX6 gene that is particularly enriched in the Finnish population significantly increases the risk of developing type 2 and gestational diabetes. Using advanced allelic series stem cell models, they demonstrate that heterozygous mutation results in RFX6 haploinsufficiency, impairing insulin secretion in vitro and in vivo without affecting beta cell mass. Complete loss of RFX6 was associated with reduced generation of the pancreatic progenitor pool and increased apoptosis. The authors conclude that these findings enhance our understanding of how specific genetic mutations can lead to diabetes and may guide future therapies aimed at restoring normal beta cell function.