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 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) display impaired glucose tolerance, while females are slightly hypoglycemic with improved blood glucose clearance. Only MafA males show transiently higher MafA protein levels preceding glucose intolerance and sex-dependent changes to genes involved in Ca signaling, DNA damage, aging, and senescence. MAFA production in male human β cells also accelerate cellular senescence and increase senescence-associated secretory proteins compared to cells expressing MAFA. These results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFA carriers in a sex-biased manner.