title: A potential mechanism of metformin-mediated regulation of glucose homeostasis: inhibition of Thioredoxin-interacting protein (Txnip) gene expression.
abstract: Metformin (dimethylbiguanide) is widely used among diabetic patients to lower the blood sugar level. Although several mechanisms have been proposed, its mode of action in enhancing peripheral glucose uptake and inhibiting hepatic glucose production is not fully understood. Thioredoxin-interacting protein (Txnip) is known to play important roles in glucose metabolism by inhibiting cellular glucose uptake and metabolism and promoting hepatic gluconeogenesis. The expression of the gene encoding Txnip is regulated in a glucose dependent manner via the Mondo:MLX transcription factor complex. In the present study, we report that Txnip mRNA as well as protein expression in cultured cells is markedly reduced upon metformin administration. The binding of Mondo:MLX to the Txnip gene promoter is reduced, suggesting that the transcription of the Txnip gene is repressed by metformin. Moreover, we show that the effect of metformin on Txnip gene transcription is due to the inhibition of mitochondrial complex I and increased glycolysis, and is partially mediated by the AMP activated kinase (AMPK). These observations prompt us to propose that the novel action of metformin on the Txnip gene expression may contribute to its therapeutic effects in the treatment of type II diabetes.
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Tin Fan
authors.initials: TF
authors.lastname: Chai
authors.forename: Shin Yee
authors.initials: SY
authors.lastname: Hong
authors.forename: Hongpeng
authors.initials: H
authors.lastname: He
authors.forename: Liling
authors.initials: L
authors.lastname: Zheng
authors.forename: Thilo
authors.initials: T
authors.lastname: Hagen
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Fa-Xing
authors.initials: FX
authors.lastname: Yu
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D020869:Gene Expression Profiling; D006367:HeLa Cells; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D012333:RNA, Messenger; C486715:TXNIP protein, human; C445672:Txnip protein, mouse; D013879:Thioredoxins; D008687:Metformin