Department of Insect Biomedical Research, Kyoto Institute of Technology, Matsugasaki, Kyoto 606-0962, Sakyo, Japan.
Int J Mol Sci. 2021 Nov 7;22(21):12038. doi: 10.3390/ijms222112038.
Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINS and hINS, neither of which secreted from the β-cells, could not stimulate the growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of () in imaginal disc cells. ER stress induced by hINS also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis.
胰岛素基因（INS）的突变常与人类永久性新生儿糖尿病有关。然而，这种遗传疾病的发病机制尚未完全阐明。我们利用其异位表达系统在 中诱导两种类型的人突变 INS 的表达，并研究了其在发育过程中的反应。野生型前胰岛素在胰岛素产生细胞（IPCs）中的表达在整个幼虫阶段都能刺激整体和翅膀的生长。然而，不能从β细胞分泌的人突变前胰岛素 hINS 和 hINS 的异位表达不能刺激 的生长。此外，这两种突变多肽都没有诱导 caspase 激活导致细胞凋亡。相反，它们诱导了几种标志分子的表达，表明未折叠蛋白反应的激活，如 ER 应激依赖性 的 mRNA 剪接和 ER 伴侣的诱导。我们新发现，突变多肽在 imaginal disc 细胞中诱导了 （）的表达。hINS 诱导的 ER 应激也激活了 JAK-STAT 信号通路，该通路参与炎症反应。总之，我们推测，糖尿病样生长缺陷的出现是由于人突变前胰岛素的表达导致 IPCs 功能障碍，而不是细胞凋亡。
