A heterozygous missense mutation producing a variant of the islet β-cell-enriched MAFA transcription factor (Ser(S)64Phe(F) MAFA) was identified in humans who developed adult-onset, β-cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes. 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 displaying impaired glucose tolerance while females were slightly hypoglycemic with improved blood glucose clearance. Only heterozygous males showed transiently higher MafA protein levels preceding the onset of glucose intolerance and sex-dependent, differential expression of genes involved in calcium signaling, DNA damage, aging, and senescence. Functional changes in islet calcium handling and signs of islet aging and senescence processes were uniquely observed in male animals. In addition, S64F MAFA expression in human, male EndoC-βH2 β cells accelerated cellular senescence and increased production of senescence-associated secretory proteins compared to cells expressing wild-type MAFA. Together, these results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in S64F MAFA carriers in a sex-dependent manner.

中文翻译：

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偏爱的胰岛β细胞功能异常是由MODY MAFA S64F变体导致的，原因是它诱导了男性的过早衰老和衰老

在发育成成人的β细胞功能障碍（糖尿病或胰岛素瘤病）的人中，发现了杂合的错义突变，该突变产生富含胰岛β细胞的MAFA转录因子（Ser（S）64Phe（F）MAFA）的变体。男性更容易患糖尿病。该突变增强了对通常不稳定的MAFA蛋白的稳定性。为了深入了解此变体如何影响β细胞功能，我们开发了一种表达S64F MafA的小鼠模型，并发现了性别依赖性表型，杂合突变体的男性表现出葡萄糖耐量降低，而女性则表现为低血糖，改善了血糖清除率。只有杂合的男性在出现葡萄糖耐受不良和性别依赖性，钙信号传导，DNA损伤，衰老，和衰老。在雄性动物中独特地观察到胰岛钙处理中的功能变化以及胰岛衰老和衰老过程的迹象。另外，与表达野生型MAFA的细胞相比，S64F MAFA在人的雄性EndoC-βH2β细胞中的表达加速了细胞的衰老并增加了衰老相关分泌蛋白的产生。总之，这些结果暗示了加速胰岛衰老和衰老的保守机制以性别依赖性方式促进S64F MAFA携带者的糖尿病。与表达野生型MAFA的细胞相比，雄性EndoC-βH2β细胞可加速细胞衰老并增加衰老相关分泌蛋白的产生。总之，这些结果暗示了加速胰岛衰老和衰老的保守机制以性别依赖性方式促进S64F MAFA携带者的糖尿病。与表达野生型MAFA的细胞相比，雄性EndoC-βH2β细胞可加速细胞衰老并增加衰老相关分泌蛋白的产生。总之，这些结果暗示了加速胰岛衰老和衰老的保守机制以性别依赖性方式促进S64F MAFA携带者的糖尿病。