Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Cell Rep. 2021 Oct 12;37(2):109813. doi: 10.1016/j.celrep.2021.109813.
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.
胰岛 β 细胞丰富的 MAFA 转录因子（p.Ser64Phe [S64F]）的杂合错义突变存在于成年发病的β 细胞功能障碍（糖尿病或胰岛素瘤病）患者中，男性比女性更容易患糖尿病。这种突变使不稳定的 MAFA 蛋白更稳定。在这里，我们构建了一个 S64F MafA 小鼠模型，以确定β细胞功能如何受到影响，并发现性别依赖性表型。杂合突变雄性（MafA）表现出葡萄糖耐量受损，而雌性则表现出轻度低血糖，血糖清除率提高。只有 MafA 雄性在葡萄糖耐量受损和与 Ca 信号转导、DNA 损伤、衰老和衰老相关的基因发生性别依赖性变化之前，才会短暂出现更高的 MafA 蛋白水平。与表达 MAFA 的细胞相比，人 β 细胞中 MAFA 的产生也加速了细胞衰老，并增加了与衰老相关的分泌蛋白。这些结果表明，在以性别偏倚的方式促进 MAFA 携带者发生糖尿病方面，胰岛老化和衰老的保守机制加速。
