PMID- 25879666
OWN - NLM
STAT- MEDLINE
DCOM- 20160415
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 4
DP  - 2015
TI  - Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and 
      diabetic C57BL/KsJ-+Leprdb/+Leprdb mice.
PG  - e0124081
LID - 10.1371/journal.pone.0124081 [doi]
LID - e0124081
AB  - 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.
FAU - Ohno, Tomohiko
AU  - Ohno T
AD  - Department of Gastroenterology/Internal Medicine, Gifu University Graduate School 
      of Medicine, Gifu, Japan.
FAU - Shimizu, Masahito
AU  - Shimizu M
AD  - Department of Gastroenterology/Internal Medicine, Gifu University Graduate School 
      of Medicine, Gifu, Japan.
FAU - Shirakami, Yohei
AU  - Shirakami Y
AD  - Department of Gastroenterology/Internal Medicine, Gifu University Graduate School 
      of Medicine, Gifu, Japan.
FAU - Baba, Atsushi
AU  - Baba A
AD  - Department of Gastroenterology/Internal Medicine, Gifu University Graduate School 
      of Medicine, Gifu, Japan.
FAU - Kochi, Takahiro
AU  - Kochi T
AD  - Department of Gastroenterology/Internal Medicine, Gifu University Graduate School 
      of Medicine, Gifu, Japan.
FAU - Kubota, Masaya
AU  - Kubota M
AD  - Department of Gastroenterology/Internal Medicine, Gifu University Graduate School 
      of Medicine, Gifu, Japan.
FAU - Tsurumi, Hisashi
AU  - Tsurumi H
AD  - Department of Gastroenterology/Internal Medicine, Gifu University Graduate School 
      of Medicine, Gifu, Japan.
FAU - Tanaka, Takuji
AU  - Tanaka T
AD  - Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, 
      Japan.
FAU - Moriwaki, Hisataka
AU  - Moriwaki H
AD  - Department of Gastroenterology/Internal Medicine, Gifu University Graduate School 
      of Medicine, Gifu, Japan.
LA  - eng
PT  - Journal Article
DEP - 20150416
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Adipokines)
RN  - 0 (Hypoglycemic Agents)
RN  - 3IQ78TTX1A (Diethylnitrosamine)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adipokines/metabolism
MH  - Animals
MH  - Animals, Newborn
MH  - Carcinogenesis/*metabolism
MH  - Diabetes Mellitus, Experimental/*metabolism
MH  - Diethylnitrosamine
MH  - Female
MH  - Hypoglycemic Agents/pharmacology
MH  - Insulin Resistance
MH  - Liver/*drug effects
MH  - Liver Neoplasms/*metabolism
MH  - Male
MH  - Metformin/*pharmacology
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Obesity/*metabolism
MH  - Oncogene Protein v-akt/metabolism
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC4399835
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/04/17 06:00
MHDA- 2016/04/16 06:00
PMCR- 2015/04/16
CRDT- 2015/04/17 06:00
PHST- 2014/09/19 00:00 [received]
PHST- 2015/03/03 00:00 [accepted]
PHST- 2015/04/17 06:00 [entrez]
PHST- 2015/04/17 06:00 [pubmed]
PHST- 2016/04/16 06:00 [medline]
PHST- 2015/04/16 00:00 [pmc-release]
AID - PONE-D-14-39992 [pii]
AID - 10.1371/journal.pone.0124081 [doi]
PST - epublish
SO  - PLoS One. 2015 Apr 16;10(4):e0124081. doi: 10.1371/journal.pone.0124081. 
      eCollection 2015.