Glucose-transporter–mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients Dirk von Lewinski a, ⁎ , Peter P. Rainer a , Robert Gasser a , Marie-Sophie Huber a , Mounir Khafaga a , Bastian Wilhelm b , Tobias Haas c , Heinrich Mächler d , Ulrich Rössl a , Burkert Pieske a a Department of Cardiology, Medical University Graz, 8036 Graz, Austria b Department of Cardiology and Pneumology, University of Göttingen, 37099 Göttingen, Germany c Merck KGaA, 64293 Darmstadt, Germany d Division of Cardiac Surgery, Medical University Graz, 8036 Graz, Austria Received 7 March 2009; accepted 26 October 2009 Abstract Insulin causes inotropic effects via Ca 2+ -dependent and Ca 2+ -independent pathways. The latter one is potentially glucose dependent. We examined inotropic responses and signal transduction of insulin in human atrial myocardium of diabetic and nondiabetic patients to test for the role of glucose transporters. Experiments were performed in isolated atrial myocardium of 88 patients undergoing cardiac surgery and 28 ventricular muscle samples of explanted hearts. Influence of insulin (0.02 μmol/L) on isometric twitch force was examined with and without blocking glucose transporter (GLUT) 4 translocation (latrunculin), sodium-coupled glucose transporter (SGLT) 1 (phlorizin, T-1095A), or PI3-kinase (wortmannin). Experiments were performed in Tyrode solution containing glucose or pyruvate as energetic substrate. Messenger RNA expression of glucose transporters (GLUT1, GLUT4, SGLT1, SGLT2) was analyzed in atrial and ventricular myocardium of both diabetic and nondiabetic patients. Developed force increases after insulin (to 117.8% ± 2.4% and 115.8% ± 1.9%) in trabeculae from patients with and without diabetes. Inotropic effect was reduced after displacing glucose with pyruvate as well as after PI3-kinase inhibition (to 103% ± 2%) or inhibition of glucose transporters GLUT4 (to 105% ± 2%) and SGLT1 (phlorizin to 106% ± 2%, T-1095A to 105% ± 2%), without differences between the 2 groups. In glucose-free pyruvate-containing solution, only inhibition of PI3-kinase but not blocking glucose transporters resulted in further inhibitory effects. Messenger RNA expression did not show significant differences between patients with or without diabetes. Insulin exerts positive inotropic effects in human atrial myocardium. These effects are mediated via a PI3-kinase–sensitive and a glucose-transport–sensitive pathway. Differences in functional effects or messenger RNA expression of glucose transporters were not detectable between patients with and without diabetes. © 2010 Published by Elsevier Inc. 1. Introduction Diabetes is a major risk factor for cardiovascular morbidity, and patients with chronic heart disease often suffer from insulin resistance, diabetes, or altered glucose metabolism [1,2]. The onset of insulin resistance has been shown to coincide with the transition of hypertrophy to dilatation [3]. Whole-body insulin resistance is prevalent in congestive heart failure patients with either ischemic heart failure or idiopathic dilated cardiomyopathy [4,5]. According to a recent analysis from the Framingham Heart Study, the proportion of cardiovascular disease attributable to diabetes has substantially increased over the past decades [6]. Besides its known metabolic characteristics, insulin exerts functional effects in myocardial tissue, that is, inotropic effects. These functional effects of insulin have been tested in many models, leaving controversial data of either positive inotropic effects [7-13] or no functional effects [14-16]. Differences in functional effects between control and diabetic animals have been described in various models including lamb [17], rats [9,18], and humans [10,19]. Nevertheless, we have not observed significant differences on developed force in a small substudy in failing human myocardium [13]. Available online at www.sciencedirect.com Metabolism Clinical and Experimental 59 (2010) 1020 – 1028 www.metabolismjournal.com ⁎ Corresponding author. Abteilung Kardiologie, Medizinische Univer- sität Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Tel.: +43 316 385 80684; fax: +43 316 385 3733. E-mail address: dirk.von-lewinski@medunigraz.at (D. von Lewinski). 0026-0495/$ – see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.metabol.2009.10.025