State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Reproductive Medical Center, Department of Obstetrics and Gynecology, the Seventh Medical Center of PLA General Hospital, Beijing 100007, China.
Endocrinology. 2023 Nov 20;165(1). doi: 10.1210/endocr/bqad152.
Insulin secreted by pancreatic β cells is essential for maintaining blood glucose levels. Diabetes is caused primarily by a loss of β cells or impairment of β-cell function. A previous whole-transcriptome analysis of islets from a type 2 diabetes group and a control group showed that a splicing disorder occurred in approximately 25% of splicing events. Breast carcinoma amplified sequence 2 (BCAS2) is a spliceosome component whose function in islet β cells is unclear. Here, we report that knockdown of Bcas2 decreased glucose- and KCl-stimulated insulin secretion in the NIT-1 cell line. Pancreas weight, glucose tolerance, and insulin sensitivity were measured in normal chow-fed Bcas2 f/f-βKO mice, and β-cell mass and islet size were analyzed by immunohistochemistry. Glucose intolerance developed in Bcas2 f/f-βKO mice, but there were no significant differences in pancreas weight, insulin sensitivity, β-cell mass, or islet size. Furthermore, observation of glucose-stimulated insulin secretion and insulin secretion granules in normal chow-fed mice revealed that the insulin level in serum and the number of insulin secretion granules were decreased in Bcas2 f/f-βKO mice. These differences were related to abnormal splicing of Syt7 and Tcf7l2 pre-mRNA. Taken together, these results demonstrate that BCAS2 is involved in alternative splicing during insulin synthesis and secretion.
胰岛β细胞分泌的胰岛素对于维持血糖水平至关重要。糖尿病主要是由于β细胞丧失或β细胞功能受损引起的。先前对 2 型糖尿病组和对照组胰岛的全转录组分析表明，大约 25%的剪接事件发生了剪接紊乱。乳腺癌扩增序列 2（BCAS2）是剪接体的一个组成部分，但其在胰岛β细胞中的功能尚不清楚。在这里，我们报告说，Bcas2 的敲低降低了 NIT-1 细胞系中葡萄糖和 KCl 刺激的胰岛素分泌。在正常饲料喂养的 Bcas2 f/f-βKO 小鼠中测量了胰腺重量、葡萄糖耐量和胰岛素敏感性，并通过免疫组织化学分析了β细胞质量和胰岛大小。Bcas2 f/f-βKO 小鼠出现葡萄糖不耐受，但胰腺重量、胰岛素敏感性、β细胞质量或胰岛大小没有显著差异。此外，对正常饲料喂养小鼠的葡萄糖刺激胰岛素分泌和胰岛素分泌颗粒的观察表明，血清中的胰岛素水平和胰岛素分泌颗粒的数量在 Bcas2 f/f-βKO 小鼠中减少。这些差异与 Syt7 和 Tcf7l2 前体 mRNA 的异常剪接有关。总之，这些结果表明 BCAS2 参与胰岛素合成和分泌过程中的可变剪接。
