To assess the metabolic effects of myocardial substrate alteration In patients with coronary artery disease, glucose-insulin-potassium solution was administered intravenously for 30 minutes to 14 men with stable angiographically documented coronary artery disease. The glucose-insulin-potassium solution (300 g of glucose, 50 units of regular insulin and 80 mEq of potassium chloride per liter of water) was infused at a constant rate in each patient, but individual infusion rates ranged from 0.013 to 0.032 ml/kg per min (4 to 10 mg glucose/kg per min) in the 14 patients. Simultaneous arterial and coronary sinus samples were obtained at 15 minute intervals during a stable 30 minute control period and again at 15 minute intervals during the infusion; samples were assayed for glucose, lactate, free fatty acid and oxygen content. In all 14 patients, during the glucose-insulin-potassium infusion, arterial glucose and lactate increased and arterial free fatty acid levels fell; the magnitude of the changes in arterial lactate and free fatty acids as related to the rate of infusion. Arterial-coronary sinus differences (A-Cs) for glucose, lactate and free fatty acid levels correlated with the arterial concentrations of these substrates (r = 0.66, 0.87 and 0.79, respectively). Regression analyses demonstrated myocardial thresholds for the uptake of these substrates as follows: glucose 79 mg/100 ml; lactate 300 μmole/liter; and free fatty acids 100 to 200 μEq/liter. Finally and most importantly, the reduction in A-Cs oxygen values after glucose-insulin-potassium infusion correlated with the reduction in A-Cs free fatty acid levels (r = 0.64, P < 0.0001). This observation suggests that, in patients with coronary artery disease, glucose-insulin-potassium infusion may significantly diminish myocardial oxygen requirements by reduction of myocardial free fatty acid utilization and simultaneous enhancement of myocardial carbohydrate utilization. Myocardial substrate availability may be an important determinant of myocardial oxygen demand in patients with coronary artery disease. Infusion of glucose-insulin-potassium solution has the potential to alter myocardial substrate availability, thus improving the balance between myocardial oxygen demand and supply. © 1975.