title: Metformin sensitizes insulin signaling through AMPK-mediated PTEN down-regulation in preadipocyte 3T3-L1 cells.
abstract: 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.
authors.affiliation: Department of Anatomy, Korea University College of Medicine, Seoul, Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Lee
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Lee
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Kim
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Ga Young
authors.initials: GY
authors.lastname: You
authors.forename: Ji Wook
authors.initials: JW
authors.lastname: Moon
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Jung
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Park
authors.forename: Kyung-Ok
authors.initials: KO
authors.lastname: Uhm
authors.forename: Ji Man
authors.initials: JM
authors.lastname: Park
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D005947:Glucose