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 RNAi-induced 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 end products (AGEs) and reactive oxygen species (ROS). Rearing PI3KRNAi flies in a medium supplemented with pyridoxal 5’-phosphate (PLP, the catalytically active form of vitamin B6) rescues DNA damage while, in contrast, treating PI3KRNAi larvae with the PLP inhibitor 4-deoxypiridoxine (4DP) 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 relation 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.

Vitamin B6 rescues insulin resistance and glucose-induced DNA damage caused by reduced activity of Drosophila PI3K / Mascolo, Elisa; Liguori, Francesco; Merigliano, Chiara; Schiano, Ludovica; Gnocchini, Eleonora; Pilesi, Eleonora; Volontè, Cinzia; Di Salvo, Luigi Martino; Contestabile, Roberto; Tramonti, Angela; Vernì, Fiammetta. - In: JOURNAL OF CELLULAR PHYSIOLOGY. - ISSN 0021-9541. - (2022). [10.1002/jcp.30812]

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

Mascolo, Elisa;Merigliano, Chiara;Schiano, Ludovica;Pilesi, Eleonora;Di Salvo, Luigi Martino;Contestabile, Roberto;Vernì, Fiammetta
2022

Abstract

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 RNAi-induced 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 end products (AGEs) and reactive oxygen species (ROS). Rearing PI3KRNAi flies in a medium supplemented with pyridoxal 5’-phosphate (PLP, the catalytically active form of vitamin B6) rescues DNA damage while, in contrast, treating PI3KRNAi larvae with the PLP inhibitor 4-deoxypiridoxine (4DP) 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 relation 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.
2022
DNA damage; Drosophila; insulin signaling; phosphatidylinositol 3‐Kinase; pyridoxal phosphate
01 Pubblicazione su rivista::01a Articolo in rivista
Vitamin B6 rescues insulin resistance and glucose-induced DNA damage caused by reduced activity of Drosophila PI3K / Mascolo, Elisa; Liguori, Francesco; Merigliano, Chiara; Schiano, Ludovica; Gnocchini, Eleonora; Pilesi, Eleonora; Volontè, Cinzia; Di Salvo, Luigi Martino; Contestabile, Roberto; Tramonti, Angela; Vernì, Fiammetta. - In: JOURNAL OF CELLULAR PHYSIOLOGY. - ISSN 0021-9541. - (2022). [10.1002/jcp.30812]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1641668
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