REVIEW ARTICLE

Potential beneficial mechanisms of insulin

(glucose-potassium) in acute myocardial

infarction I.C.C. van der Horst, F. Zijlstra

In the time-span ofalmost a century, a large amount of experimental evidence has been accumulated that underlines the importance of glucose metabolism during ischaemia/rrfusion of the heart. As early as 1912, Goulston suggested that treatment with glucose could be beneficial in several heart diseases.1 The first experimental results on the mehanical effects of insulin and glucose in the isolated heart were reported by Visscher and Muller in 1926.2 In 1935, Evans and colleagues showed that the uptake of glucose is increased in the ischaemic myocardium.3 Almost 30 years later, Sodi-Pallares and colleagues suggested that metabolic interference during myocardial ischaemia with GIK infusion decreased electrocardiographic signs of ischaemia.4 They also showed that glucoseinsulin-potassium (GIK) infusion resulted in a lower occurrence of arrhythmias.4 They attributed this effect mainly to the influx of potassium in ischaemic cardiomyocytes.5 In order to fiurther stimulate potassium transport into the cell, insulin was administered.6 Consequently, the rise of intercellular calcium is curtailed by the influx of potassium and so the incidence of arrhythmias is reduced.7'10 However, systemic infusion of insulin stimulates the uptake of glucose in many celltypes," which may result in hypoglycaemic episodes.'2 Consequently, it is not possible to administer potassium and insulin in high concentrations without adding glucose. Interventions in the glucose metabolism in the clinical arena, whether or not used to correct acute hyperglycaenmia, encompass three potentially effective elements: glucos ,insulin and potassium. (Netd HeartJ2005;6:233-8.) I.C.C. van der Horst F. ZQlsa Departrnent of Cardiology, Thoraxcentre, University Medical Centre Groningen

Correspondence to: I.C.C. van der Horst Department of Cardiology, University Medical Centre Groningen, P0 Box 30.001, 9700 RB Groningen E-mail: [email protected]

Netherlands Heart Journal, Volume 13, Number 6, June 2005

Key words: insulin, glucose, mechanism, metabolism, myocardial infarction Metabolism during myocardlal Ischaemia Ischaemia induces many changes in the heart's metabolism, including shifts from aerobic fatty acid metabolism to anaerobic glycolysis, which provides energy for critical myocardial cellular ftmction (figure 1)."3-' During most clinical ischaemic syndromes, including acute myocardial infarction (MI), residual or collateral blood flow usually provides at least 10% of the normal level ofperfusion to a significant portion ofthe ischaemic myocardium. This small amount ofperfusion provides such a level of oxygen delivery that oxidative adenosine triphosphate (ATP) synthesis from both glucose and free fatty acids greatly exceeds ATP synthesis from anaerobic glycolysis.'6"17 Thus, a mixture of aerobic and anaerobic metabolism occurs. With progressively severe ischaemia, anaerobic glycolysis becomes a progressively more important source of energy for a limited amount of ATP, which may or may not suffice to support the most essential cellular functions. Glycogen is rapidly mobilised during ischaemia, and reduced glycogen concentrations impair force development, calcium release, and contractile function.'8 Key intermediates of the Krebs cycle are also depleted, which may impair energy transfer.'9 The ischaemia-mediated increase in glucose utilisation is characterised by enhanced rates of exogenous glucose uptake in vivo, which requires greater rates of transport across the plasma membrane.20'2' Of the seven reported members of the facilitative glucose transporter family, glucose transporter (GLUT)-4 and GLUT-1 are the primary forms expressed in adult mammalian heart muscle.22 During low-flow ischaemia the expression ofGLUT-4 is doubled.23 Islin inreases the translocation of GLUT-4 via a pathway mediated by phosphatidylinositol 3-kinase (PI3-K). During ischaemia and hypoxia GLUT-4 translocation is stimulated through a PI3-K-independent pathway. Adenosine monophospate (AMP)-activated protein kinase plays a role in the translocation during ischaemia.24 Opie proposed the glucose hypothesis: the enhanced uptake and metabolism of glucose delays cellular

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Potential beneficial mechanisms of insulin (glucose-potassium) in acute myocardial infarction

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damage.2526 Glucose utilisation during ischaemia prevents the breakdown of glycogen stores and leads to increased net intramyocardial glycogen synthesis, thereby limiting enzymatic infarct size and contracture.'727 Two studies showed that infusion of GIK in isolated hearts with regional ischaemia resulted in decreased infarct size, increased high-energy phosphate levels, and improved ventricular function.28'29 Acute MI patients treated with GIK also showed better stress tolerance and ischaemic threshold improvement, analysed by technetium-99m-tetrofosmin-gated SPECT.30 The improved energetic profile results in improved systolic and diastolic function during ischaemia and reperfusion, as well as coronary vasodilatation.'7 Also, glucose uptake has been shown to reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes.3' The observed benefits of GIK infusion have been attributed to a number of mechanisms, which are summarised in table 1 and in part discussed. Glucose

The potential positive effects of glucose are based on the fact that glucose is a source of energy for cells.32 The uptake of glucose into the cell is influenced by insulin, 234

although there is also an insulin-independent transport of glucose.33 It has been observed that AMP-activated protein kinase is responsible for activation of glucose uptake and glycolysis during low-flow ischaemia.34 During MI, low-flow perfusion of the ischaemic area is often present, making the administration glucose useful.'8 In an experimental study it was observed that a high glucose concentration stimulated translocation of GLUT-4.35 It was already known that the combination of glucose and insulin is more effective than either one alone in stimulating glycolysis under ischaemic conditions.'7 Administering glucose can prevent insulin-induced hypoglycaemia. If the hypoglycaemic episodes persist or if they are severe (