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Open Access Research article

High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells

Yoon-Ok Jang1, Xianglan Quan2, Ranjan Das2, Shanhua Xu2, Choon-Hee Chung14, Chan Mug Ahn34, Soon-Koo Baik14, In Deok Kong24, Kyu-Sang Park24* and Moon Young Kim14*

Author Affiliations

1 Department of Internal Medicine, Yonsei University, Wonju College of Medicine, Wonju, 220-701, Korea

2 Department of Physiology, Yonsei University, Wonju College of Medicine, Wonju, 220-701, Korea

3 Department of Basic Science, Yonsei University, Wonju College of Medicine, Wonju, 220-701, Korea

4 Institute of Lifestyle Medicine, Yonsei University, Wonju College of Medicine, Wonju, 220-701, Korea

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BMC Gastroenterology 2012, 12:4  doi:10.1186/1471-230X-12-4

Published: 10 January 2012



Clevudine is a nucleoside analog reverse transcriptase inhibitor that exhibits potent antiviral activity against hepatitis B virus (HBV) without serious side effects. However, mitochondrial myopathy has been observed in patients with chronic HBV infection taking clevudine. Moreover, the development of diabetes was recently reported in patients receiving long-term treatment with clevudine. In this study, we investigated the effects of clevudine on mitochondrial function and insulin release in a rat clonal β-cell line, INS-1E.


The mitochondrial DNA (mtDNA) copy number and the mRNA levels were measured by using quantitative PCR. MTT analysis, ATP/lactate measurements, and insulin assay were performed.


Both INS-1E cells and HepG2 cells, which originated from human hepatoma, showed dose-dependent decreases in mtDNA copy number and cytochrome c oxidase-1 (Cox-1) mRNA level following culture with clevudine (10 μM-1 mM) for 4 weeks. INS-1E cells treated with clevudine had reduced total mitochondrial activities, lower cytosolic ATP contents, enhanced lactate production, and more lipid accumulation. Insulin release in response to glucose application was markedly decreased in clevudine-treated INS-1E cells, which might be a consequence of mitochondrial dysfunction.


Our data suggest that high-dose treatment with clevudine induces mitochondrial defects associated with mtDNA depletion and impairs glucose-stimulated insulin secretion in insulin-releasing cells. These findings partly explain the development of diabetes in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity.

clevudine; mitochondrial DNA; mitochondrial dysfunction; glucose-stimulated insulin secretion