Abstract
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 Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C 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.
Highlights
In this paper we demonstrated that Hex-A is expressed in Drosophila insulin producing cells (IPCs) and that it is involved in insulin secretion, mimicking the mammalian glucokinase enzyme (GCK) pancreatic isoform
In the course of a study aimed at investigating the relationship between hyperglycemia and DNA damage in Drosophila, we found that the silencing of two GCK orthologs
Before studying the involvement of these two genes in DNA damage, we explored their role in glucose homeostasis
Summary
Maturity-onset diabetes of the young (MODY) is a heterogeneous group of disorders due to mutations in single genes involved in insulin metabolism. It is inherited as an autosomal dominant trait and represents 2–5% of diabetes cases [1,2]. GCK is expressed in pancreatic β-cells, in liver, and in few brain and gastrointestinal neuroendocrine cells [6]. This differential expression is explained by the presence of two tissue-specific promoters, leading to the production of transcripts different only for their first exon size [7,8]. GCK functions as a glucose sensor [6,7,9,10] and regulates insulin secretion in response to blood glucose levels [9,10]
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