title: Insulin causes [Ca2+]i-dependent and [Ca2+]i-independent positive inotropic effects in failing human myocardium.
abstract: 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.
  
  
  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 degrees 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.
authors.affiliation: Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Göttingen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: von Lewinski
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bruns
authors.forename: Stefanie
authors.initials: S
authors.lastname: Walther
authors.forename: Harald
authors.initials: H
authors.lastname: Kögler
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003920:Diabetes Mellitus; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D007328:Insulin; D012964:Sodium; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium