BMB Reports

생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
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Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis

  • Hwang, Yeo Jin (Division of Electronics & Information System, Daegu Gyeongbuk Institute of Science and Technology) ;
  • Jung, Gwon-Soo (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Jeon, WonBae (Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology) ;
  • Lee, Kyeong-Min (Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology)
  • 투고 : 2020.11.13
  • 심사 : 2021.03.09
  • 발행 : 2021.04.30
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초록

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/mT pathway.

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과제정보

This work was supported by DGIST projects 21-BT-06, NRF-2021R1A2C1011314 and NRF-2018R1C1B6008955 from the National Research Foundation of Korea funded by the Ministry of Science, ICT of the Republic of Korea.

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