This Article Full Text Full Text (PDF) All Versions of this Article: 111/20/2588    most recent CIRCULATIONAHA.104.497461v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by von Lewinski, D. Articles by Pieske, B. Search for Related Content PubMed PubMed Citation Articles by von Lewinski, D. Articles by Pieske, B. Related Collections Contractile function Type 2 diabetes Calcium cycling/excitation-contraction coupling Heart failure - basic studies

(Circulation. 2005;111:2588-2595.)
© 2005 American Heart Association, Inc.

Heart Failure

Insulin Causes [Ca²⁺]_i-Dependent and [Ca²⁺]_i-Independent Positive Inotropic Effects in Failing Human Myocardium

Dirk von Lewinski, MD; Sebastian Bruns; Stefanie Walther; Harald Kögler, MD; Burkert Pieske, MD

From Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Göttingen, Germany.

Correspondence to Prof Dr Burkert Pieske, Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany. E-mail pieske{at}med.uni-goettingen.de

Received August 10, 2004; revision received December 20, 2004; accepted January 20, 2005.

Background— Insulin has been shown to exert positive inotropic effects in several in vitro and in vivo models, but signal transduction and substrate dependency remain unclear. We examined inotropic responses and signal transduction mechanisms of insulin in human myocardium.

Methods and Results— Experiments were performed in isolated trabeculae from end-stage failing hearts of 58 nondiabetic and 3 diabetic patients undergoing heart transplantation. The effect of insulin (0.3 and 3 IU/L) on isometric twitch force (37°C, 1 Hz) was tested in the presence of glucose or pyruvate as energetic substrate. Furthermore, intracellular Ca²⁺ transients (aequorin method), sarcoplasmic reticulum (SR) Ca²⁺ content (rapid cooling contractures), and myofilament Ca²⁺ sensitivity (semiskinned fibers) were assessed. In addition, potential signaling pathways were tested by blocking glycolysis, PI-3-kinase, protein kinase C, diacylglycerol kinase, insulin-like growth factor-1 receptors, or transsarcolemmal Ca²⁺ entry via the Na⁺/Ca²⁺ exchanger. Insulin exerted concentration-dependent and partially substrate-dependent positive inotropic effects. The phosphatidylinositol-3-kinase inhibitor wortmannin and the Na²⁺/Ca²⁺ exchanger reverse-mode inhibitor KB-R7943 completely or partially prevented the functional effects of insulin. In contrast, insulin-like growth factor-1 receptor blockade, protein kinase C inhibition, and diacylglycerol kinase blockade were without effect. The inotropic response was associated with increases in intracellular Ca²⁺ transients, SR Ca²⁺ content, and increased myofilament Ca²⁺ sensitivity.

Conclusions— Insulin exerts Ca²⁺-dependent and -independent positive inotropic effects through a phosphatidylinositol-3-kinase–dependent pathway in failing human myocardium. The increased [Ca²⁺]_i originates at least in part from enhanced reverse-mode Na⁺/Ca²⁺ exchange and consequently increased SR-Ca²⁺ load. These nongenomic functional effects of insulin may be of clinical relevance, eg, during insulin-glucose-potassium infusions.

Key Words: insulin • calcium • heart failure • myocardium • contractility

This article has been cited by other articles:

				M. C. Villa-Abrille, A. Sidor, and B. O'Rourke Insulin Effects on Cardiac Na+/Ca2+ Exchanger Activity: ROLE OF THE CYTOPLASMIC REGULATORY LOOP J. Biol. Chem., June 13, 2008; 283(24): 16505 - 16513. [Abstract] [Full Text] [PDF]

				S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]

				R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]

				A. M. Ranasinghe, C. J. McCabe, D. W. Quinn, S. R. James, D. Pagano, J. A. Franklyn, and R. S. Bonser How Does Glucose Insulin Potassium Improve Hemodynamic Performance?: Evidence for Altered Expression of Beta-Adrenoreceptor and Calcium Handling Genes Circulation, July 4, 2006; 114(1_suppl): I-239 - I-244. [Abstract] [Full Text] [PDF]

				A. M. Ranasinghe, D. W. Quinn, D. Pagano, N. Edwards, M. Faroqui, T. R. Graham, B. E. Keogh, J. Mascaro, D. W. Riddington, S. J. Rooney, et al. Glucose-Insulin-Potassium and Tri-Iodothyronine Individually Improve Hemodynamic Performance and Are Associated With Reduced Troponin I Release After On-Pump Coronary Artery Bypass Grafting Circulation, July 4, 2006; 114(1_suppl): I-245 - I-250. [Abstract] [Full Text] [PDF]

				C.-H. Hsu, C.-I Lin, J. Wei, D. von Lewinski, S. Bruns, S. Walther, H. Kogler, and B. Pieske Letter Regarding Article by von Lewinski et al, "Insulin Causes [Ca2+]i-Dependent and [Ca2+]i-Independent Positive Inotropic Effects in Failing Human Myocardium" * Response Circulation, December 20, 2005; 112(25): e367 - e367. [Full Text] [PDF]