Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan.
Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan.
Cell Rep. 2023 Aug 29;42(8):112914. doi: 10.1016/j.celrep.2023.112914. Epub 2023 Aug 8.
The adaptive increase in insulin secretion in early stages of obesity serves as a safeguard mechanism to maintain glucose homeostasis that cannot be sustained, and the eventual decompensation of β cells is a key event in the pathogenesis of diabetes. Here we describe a crucial system orchestrated by a transcriptional cofactor CtBP2. In cultured β cells, insulin gene expression is coactivated by CtBP2. Global genomic mapping of CtBP2 binding sites identifies a key interaction between CtBP2 and NEUROD1 through which CtBP2 decompacts chromatin in the insulin gene promoter. CtBP2 expression is diminished in pancreatic islets in multiple mouse models of obesity, as well as human obesity. Pancreatic β cell-specific CtBP2-deficient mice manifest glucose intolerance with impaired insulin secretion. Our transcriptome analysis highlights an essential role of CtBP2 in the maintenance of β cell integrity. This system provides clues to the molecular basis in obesity and may be targetable to develop therapeutic approaches.
肥胖早期胰岛素分泌的适应性增加是维持葡萄糖内稳态的保障机制，但这种机制无法持续，β 细胞的最终衰竭是糖尿病发病机制中的一个关键事件。在这里，我们描述了一个由转录共因子 CtBP2 协调的关键系统。在培养的β细胞中，CtBP2 共同激活胰岛素基因的表达。CtBP2 结合位点的全基因组图谱鉴定出 CtBP2 与 NEUROD1 之间的关键相互作用，通过这种相互作用，CtBP2 在胰岛素基因启动子中解压缩染色质。肥胖的多种小鼠模型以及人类肥胖症的胰岛中 CtBP2 的表达减少。胰腺β细胞特异性的 CtBP2 缺陷型小鼠表现出葡萄糖不耐受伴胰岛素分泌受损。我们的转录组分析强调了 CtBP2 在维持β细胞完整性方面的重要作用。该系统为肥胖症的分子基础提供了线索，可能成为开发治疗方法的靶点。
