title: Comparison of gene expression changes induced by biguanides in db/db mice liver.
abstract: 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 By contrast, another biguanide, phenformin, has been withdrawn from major markets because of a high incidence of serious adverse effects.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.
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., Osaka.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Heishi
authors.forename: Koji
authors.initials: K
authors.lastname: Hayashi
authors.forename: Junji
authors.initials: J
authors.lastname: Ichihara
authors.forename: Hironori
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Takao
authors.initials: T
authors.lastname: Kawamura
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kanaoka
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Taiji
authors.forename: Toru
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D020411:Oligonucleotide Array Sequence Analysis; D010629:Phenformin / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D008687:Metformin; D010629:Phenformin