Sex-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant by inducing premature aging and senescence in males

A heterozygous missense mutation of the islet b cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset b cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than women.This mutation engenders increased stability to the unstable MAFA protein.Here, we develop a S64F MafA mouse model to determine how b cell function is affected and find sex-dependent phenotypes.Heterozygous mutant males (MafA S64F/+ ) display impaired glucose tolerance, while females are slightly hypoglycemic with improved blood glucose clearance.Only MafA S64F/+ males show transiently higher MafA protein levels preceding glucose intolerance and sex-dependent changes to genes involved in Ca 2+ signaling, DNA damage, aging, and senescence.MAFA S64F production in male human b cells also accelerate cellular senescence and increase senescence-associated secretory proteins compared to cells expressing MAFA WT .These results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFA S64F carriers in a sex-biased manner.