Although free fatty acids are the dominant substrate for myocardial cells under aerobic conditions, under ischemic conditions, a shift occurs toward anaerobic glycolysis, and long-chain free fatty acids can have deleterious effects. As stated by Hendrickson et al, 11 free fatty acids can result in “accumulation of toxic intermediates of free fatty acid metabolism..., inhibition of glucose utilization, particularly glycolysis during ischemia/and or reperfusion, and uncoupling of oxidative metabolism from electron transfer.” Because enhancement of glycolysis during ischemia has been shown to reduce ischemic damage, 12 factors that inhibit glycolysis, such as free fatty acids, would be expected to have a deleterious effect during ischemia/reperfusion. Free fatty acid metabolism in this setting also results in higher production of lactate and hydrogen ions, which can reduce cardiac contractility, cause diastolic dysfunction, and reduce the heart’s threshold for arrhythmias. Rogers et al13 reported a study of 70 patients with acute myocardial infarction in whom an infusion of GIK caused a dramatic fall in free fatty acid levels. Compared with a matched control group of patients, the mortality rate was reduced 4-fold in those receiving GIK.

Although an earlier theory held that GIK worked by both increasing the availability and facilitating the entry of glucose into the cardiomyocyte, this “oversupply” of glucose (depending on the GIK formulation used) can lead to acute elevation of glucose compared with the pretreatment level. Hyperglycemia is now recognized to be associated with a host of negative cardiovascular phenomena, including abnormal vascular responsiveness, thrombus formation, increased platelet aggregation, and inflammation, 14, 15 as well as having direct effects on cardiac systolic and diastolic function. As will be discussed later, any benefit due to GIK could be counterbalanced or neutralized by the hyperglycemia that often accompanies GIK administration, particularly when given in high-dose formulation. In contrast, insulin is thought to have an antiinflammatory, antioxidant effect, as well as a vasodilatory effect through the release of nitric oxide and increased expression of endothelial nitric oxide synthase. Insulin also inhibits platelet aggregation and has a profibrinolytic affect. The mechanisms by which insulin may have a cardioprotective effect are complex and are shown in further detail in Figure 1. A glucose and insulin infusion causes potassium to move intracellularly, so the addition of exogenous potassium helps prevent hypokalemia and helps to electrically stabilize the myocardial cell membrane to avoid arrhythmias.