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

Mascolo, Elisa; Liguori, Francesco; Mecarelli, Lorenzo Stufera; Amoroso, Noemi; Merigliano, Chiara; Amadio, Susanna; Volonté, Cinzia; Contestabile, Roberto; Tramonti, Angela; Vernı̀, Fiammetta

doi:10.3390/ijms22020918

Cited by 9 publications

(6 citation statements)

References 68 publications

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“…Reactive oxygen species (ROS) measurement was performed in larval hemolymph from larvae reared in standard, PLP‐ or AA‐supplemented medium, using the nitro blue tetrazolium (NBT) as previously described (Mascolo et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

Vitamin B6 rescues insulin resistance and glucose‐induced DNA damage caused by reduced activity of Drosophila PI3K

Mascolo

Liguori

Merigliano

et al. 2022

Journal Cellular Physiology

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The insulin signaling pathway controls cell growth and metabolism, thus its deregulation is associated with both cancer and diabetes. Phosphatidylinositol 3-kinase (PI3K) contributes to the cascade of phosphorylation events occurring in the insulin pathway by activating the protein kinase B (PKB/AKT), which phosphorylates several substrates, including those involved in glucose uptake and storage. PI3K inactivating mutations are associated with insulin resistance while activating mutations are identified in human cancers. Here we show that RNAiinduced depletion of the Drosophila PI3K catalytic subunit (Dp110) results in diabetic phenotypes such as hyperglycemia, body size reduction, and decreased glycogen content. Interestingly, we found that hyperglycemia produces chromosome aberrations (CABs) triggered by the accumulation of advanced glycation endproducts and reactive oxygen species. Rearing PI3K RNAi flies in a medium supplemented with pyridoxal 5′-phosphate (PLP; the catalytically active form of vitamin B6) rescues DNA damage while, in contrast, treating PI3K RNAi larvae with the PLP inhibitor 4-deoxypyridoxine strongly enhances CAB frequency. Interestingly, PLP supplementation rescues also diabetic phenotypes. Taken together, our results provide a strong link between impaired PI3K activity and genomic instability, a crucial relationship that needs to be monitored not only in diabetes due to impaired insulin signaling but also in cancer therapies based on PI3K inhibitors. In addition, our findings confirm the notion that vitamin B6 is a good natural remedy to counteract insulin resistance and its complications.

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Section: Methodsmentioning

confidence: 99%

Vitamin B6 rescues insulin resistance and glucose‐induced DNA damage caused by reduced activity of Drosophila PI3K

Mascolo

Liguori

Merigliano

et al. 2022

Journal Cellular Physiology

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“…A model of MODY2 was generated by Mascolo and co-workers [ 144 ]. Differently from mammals which possess only one GCK gene and different tissue-specific isoforms, Drosophila has two main GCK orthologs: Hex-C expressed in the fat body and Hex-A expressed in IPCs, which perform the functions of hepatic and pancreatic mammalian GCK, respectively [ 144 ]. Moreover, Hex-A is required for insulin secretion and to trigger the expression of Hex-C in the fat body [ 144 ].…”

Section: Drosophila As a Diabetes Modelmentioning

confidence: 99%

“…Differently from mammals which possess only one GCK gene and different tissue-specific isoforms, Drosophila has two main GCK orthologs: Hex-C expressed in the fat body and Hex-A expressed in IPCs, which perform the functions of hepatic and pancreatic mammalian GCK, respectively [ 144 ]. Moreover, Hex-A is required for insulin secretion and to trigger the expression of Hex-C in the fat body [ 144 ]. RNAi-induced silencing of Hex-A or Hex-C genes resulted in diabetic phenotypes similar to those observed in MODY2 patients.…”

Section: Drosophila As a Diabetes Modelmentioning

confidence: 99%

“…Interestingly, this Drosophila MODY2 model has been useful to discover that hyperglycemia due to GCK loss causes chromosome aberrations through the formation of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This finding indicates that, although MODY2 rarely produces complications, it may impact on genome integrity [ 144 ].…”

Section: Drosophila As a Diabetes Modelmentioning

confidence: 99%

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The Genetics of Diabetes: What We Can Learn from Drosophila

Liguori

Mascolo

Vernı̀

2021

IJMS

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Diabetes mellitus is a heterogeneous disease characterized by hyperglycemia due to impaired insulin secretion and/or action. All diabetes types have a strong genetic component. The most frequent forms, type 1 diabetes (T1D), type 2 diabetes (T2D) and gestational diabetes mellitus (GDM), are multifactorial syndromes associated with several genes’ effects together with environmental factors. Conversely, rare forms, neonatal diabetes mellitus (NDM) and maturity onset diabetes of the young (MODY), are caused by mutations in single genes. Large scale genome screenings led to the identification of hundreds of putative causative genes for multigenic diabetes, but all the loci identified so far explain only a small proportion of heritability. Nevertheless, several recent studies allowed not only the identification of some genes as causative, but also as putative targets of new drugs. Although monogenic forms of diabetes are the most suited to perform a precision approach and allow an accurate diagnosis, at least 80% of all monogenic cases remain still undiagnosed. The knowledge acquired so far addresses the future work towards a study more focused on the identification of diabetes causal variants; this aim will be reached only by combining expertise from different areas. In this perspective, model organism research is crucial. This review traces an overview of the genetics of diabetes and mainly focuses on Drosophila as a model system, describing how flies can contribute to diabetes knowledge advancement.

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“…In the third study, Mascolo et al generated a fly model of MODY-2, a rare human disorder caused by pathogenic variants in glucokinase (GCK). By knocking down the fly homologs of GCK, the authors found that this manipulation leads to genomic instability, likely caused by reactive oxygen species production triggered by advanced glycation end-products [5]. The authors further showed that treating MODY-2 model flies with an antioxidant vitamin B6 can suppress this phenotype, suggesting potential therapeutic avenues for this disorder.…”

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confidence: 98%