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

Yoon Ok Jang, Xianglan Quan, Ranjan Das, Shanhua Xu, Choon Hee Chung, Chan Mug Ahn, Soon Koo Baik, In Deok Kong, Kyu Sang Park, Moon Young Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: 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.Methods: 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.Results: 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.Conclusions: 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.

Original languageEnglish
Article number4
JournalBMC Gastroenterology
Volume12
DOIs
Publication statusPublished - 2012 Jan 10

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Insulin
Glucose
Mitochondrial DNA
Hepatitis B virus
Lactic Acid
Adenosine Triphosphate
Mitochondrial Myopathies
Cytochromes c1
Clevudine
Messenger RNA
Reverse Transcriptase Inhibitors
Chronic Hepatitis B
Hep G2 Cells
Electron Transport Complex IV
Virus Diseases
Nucleosides
Antiviral Agents
Hepatocellular Carcinoma
Lipids
Cell Line

All Science Journal Classification (ASJC) codes

  • Gastroenterology

Cite this

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title = "High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells",
abstract = "Background: 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.Methods: 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.Results: 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.Conclusions: 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.",
author = "Jang, {Yoon Ok} and Xianglan Quan and Ranjan Das and Shanhua Xu and Chung, {Choon Hee} and Ahn, {Chan Mug} and Baik, {Soon Koo} and Kong, {In Deok} and Park, {Kyu Sang} and Kim, {Moon Young}",
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High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells. / Jang, Yoon Ok; Quan, Xianglan; Das, Ranjan; Xu, Shanhua; Chung, Choon Hee; Ahn, Chan Mug; Baik, Soon Koo; Kong, In Deok; Park, Kyu Sang; Kim, Moon Young.

In: BMC Gastroenterology, Vol. 12, 4, 10.01.2012.

Research output: Contribution to journalArticle

TY - JOUR

T1 - High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells

AU - Jang, Yoon Ok

AU - Quan, Xianglan

AU - Das, Ranjan

AU - Xu, Shanhua

AU - Chung, Choon Hee

AU - Ahn, Chan Mug

AU - Baik, Soon Koo

AU - Kong, In Deok

AU - Park, Kyu Sang

AU - Kim, Moon Young

PY - 2012/1/10

Y1 - 2012/1/10

N2 - Background: 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.Methods: 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.Results: 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.Conclusions: 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.

AB - Background: 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.Methods: 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.Results: 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.Conclusions: 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.

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