Cellular Responses to the Metal-Binding Properties of Metformin

• DOI: 10.2337/db11-0961
• Publication Date: 2012-04-10T02:06:35Z
• Authors: Lisa Logie; Jean Harthill; Kashyap Patel; Sandra Bacon; D. Lee Hamilton; Katherine Macrae; Gordon McDougall; Huan-Huan Wang; Lin Xue; Hua Jiang; Kei Sakamoto; Alan R. Prescott; Graham Rena
• Keywords: Biguanide; AMP-Activated Protein Kinase; Pioglitazone

In recent decades, the antihyperglycemic biguanide metformin has been used extensively in treatment of type 2 diabetes, despite continuing uncertainty over its direct target. this article, using two independent approaches, we demonstrate that cellular actions are disrupted by interference with metal-binding properties, which have known for a century but little studied biologists. We copper sequestration opposes not only on AMP-activated protein kinase (AMPK)-dependent signaling, also S6 phosphorylation. Biguanide/metal interactions stabilized extensive π-electron delocalization and investigating analogs metformin; provide evidence intrinsic property enables biguanides to regulate AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration, binding. contrast, regulation phosphorylation is prevented modification metal-liganding groups structure, supporting data AMPK regulated independently biguanides. Additional studies pioglitazone suggest targeted both these clinically important drugs. Together, results effects depend their properties. This link may illuminate better understanding molecular mechanisms enabling drug action.