Cellular Responses to the Metal-Binding Properties of Metformin
نویسندگان
چکیده
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.
منابع مشابه
Density Functional Theory Calculations of Functionalized Carbon Nanotubes with Metformin as Vehicles for Drug Delivery
Drug delivery by nanomaterials is an active emergent research area and CNTs draws considerable potential application owing to its unique quasi one-dimensional structure and electronic properties. Single walled carbon nanotubes and carbon fullerenes can be used in drug delivery due to their mechanical and chemical stability. The past few years, increasing attention by several reputed groups has ...
متن کاملMetal ions binding study on human growth hormone by isothermal titration calorimetric method
The interaction of hGH with some metal ions ( ) at 27°C in NaC1 solution, 50 mM was studied using Isothermal titration calorimetry. There is a set of three identical and non-interacting binding sites for binding of all these metal ions, expect . The intrinsic association equilibrium constants () are not very different for and , and also their molar enthalpies of binding (KJ/mol for and KJ/mo...
متن کاملComparative Effects of Metformin and Glibenclamide on Aortic Reactivity to Vasodilator and Vasoconstrictor Agents in STZ-Induced Diabetic Rats
Background: Diabetes is an important risk factor for cardiovascular events. Endothelial dysfunction is the main reason cause of disability and death in diabetic patients and death. The present study investigates the effects of metformin and glibenclamide on vasoconstrictive and vasodilative responses in the diabetic rat aorta. Methods: Rats were divided into four experimental groups (con...
متن کاملEffects of Three Medicinal Plants Extracts in Experimental Diabetes: Antioxidant Enzymes Activities and Plasma Lipids Profiles in Comparison with Metformin
In the present study we aimed to evaluate the effects of methanolic extracts of the bulbs of Garlic (Allium sativum L., Alliaceae) and Persian shallot (Allium ascalonicum L., Alliaceae ) and leaves of Sage (Salvia officinalis L., Lamiaceae ), ASE, AAE and SOE respectively, on the antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) activities an...
متن کاملInfluence of Interface Thermal Resistance on Relaxation Dynamics of Metal-Dielectric Nanocomposite Materials under Ultrafast Pulse Laser Excitation
Nanocomposite materials, including noble metal nanoparticles embedded in a dielectric host medium, are interesting because of their optical properties linked to surface plasmon resonance phenomena. For studding of nonlinear optical properties and/or energy transfer process, these materials may be excited by ultrashort pulse laser with a temporal width varying from some femtoseconds to some hund...
متن کامل