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 producing a variant of the islet β-cell- enriched MAFA transcription factor (p.Ser64Phe (S64F)) was identified in patients who developed adult-onset, β-cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than women. This mutation engenders increased stability to the normally unstable MAFA protein. To obtain insight into how this variant impacts β cell function, we developed a mouse model expressing S64F MafA and found sex- dependent phenotypes, with heterozygous mutant males (MafAS64F/+) displaying impaired glucose tolerance while females were slightly hypoglycemic with improved blood glucose clearance. Only MafAS64F/+ males showed transiently higher MafA protein levels preceding the onset of glucose intolerance and sex-dependent, differential expression of genes involved in Ca2+ signaling, DNA damage, aging, and senescence. Functional changes in islet Ca2+ handling and signs of islet aging and senescence processes were uniquely observed in male animals. In addition, MAFAS64F expression in male human β cells accelerated cellular senescence and increased production of WT senescence-associated secretory proteins compared to cells expressing MAFA Together, these results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFAS64F carriers in a sex-dependent manner.