Wu Hui-Hui, Ma Qian-Wen, Liu Yi-Meng, Wu Xia, Wen Jie
Department of Endocrinology and Metabolism, Jing'an District Center Hospital of Shanghai, Fudan University, Shanghai, China.
Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China.
Clin Med Insights Endocrinol Diabetes. 2024 Oct 26;17:11795514241295620. doi: 10.1177/11795514241295620. eCollection 2024.
Transcription factor 7-like 2 (TCF7L2) variants seem to affect diabetes susceptibility through β-cell dysfunction, underlying basis of which has been considered to be β-cell dedifferentiation rather than apoptotic β-cell death. The Extracellular regulated protein kinases/Mitogen-activated protein kinase signaling pathway (ERK/MAPK signaling pathway) has been confirmed to be significantly associated with multiple cellular process, including cellular dedifferentiation. However, the effects of TCF7L2 on β-cell function and ERK/MAPK signaling pathway are poorly understood.
This study aimed to elucidate the regulation of TCF7L2 in β-cell function and ERK/MAPK signaling pathway, which further participate in glucose metabolism and diabetes progression.
After transfection of TCF7L2 siRNA and lenti-TCF7L2 plasmids, the activation of ERK/MAPK signaling and β-cell dedifferentiation were evaluated respectively. Six week-old male / mice were randomly grouped and fed a normal or high-fat diet, and then pancreatic level of TCF7L2 protein were measured respectively when the mice were fed to 8, 12, and 16 weeks of age. Furthermore, the contributions of TCF7L2 to ERK/MAPK signaling and glucose metabolism were investigated in a β-cell-specific TCF7L2 deletion mice model (TCF7L2).
The results demonstrated that impaired TCF7L2 induces β-cell dedifferentiation and decreases insulin secretion of MIN6 cells via ERK/MAPK signaling pathway. Consistently, decreased pancreatic TCF7L2 protein in parallel with reduced functional β-cells were observed in / mice after weeks of normal or high-fat diet. However, the differences between were only significant when the mice were fed to 12 weeks of age. After weeks of high-fat diet feeding, impaired glucose tolerance and increased activation of ERK/MAPK signaling were simultaneously observed in TCF7L2 mice.
The study indicate that the induction of β-cell dedifferentiation mediated by ERK/MAPK signaling pathway might be an essential component of TCF7L2 variants in the development of diabetes.
转录因子7样蛋白2（TCF7L2）变体似乎通过β细胞功能障碍影响糖尿病易感性，其潜在机制被认为是β细胞去分化而非凋亡性β细胞死亡。细胞外调节蛋白激酶/丝裂原活化蛋白激酶信号通路（ERK/MAPK信号通路）已被证实与包括细胞去分化在内的多个细胞过程显著相关。然而，TCF7L2对β细胞功能和ERK/MAPK信号通路的影响尚不清楚。
本研究旨在阐明TCF7L2对β细胞功能和ERK/MAPK信号通路的调节作用，进而参与葡萄糖代谢和糖尿病进展。
转染TCF7L2 siRNA和慢病毒-TCF7L2质粒后，分别评估ERK/MAPK信号通路的激活和β细胞去分化情况。将6周龄雄性小鼠随机分组，给予正常或高脂饮食，分别在小鼠喂养至8、12和16周龄时检测胰腺中TCF7L2蛋白水平。此外，在β细胞特异性TCF7L2缺失小鼠模型（TCF7L2）中研究TCF7L2对ERK/MAPK信号通路和葡萄糖代谢的作用。
结果表明，TCF7L2功能受损通过ERK/MAPK信号通路诱导β细胞去分化并降低MIN6细胞的胰岛素分泌。同样，在正常或高脂饮食喂养数周后的小鼠中观察到胰腺TCF蛋白水平降低与功能性β细胞减少平行。然而，仅在小鼠喂养至12周龄时两者之间的差异才具有统计学意义。高脂饮食喂养数周后，在TCF7L2小鼠中同时观察到糖耐量受损和ERK/MAPK信号通路激活增加。
该研究表明，ERK/MAPK信号通路介导的β细胞去分化诱导可能是糖尿病发生发展中TCF7L2变体的重要组成部分。
