Cellular Responses to the Metal-Binding Properties of Metformin
Open Access
- 14 May 2012
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 61 (6), 1423-1433
- https://doi.org/10.2337/db11-0961
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.Keywords
This publication has 41 references indexed in Scilit:
- Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signalingProceedings of the National Academy of Sciences, 2010
- Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy stateJCI Insight, 2010
- Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK ActivationCell Metabolism, 2010
- Cardiac Copper Deficiency Activates a Systemic Signaling Mechanism that Communicates with the Copper Acquisition and Storage OrgansCell Metabolism, 2010
- Metformin, Independent of AMPK, Inhibits mTORC1 in a Rag GTPase-Dependent MannerCell Metabolism, 2010
- Rosiglitazone Stimulates Nitric Oxide Synthesis in Human Aortic Endothelial Cells via AMP-activated Protein Kinase*Journal of Biological Chemistry, 2008
- Studies on antidiabetic agents. I. Synthesis of 5-(4-(2-methyl-2-phenylpropoxy)-benzyl)thiazolidine-2,4-dione (AL-321) and related compounds.CHEMICAL & PHARMACEUTICAL BULLETIN, 1982
- Hypoglycemic Agents. III.1—3 N1-Alkyl- and AralkylbiguanidesJournal of the American Chemical Society, 1959
- Über Biguanide, I.: Zur Konstitution der Schwermetall‐Komplexverbindungen des BiguanidsBerichte der deutschen chemischen Gesellschaft (A and B Series), 1929
- Ueber BiguanidEuropean Journal of Inorganic Chemistry, 1879