Metformin sensitizes insulin signaling through AMPK-mediated pten down-regulation in preadipocyte 3T3-L1 cells
Insulin resistance is the primary cause responsible for type 2 diabetes. Phosphatase and tensin homolog (PTEN) plays a negative role in insulin signaling and its inhibition improves insulin sensitivity. Metformin is a widely used insulin‐sensitizing drug; however, the mechanism by which metformin ac...
Saved in:
Published in | Journal of cellular biochemistry Vol. 112; no. 5; pp. 1259 - 1267 |
---|---|
Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.05.2011
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Insulin resistance is the primary cause responsible for type 2 diabetes. Phosphatase and tensin homolog (PTEN) plays a negative role in insulin signaling and its inhibition improves insulin sensitivity. Metformin is a widely used insulin‐sensitizing drug; however, the mechanism by which metformin acts is poorly understood. To gain insight into the role of PTEN, we examined the effect of metformin on PTEN expression. Metformin suppressed the expression of PTEN in an AMP‐activated protein kinase (AMPK)‐dependent manner in preadipocyte 3T3‐L1 cells. Knock‐down of PTEN potentiated the increase in insulin‐mediated phosphorylation of Akt/ERK. Metformin also increased the phosphorylation of c‐Jun N‐terminal kinase (JNK)‐c‐Jun and mammalian target of rapamycin (mTOR)‐p70S6 kinase pathways. Both pharmacologic inhibition and knock‐down of AMPK blocked metformin‐induced phosphorylation of JNK and mTOR. Knock‐down of AMPK recovered the metformin‐induced PTEN down‐regulation, suggesting the involvement of AMPK in PTEN regulation. PTEN promoter activity was suppressed by metformin and inhibition of mTOR and JNK by pharmacologic inhibitors blocked metformin‐induced PTEN promoter activity suppression. These findings provide evidence for a novel role of AMPK on PTEN expression and thus suggest a possible mechanism by which metformin may contribute to its beneficial effects on insulin signaling. J. Cell. Biochem. 112: 1259–1267, 2011. © 2010 Wiley‐Liss, Inc. |
---|---|
Bibliography: | istex:009ACFA0864135A875B39625F64B3B05C1878950 ArticleID:JCB23000 ark:/67375/WNG-X39QXQJK-H Korea Healthcare Technology R & D Project, Ministry of Health & Welfare, Republic of Korea R1009171 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0730-2312 1097-4644 |
DOI: | 10.1002/jcb.23000 |