Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing post-translational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in mitochondria. We showed that mice with a global loss of SIRT4 (SIRT4KO mice) developed an increase in glucose- and leucine-stimulated insulin secretion, and this was followed by accelerated age-induced glucose intolerance and insulin resistance. Since whole body SIRT4KO mice had alterations to nutrient-stimulated insulin secretion, we hypothesized that SIRT4 plays a direct role in regulating pancreatic beta-cell function. Thus, we tested whether beta-cell specific ablation of SIRT4 would recapitulate the elevated insulin secretion seen in mice with a global loss of SIRT4. Tamoxifen-inducible beta-cell specific SIRT4KO mice were generated and their glucose tolerance, and glucose- and leucine-stimulated insulin secretion were measured over time. These mice exhibited normal glucose- and leucine-stimulated insulin secretion and maintained normal glucose tolerance even as they aged. Furthermore, 832/13 beta-cells with a CRISPR/Cas9n-mediated loss of SIRT4 did not show any alterations in nutrient-stimulated insulin secretion. Despite the fact that whole body SIRT4KO mice demonstrated an age-induced increase in glucose- and leucine- stimulated insulin secretion, our current data indicate that the loss of SIRT4 specifically in pancreatic beta-cells, both in vivo and in vitro, does not have a significant impact on nutrient-stimulated insulin secretion. These data suggest that SIRT4 controls nutrient-stimulated insulin secretion during aging by acting on tissues external to the beta-cell, which warrants further study.

中文翻译：

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Sirtuin 4 的 β 细胞特异性消融不影响小鼠中营养刺激的胰岛素分泌。

Sirtuins 是一个蛋白质家族，可通过去除翻译后修饰 (PTM) 来调节细胞应激和衰老等生物过程。我们最近发现了几种可以被线粒体中发现的 Sirtuin 4 (SIRT4) 去除的新型 PTM。我们发现，SIRT4 整体缺失的小鼠（SIRT4KO 小鼠）的葡萄糖和亮氨酸刺激的胰岛素分泌增加，随后加速了年龄诱导的葡萄糖耐受不良和胰岛素抵抗。由于全身 SIRT4KO 小鼠对营养刺激的胰岛素分泌发生了改变，我们假设 SIRT4 在调节胰腺 β 细胞功能中起直接作用。因此，我们测试了 SIRT4 的 β 细胞特异性消融是否会重现在 SIRT4 整体丢失的小鼠中观察到的胰岛素分泌升高。产生了他莫昔芬诱导的 β 细胞特异性 SIRT4KO 小鼠，并随时间测量了它们的葡萄糖耐量和葡萄糖和亮氨酸刺激的胰岛素分泌。这些小鼠表现出正常的葡萄糖和亮氨酸刺激的胰岛素分泌，并且即使随着年龄的增长也保持正常的葡萄糖耐量。此外，具有 CRISPR/Cas9n 介导的 SIRT4 缺失的 832/13 β 细胞在营养刺激的胰岛素分泌方面没有表现出任何改变。尽管全身 SIRT4KO 小鼠表现出年龄诱导的葡萄糖和亮氨酸刺激的胰岛素分泌增加，但我们目前的数据表明，在体内和体外，胰腺 β 细胞中特异性的 SIRT4 丢失都没有对营养刺激的胰岛素分泌有显着影响。