Lund University Diabetes Center, CRC 91-11 SUS, Jan Waldenströms gata 35, SE-20502 Malmö, Sweden.
Medical Research Center, Hawler Medical University, 44001 Erbil, Iraq.
Nat Commun. 2017 Jun 6;8:15652. doi: 10.1038/ncomms15652.
Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca-influx and β-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key β-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of β-cell phenotype and function.
2 型糖尿病（T2D）的特征是胰岛素抵抗和胰岛素分泌受损，但胰岛素分泌衰竭的机制尚不完全清楚。在这里，我们显示了一组共同表达的基因，这些基因富集了具有胰岛选择性开放染色质的基因，与 T2D 相关。这些基因在 T2D 中受到干扰，并且其表达模式与去分化的胰岛相似。我们确定 Sox5 是该模块的调节剂。Sox5 的敲低诱导类似于在 T2D 和糖尿病动物中观察到的基因表达变化，并对胰岛素分泌有深远影响，包括减少去极化诱发的 Ca 内流和β细胞胞吐作用。SOX5 的过表达逆转了在 T2D 小鼠模型中观察到的表达扰动，增加了关键的β细胞基因的表达，并改善了来自 T2D 供体的人胰岛对葡萄糖刺激的胰岛素分泌。我们认为，T2D 中的人类胰岛显示出类似于去分化的变化，并强调 SOX5 是β细胞表型和功能的调节剂。
