Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In pancreas GCK regulates insulin secretion, while liver it promotes utilization and storage. We showed that silencing DrosophilaGCK orthologs Hex-A Hex-C results MODY-2-like hyperglycemia. Targeted knock-down revealed expressed producing cells (IPCs) whereas specifically fat body. essential secretion required expression. Reduced levels either or resulted chromosome aberrations (CABs), together with an increased production advanced glycation end-products (AGEs) reactive oxygen species (ROS). This result suggests CABs, depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. agreement this hypothesis, treating GCK-depleted larvae antioxidant vitamin B6 rescued treatment inhibitor enhanced genomic instability. Although MODY-2 rarely complications, our data possibility impacts genome integrity.