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

A heterozygous missense variant in the islet β-cell-enriched MAFA (Ser(S)64Phe(F)) transcription factor was identified in humans who developed either diabetes or insulinomatosis, with males more prone to diabetes. This mutation engenders increased stability to the normally unstable MAFA protein. To obtain insight into how this impacts β cell function, we developed a mouse model expressing S64F MafA and found sex-dependent phenotypes, with heterozygous mutant males displaying impaired glucose tolerance while females were slightly hypoglycemic and had improved blood glucose clearance. Only heterozygous males showed higher MafA protein levels, which preceded the onset of glucose intolerance and sex dependent variations in expression of genes involved in aging, DNA damage, calcium signaling, and senescence. Changes in islet calcium handling and signs of aging and senescence processes were validated in male animals. Together, these results implicate accelerated islet aging and senescence in promoting diabetes in male human S64F MAFA carriers.