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

A heterozygous missensemutation of the islet beta cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset beta 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 mousemodel to determine how beta 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 beta 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.

Automated summary

A study has shown that a mutation in the MAFA transcription factor affects beta cell function and leads to diabetes, with males being more predisposed to the disease. Sex-dependent phenotypes were observed in mouse models and human beta cells, suggesting a potential link between islet cell aging, senescence, and the development of diabetes.