title: Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice.
abstract: Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR), and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Tomohiko
authors: T
authors: Ohno
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Masahito
authors: M
authors: Shimizu
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Yohei
authors: Y
authors: Shirakami
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Atsushi
authors: A
authors: Baba
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Takahiro
authors: T
authors: Kochi
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Masaya
authors: M
authors: Kubota
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Hisashi
authors: H
authors: Tsurumi
authors: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Takuji
authors: T
authors: Tanaka
authors: Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors: Hisataka
authors: H
authors: Moriwaki
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D063646:Carcinogenesis / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004052:Diethylnitrosamine; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D054392:Adipokines; D007004:Hypoglycemic Agents; D004052:Diethylnitrosamine; D008687:Metformin; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases