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

A heterozygous missense mutation of the islet β cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset β 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 β 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 Ca²⁺ signaling, DNA damage, aging, and senescence. MAFA^S64F production in male human β 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.