Comparison of gene expression changes induced by biguanides in db/db mice liver

Large-scale clinical studies have shown that the biguanide drug metformin, widely used for type 2 diabetes, to be very safe. By contrast, another biguanide, phenformin, has been withdrawn from major markets because of a high incidence of serious adverse effects. The difference in mode of action betw...

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Bibliographic Details
Published in:Journal of toxicological sciences 2008/08/01, Vol.33(3), pp.339-347
Main Authors: Heishi, Masayuki, Hayashi, Koji, Ichihara, Junji, Ishikawa, Hironori, Kawamura, Takao, Kanaoka, Masaharu, Taiji, Mutsuo, Kimura, Toru
Format: Article
Language:English
Subjects:
Animals
Blood Glucose - analysis
Computational Biology
db/db Mouse
Dose-Response Relationship, Drug
Gene Expression Profiling
Hypoglycemic Agents - pharmacology
Liver - drug effects
Liver - metabolism
Male
Metformin
Metformin - pharmacology
Mice
Mice, Inbred C57BL
Mice, Obese
Microarray
Oligonucleotide Array Sequence Analysis
Phenformin
Phenformin - pharmacology
Phenformin - toxicity
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Summary:Large-scale clinical studies have shown that the biguanide drug metformin, widely used for type 2 diabetes, to be very safe. By contrast, another biguanide, phenformin, has been withdrawn from major markets because of a high incidence of serious adverse effects. The difference in mode of action between the two biguanides remains unclear. To gain insight into the different modes of action of the two drugs, we performed global gene expression profiling using the livers of obese diabetic db/db mice after a single administration of phenformin or metformin at levels sufficient to cause a significant reduction in blood glucose level. Metformin induced modest expression changes, including G6pc in the liver as previously reported. By contrast, phenformin caused changes in expression level of many additional genes. We used a knowledge-based bioinformatic analysis to study the effects of phenformin. Differentially expressed genes identified in this study constitute a large gene network, which may be related to cell death, inflammation or wound response. Our results suggest that the two biguanides show a similar hypoglycemic effect in db/db mice, but phenformin induces a greater stress on the liver even a short time after a single administration. These findings provide a novel insight into the cause of the relatively high occurrence of serious adverse effect after phenformin treatment.
ISSN:0388-1350
1880-3989
DOI:10.2131/jts.33.339