Cellular Responses to the Metal-Binding Properties of Metformin

doi:10.2337/db11-0961

CORC > 化学研究所 > 中国科学院化学研究所

	Cellular Responses to the Metal-Binding Properties of Metformin
	Logie, Lisa 1; Harthill, Jean 1; Patel, Kashyap 2; Bacon, Sandra 1,3; Hamilton, D. Lee 1; Macrae, Katherine 4; McDougall, Gordon 3; Wang, Huan-Huan 5; Xue, Lin 5; Jiang, Hua 5
刊名	DIABETES
	2012-06-01
卷号	61 期号:6 页码:1423-1433
ISSN号	0012-1797
DOI	10.2337/db11-0961
英文摘要	In recent decades, the antihyperglycemic biguanide metformin has been used extensively in the treatment of type 2 diabetes, despite continuing uncertainty over its direct target. In this article, using two independent approaches, we demonstrate that cellular actions of metformin are disrupted by interference with its metal-binding properties, which have been known for over a century but little studied by biologists. We demonstrate that copper sequestration opposes known actions of metformin not only on AMP-activated protein kinase (AMPK)-dependent signaling, but also on S6 protein phosphorylation. Biguanide/metal interactions are stabilized by extensive pi-electron delocalization and by investigating analogs of metformin; we provide evidence that this intrinsic property enables biguanides to regulate AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration, and mitochondrial copper binding. In contrast, regulation of S6 phosphorylation is prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting recent data that AMPK and S6 phosphorylation are regulated independently by biguanides. Additional studies with pioglitazone suggest that mitochondrial copper is targeted by both of these clinically important drugs. Together, these results suggest that cellular effects of biguanides depend on their metal-binding properties. This link may illuminate a better understanding of the molecular mechanisms enabling antihyperglycemic drug action. Diabetes 61:1423-1433, 2012
语种	英语
出版者	AMER DIABETES ASSOC
WOS记录号	WOS:000304490100019
内容类型	期刊论文
源URL	[http://ir.iccas.ac.cn/handle/121111/48585]
专题	中国科学院化学研究所
通讯作者	Rena, Graham
作者单位	1.Univ Dundee, Ninewells Hosp & Med Sch, Div Cardiovasc & Diabet Med, Dundee DD1 9SY, Scotland 2.Univ Dundee, Coll Life Sci, Med Res Council Prot Phosphorylat Unit, Dundee, Scotland 3.James Hutton Inst, Dundee, Scotland 4.Univ Dundee, Coll Life Sci, Div Cell Signalling & Immunol, Dundee, Scotland 5.Chinese Acad Sci, Inst Chem, CAS Key Lab Photochem, Beijing Natl Lab Mol Sci, Beijing 100080, Peoples R China
推荐引用方式 GB/T 7714	Logie, Lisa,Harthill, Jean,Patel, Kashyap,et al. Cellular Responses to the Metal-Binding Properties of Metformin[J]. DIABETES,2012,61(6):1423-1433.
APA	Logie, Lisa.,Harthill, Jean.,Patel, Kashyap.,Bacon, Sandra.,Hamilton, D. Lee.,...&Rena, Graham.(2012).Cellular Responses to the Metal-Binding Properties of Metformin.DIABETES,61(6),1423-1433.
MLA	Logie, Lisa,et al."Cellular Responses to the Metal-Binding Properties of Metformin".DIABETES 61.6(2012):1423-1433.