Department of Biology and Biotechnology "Charles Darwin", Sapienza University, 00185 Rome, Italy.
Preclinical Neuroscience, IRCCS Santa Lucia Foundation, 00143 Rome, Italy.
Int J Mol Sci. 2021 Jan 18;22(2):918. doi: 10.3390/ijms22020918.
Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the orthologs and results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that is expressed in insulin producing cells (IPCs) whereas is specifically expressed in the fat body. We showed that is essential for insulin secretion and it is required for expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity.
青少年发病的成年型糖尿病（MODY）2 型是由编码葡萄糖激酶（GCK）的基因的杂合失活突变引起的，GCK 是葡萄糖稳态的关键酶。在胰腺中，GCK 调节胰岛素分泌，而在肝脏中，它促进葡萄糖的利用和储存。我们发现沉默 同源物 和 导致 MODY-2 样高血糖。靶向敲低显示 在胰岛素产生细胞（IPCs）中表达，而 则特异性表达在脂肪体中。我们表明 对于胰岛素分泌是必不可少的，并且它是 表达所必需的。Hex-A 或 Hex-C 的水平降低会导致染色体异常（CAB），同时产生的晚期糖基化终产物（AGEs）和活性氧（ROS）增加。这一结果表明，在 GCK 耗尽的细胞中，CAB 可能是由于高血糖通过 AGE 代谢产生氧化应激所致。与该假说一致，用抗氧化维生素 B6 治疗 GCK 耗尽的幼虫可挽救 CAB，而用 B6 抑制剂治疗则会增强基因组不稳定性。尽管 MODY-2 很少产生并发症，但我们的数据揭示了 MODY-2 可能会影响基因组完整性的可能性。
