Zmuda Erik J, Qi Ling, Zhu Michael X, Mirmira Raghavendra G, Montminy Marc R, Hai Tsonwin
Molecular, Cellular and Developmental Biology Program, Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, Columbus, Ohio 43210, USA.
Mol Endocrinol. 2010 Jul;24(7):1423-33. doi: 10.1210/me.2009-0463. Epub 2010 Jun 2.
Most people with type 2 diabetes (T2D) have reduced beta-cell mass, and apoptosis is a key factor for this reduction. Previously, we showed that ATF3, an adaptive-response gene, is induced by various stress signals relevant to T2D, such as high glucose and high fatty acid. Because ATF3 is proapoptotic in beta-cells, we tested the hypothesis that ATF3 plays a detrimental role and contributes to the development of T2D. We compared wild-type (WT) and ATF3 knockout (KO) mice in an animal model for T2D, high-fat diet-induced diabetes. We also used INS-1 beta-cells and primary islets to analyze the roles of ATF3 in beta-cell function, including insulin gene expression and glucose-induced insulin secretion. Surprisingly, WT mice performed better in glucose tolerance test than KO mice, suggesting a protective, rather than detrimental, role of ATF3. At 12 wk on high-fat diet, no beta-cell apoptosis was observed, and the WT and KO mice had comparable beta-cell areas. However, ATF3 deficiency significantly reduced serum insulin levels in the KO mice without affecting insulin sensitivity, suggesting reduced beta-cell function in the KO mice. Analyses using INS-1 cells and primary islets support the notion that this defect is due, at least partly, to reduced insulin gene transcription in the KO islets without detectable reduction in glucose-induced calcium influx, a critical step for insulin secretion. In conclusion, our results support a model in which, before apoptosis becomes obvious, expression of ATF3 can be beneficial by helping beta-cells to cope with higher metabolic demand.
大多数2型糖尿病（T2D）患者的β细胞量减少，而细胞凋亡是导致这种减少的关键因素。此前，我们发现，作为一种适应性反应基因，ATF3可被与T2D相关的各种应激信号诱导，如高血糖和高脂肪酸。由于ATF3在β细胞中具有促凋亡作用，我们检验了ATF3起有害作用并促成T2D发生的假说。我们在高脂肪饮食诱导糖尿病的T2D动物模型中比较了野生型（WT）小鼠和ATF3基因敲除（KO）小鼠。我们还使用INS-1β细胞和原代胰岛来分析ATF3在β细胞功能中的作用，包括胰岛素基因表达和葡萄糖诱导的胰岛素分泌。令人惊讶的是，WT小鼠在葡萄糖耐量试验中的表现优于KO小鼠，这表明ATF3具有保护作用而非有害作用。在高脂饮食12周时，未观察到β细胞凋亡，WT小鼠和KO小鼠的β细胞面积相当。然而，ATF3缺陷显著降低了KO小鼠的血清胰岛素水平，而不影响胰岛素敏感性，这表明KO小鼠的β细胞功能降低。使用INS-1细胞和原代胰岛进行的分析支持了以下观点：这种缺陷至少部分是由于KO胰岛中胰岛素基因转录减少，而葡萄糖诱导的钙内流未检测到减少，钙内流是胰岛素分泌的关键步骤。总之，我们的结果支持一种模型，即在细胞凋亡变得明显之前，ATF3的表达通过帮助β细胞应对更高的代谢需求可能是有益的。
