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

• Main Authors: Elisa Mascolo, Francesco Liguori, Lorenzo Stufera Mecarelli, Noemi Amoroso, Chiara Merigliano, Susanna Amadio, Cinzia Volonté, Roberto Contestabile, Angela Tramonti, Fiammetta Vernì
• Format: Article
• Language: English
• Published: MDPI AG 2021-01-01
• Series: International Journal of Molecular Sciences
• Subjects: MODY-2; <i>Drosophila melanogaster</i>; glucokinase; chromosome aberrations; vitamin B6
• Online Access: https://www.mdpi.com/1422-0067/22/2/918

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 <i>Drosophila</i> <i>GCK</i> orthologs <i>Hex-A</i> and <i>Hex-C</i> results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that <i>Hex-A</i> is expressed in insulin producing cells (IPCs) whereas <i>Hex-C</i> is specifically expressed in the fat body. We showed that <i>Hex-A</i> is essential for insulin secretion and it is required for <i>Hex-C</i> 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.