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Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis

An excessive and prolonged increase in glucose levels causes β-cell dysregulation, which is accompanied by impaired insulin synthesis and secretion, a condition known as glucotoxicity. Although it is known that both Lin28a and Lin28b regulate glucose metabolism, other molecular mechanisms that may p...

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Autores principales: Hwang, Yeo Jin, Jung, Gwon-Soo, Jeon, WonBae, Lee, Kyeong-Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093937/
https://www.ncbi.nlm.nih.gov/pubmed/33691905
http://dx.doi.org/10.5483/BMBRep.2021.54.4.255
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author Hwang, Yeo Jin
Jung, Gwon-Soo
Jeon, WonBae
Lee, Kyeong-Min
author_facet Hwang, Yeo Jin
Jung, Gwon-Soo
Jeon, WonBae
Lee, Kyeong-Min
author_sort Hwang, Yeo Jin
collection PubMed
description An excessive and prolonged increase in glucose levels causes β-cell dysregulation, which is accompanied by impaired insulin synthesis and secretion, a condition known as glucotoxicity. Although it is known that both Lin28a and Lin28b regulate glucose metabolism, other molecular mechanisms that may protect against glucotoxicity are poorly understood. We investigated whether Lin28a overexpression can improve glucotoxicity-induced β-cell dysregulation in INS-1 and primary rat islet cells. INS-1, a rat insulinoma cell line was cultured and primary rat islet cells were isolated from SD-rats. To define the effect of Lin28a in chronic high glucose-induced β-cell dysregulation, we performed several in vitro and ex-vivo experiments. Chronic exposure to high glucose led to a downregulation of Lin28a mRNA and protein expression, followed by a decrease in insulin mRNA expression and secretion in β-cells. The mRNA and protein expression levels of PDX-1 and BETA2, were reduced; The levels of apoptotic factors, including c-caspase3 and the Bax/Bcl-2 ratio, were increased due to glucotoxicity. Adenovirus-mediated Lin28a overexpression in β-cells reversed the glucotoxicity-induced reduction of insulin secretion and insulin mRNA expression via regulation of β-cell-enriched transcription factors such as PDX-1 and BETA2. Adenovirus-mediated overexpression of Lin28a downregulated the glucotoxicity-induced upregulation of c-caspase3 levels and the Bax/Bcl-2 ratio, while inhibition of endogenous Lin28a by small interfering RNA resulted in their up-regulation. Lin28a counteracted glucotoxicity-induced downregulation of p-Akt and p-mTOR. Our results suggest that Lin28a protects pancreatic β-cells from glucotoxicity through inhibition of apoptotic factors via the PI3 kinase/Akt/mTOR pathway.
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spelling pubmed-80939372021-05-13 Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis Hwang, Yeo Jin Jung, Gwon-Soo Jeon, WonBae Lee, Kyeong-Min BMB Rep Article An excessive and prolonged increase in glucose levels causes β-cell dysregulation, which is accompanied by impaired insulin synthesis and secretion, a condition known as glucotoxicity. Although it is known that both Lin28a and Lin28b regulate glucose metabolism, other molecular mechanisms that may protect against glucotoxicity are poorly understood. We investigated whether Lin28a overexpression can improve glucotoxicity-induced β-cell dysregulation in INS-1 and primary rat islet cells. INS-1, a rat insulinoma cell line was cultured and primary rat islet cells were isolated from SD-rats. To define the effect of Lin28a in chronic high glucose-induced β-cell dysregulation, we performed several in vitro and ex-vivo experiments. Chronic exposure to high glucose led to a downregulation of Lin28a mRNA and protein expression, followed by a decrease in insulin mRNA expression and secretion in β-cells. The mRNA and protein expression levels of PDX-1 and BETA2, were reduced; The levels of apoptotic factors, including c-caspase3 and the Bax/Bcl-2 ratio, were increased due to glucotoxicity. Adenovirus-mediated Lin28a overexpression in β-cells reversed the glucotoxicity-induced reduction of insulin secretion and insulin mRNA expression via regulation of β-cell-enriched transcription factors such as PDX-1 and BETA2. Adenovirus-mediated overexpression of Lin28a downregulated the glucotoxicity-induced upregulation of c-caspase3 levels and the Bax/Bcl-2 ratio, while inhibition of endogenous Lin28a by small interfering RNA resulted in their up-regulation. Lin28a counteracted glucotoxicity-induced downregulation of p-Akt and p-mTOR. Our results suggest that Lin28a protects pancreatic β-cells from glucotoxicity through inhibition of apoptotic factors via the PI3 kinase/Akt/mTOR pathway. Korean Society for Biochemistry and Molecular Biology 2021-04-30 2021-04-30 /pmc/articles/PMC8093937/ /pubmed/33691905 http://dx.doi.org/10.5483/BMBRep.2021.54.4.255 Text en Copyright © 2021 by the The Korean Society for Biochemistry and Molecular Biology https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0 (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Hwang, Yeo Jin
Jung, Gwon-Soo
Jeon, WonBae
Lee, Kyeong-Min
Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis
title Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis
title_full Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis
title_fullStr Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis
title_full_unstemmed Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis
title_short Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis
title_sort lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093937/
https://www.ncbi.nlm.nih.gov/pubmed/33691905
http://dx.doi.org/10.5483/BMBRep.2021.54.4.255
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