Modulation of Cardiomyocyte and Hepatocyte Bioenergetics by Biguanides Saeeda Almarzooqi 1* , Ali S. Alfazari 2 , Alia Albawardi 1 , Dhanya Saraswathiamma 1 , Hidaya Mohammed Abdul-Kader 2 , Sami Shaban 3 and Abdul-Kader Souid 4 1 Department of Pathology, UAE University, Al-Ain, Abu Dhabi, United Arab Emirates 2 Department of Medicine, UAE University, Al-Ain, Abu Dhabi, United Arab Emirates 3 Department of Medical Education, UAE University, Al-Ain, Abu Dhabi, United Arab Emirates 4 Department of Pediatrics, UAE University, Al-Ain, Abu Dhabi, United Arab Emirates * Corresponding author: Saeeda Almarzooqi, 1 Department of Pathology, UAE University, Al-Ain, Abu Dhabi, United Arab Emirates, Tel: +9-713-713-7471; Fax +9-713-767-2022; E-mail: saeeda.almarzooqi@uaeu.ac.ae Received date: Apr 08, 2014 Accepted date: Jun 17, 2014 Published date: Jun 20, 2014 Copyright: © 2014, Almarzooqi S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Biguanides (metformin, buformin and phenformin) have been developed for oral treatment of non-insulin- dependent diabetes mellitus. Metformin, the drug of choice in this class, controls blood glucose primarily by lowering hepatic gluconeogenesis (e.g., decreasing glucagon-mediated hepatic glucose output). Its mode-of-action, however, is more complex and may involve “refining” cellular bioenergetics (improving energy efficiency) in various cell types including myocytes. Buformin and phenformin presumably have similar mechanisms of action. The main purpose of this in vitro study was to assess the effects of these drugs on bioenergetics - cellular respiration (mitochondrial O 2 consumption) and ATP content - in tissue fragments from the heart muscle (cardiomyocytes) and liver (hepatocytes) of C57BL/6 mice. Cardiomyocyte respiration decreased by 10-26% in the presence of 100 µM metformin (p=0.093), buformin (p=0.028) or phenformin (p=0.015). Similar effects on cardiomyocyte respiration were noted with 1.0 mM drugs. Cardiomyocyte ATP, on the other hand, increased by 17-31% in the presence of 100 µM metformin (p=0.093), buformin (p=0.445) or phenformin (p=0.093). Hepatocyte respiration and ATP decreased by 11-26% and 8-25%, respectively in the presence of 1.0 mM drugs. Decreased respiration and ATP were also noted in hepatocytes exposed to 100 µM metformin for 1 ≤ t ≤ 6 hours (13% and 5%, respectively). Thus, the effects of biguanides on cardiomyocyte bioenergetics differed from that on hepatocyte bioenergetics. These findings suggest that biguanides regulate cardiomyocyte energy conversion, favoring better fuel efficiency (↓respiration/↑ATP). The drug effects in hepatocyte are ↓respiration/↓ATP, favoring less fuel production (↓hepatic gluconeogenesis). Biguanide activities in various tissues may be coupled. Keywords: Biguanides; Antidiabetic drugs; Metformin; Buformin; Phenformin; Cellular respiration; Cellular bioenergetics; Cellular ATP Introduction The oral antihyperglycemic drugs biguanides (guanyl-guanidines; H 2 N-CNH-NH-CNH-NH 2 ; e.g., metformin, buformin and phenformin) are powerful regulators of cellular bioenergetics [1,2]. These important compounds refine critical energy conversion processes within the cell, resulting in less demand for glucose production via hepatic gluconeogenesis [3-5]. Their activity spectrum, however, is complex and deserves further studies. For example, metformin (best-in-class and mostly widely used) has been shown to decrease 3'-5'-cyclic adenosine monophosphate (cAMP, thus, suppressing hepatic glucagon signaling), stimulate liver and muscle 5’- adenosine monophosphate-activated protein kinase (AMPK, catalyzes the reaction: AMP+ATP→2ADP), and inhibit AMP deaminase (catalyzes the reaction: AMP→IMP+NH 3 ) [6-8]. Inhibition of AMP deaminase increases cellular AMP that activates AMPK, thus, surging mitochondrial ADP and oxidative phosphorylation [5,9]. Consistently, metformin has been recently shown to augment cellular bioenergetics in the L6 myogenic cell line (rat skeletal muscle myoblasts) [10]. High concentrations of biguanides, however, have been shown to inhibit complex I of the respiratory chain [11-14]. Figure 1 summarizes the effects of biguanides on hepatocyte bioenergetics characteristics. Similar changes are seen in cardiomyocyte. Figure 1: Summary of effects of Biguindes on cardiomyocytes and hepatocytes. Abbreviations: AMPK: 5’-adenosine monophosphate-activated protein kinase; AMPD: AMP deaminase. This study investigated the effects of these drugs on cellular mitochondrial O 2 consumption (cellular respiration) and ATP content in cardiomyocytes and hepatocytes from C57BL/6 mice [15-17]. The main purpose of these experiments was to investigate the mode-of- action of biguanides by measuring cardiomyocyte and hepatocyte bioenergetics in the presence of the drugs. Almarzooqi et al., J Clin Toxicol 2014, 4:3 DOI: 10.4172/2161-0495.1000203 Research Article Open Access J Clin Toxicol ISSN:2161-0495 JCT, an open access journal Volume 4 • Issue 3 • 1000203 J o u r n a l o f C li n i c a l T o x i c o l o g y ISSN: 2161-0495 Journal of Clinical Toxicology