title: Cellular responses to the metal-binding properties of metformin.
abstract: 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 π-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.
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Logie
authors.forename: Jean
authors.initials: J
authors.lastname: Harthill
authors.forename: Kashyap
authors.initials: K
authors.lastname: Patel
authors.forename: Sandra
authors.initials: S
authors.lastname: Bacon
authors.forename: D Lee
authors.initials: DL
authors.lastname: Hamilton
authors.forename: Katherine
authors.initials: K
authors.lastname: Macrae
authors.forename: Gordon
authors.initials: G
authors.lastname: McDougall
authors.forename: Huan-Huan
authors.initials: HH
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Xue
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Alan R
authors.initials: AR
authors.lastname: Prescott
authors.forename: Graham
authors.initials: G
authors.lastname: Rena
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism*; D005947:Glucose / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014266:Trientine / Q000494:pharmacology
chemical_list: D002614:Chelating Agents; D007004:Hypoglycemic Agents; D003300:Copper; D008687:Metformin; D019893:Ribosomal Protein S6 Kinases; D000263:Adenylate Kinase; D005947:Glucose; D014266:Trientine