Functional inactivation of Drosophila GCK orthologs causes genomic instability and oxidative stress in a fly model of MODY-2

Abstract: Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygousinactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucosehomeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucoseutilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-Cresults in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed ininsulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showedthat Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levelsof either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increasedproduction of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). Thisresult suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which producesoxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCKdepletedlarvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our datarevealed the possibility that MODY-2 impacts genome integrity.