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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 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 sh...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831483/ https://www.ncbi.nlm.nih.gov/pubmed/33477627 http://dx.doi.org/10.3390/ijms22020918 |
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author | Mascolo, Elisa Liguori, Francesco Stufera Mecarelli, Lorenzo Amoroso, Noemi Merigliano, Chiara Amadio, Susanna Volonté, Cinzia Contestabile, Roberto Tramonti, Angela Vernì, Fiammetta |
author_facet | Mascolo, Elisa Liguori, Francesco Stufera Mecarelli, Lorenzo Amoroso, Noemi Merigliano, Chiara Amadio, Susanna Volonté, Cinzia Contestabile, Roberto Tramonti, Angela Vernì, Fiammetta |
author_sort | Mascolo, Elisa |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7831483 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-78314832021-01-26 Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2 Mascolo, Elisa Liguori, Francesco Stufera Mecarelli, Lorenzo Amoroso, Noemi Merigliano, Chiara Amadio, Susanna Volonté, Cinzia Contestabile, Roberto Tramonti, Angela Vernì, Fiammetta Int J Mol Sci Article 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. MDPI 2021-01-18 /pmc/articles/PMC7831483/ /pubmed/33477627 http://dx.doi.org/10.3390/ijms22020918 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mascolo, Elisa Liguori, Francesco Stufera Mecarelli, Lorenzo Amoroso, Noemi Merigliano, Chiara Amadio, Susanna Volonté, Cinzia Contestabile, Roberto Tramonti, Angela Vernì, Fiammetta Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2 |
title | Functional Inactivation of Drosophila
GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2 |
title_full | Functional Inactivation of Drosophila
GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2 |
title_fullStr | Functional Inactivation of Drosophila
GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2 |
title_full_unstemmed | Functional Inactivation of Drosophila
GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2 |
title_short | Functional Inactivation of Drosophila
GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2 |
title_sort | functional inactivation of drosophila
gck orthologs causes genomic instability and oxidative stress in a fly model of mody-2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831483/ https://www.ncbi.nlm.nih.gov/pubmed/33477627 http://dx.doi.org/10.3390/ijms22020918 |
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