Tetraspanin-2 promotes glucotoxic apoptosis by regulating JNK/β-catenin signaling pathway in human pancreatic β-cells

Diabetes mellitus is a complex and heterogeneous disease that has β cell dysfunction at its core. Glucose toxicity affects pancreatic islets where it leads to β cell apoptosis. However, the role of JNK/β-catenin signaling pathway in glucotoxic β-cell apoptosis is poorly understood. To identify the potential genes whose expression changed in response to high glucose, we performed microarray analysis of gene expression in the RNAKT-15 cells for 48 h. Among the 41,000 genes tested, 1394 and 741 were twofold-upregulated and -downregulated, respectively. Genes involved in carbohydrate metabolism, cell cycle control, apoptotic process, and response to reactive oxygen species were upregulated. In contrast, genes involved in intracellular protein traffic, cell cycle, cell adhesion-mediated signaling, cell cycle control, response to reactive oxygen species, and apoptotic process were downregulated under high glucose-treated RNAKT-15 cells. RNAKT-15 cells were incubated with low glucose (5mM, LC), and high glucose (33mM, HC) for 48 hours. The microarray experiments were performed in triplicate.

糖尿病是一类以β细胞（β cell）功能障碍为核心的复杂异质性疾病。糖毒性可作用于胰岛并诱导β细胞凋亡，然而JNK/β-连环蛋白信号通路（JNK/β-catenin signaling pathway）在糖毒性介导的β细胞凋亡中所发挥的作用仍不甚明确。为筛选出高糖刺激下表达发生改变的潜在靶基因，我们将RNAKT-15细胞分别置于低糖（5mM，LC组）与高糖（33mM，HC组）环境中孵育48小时，随后提取其总RNA开展基因表达微阵列分析，且所有芯片实验均设置三次独立重复。在所检测的41000个基因中，分别有1394个基因上调两倍、741个基因下调两倍；参与碳水化合物代谢、细胞周期调控、细胞凋亡过程以及活性氧（reactive oxygen species）应答的基因呈现上调趋势。与之相反，经高糖处理的RNAKT-15细胞中，参与细胞内蛋白质转运、细胞周期、细胞黏附介导的信号通路、细胞周期调控、活性氧应答以及细胞凋亡过程的基因则发生下调。