Muscle glycogen and plasma glucose are oxidized by skeletal muscle to supply the carbohydrate energy needed to exercise strenuously for several hours (i.e., 70% maximal O2 consumption). With increasing exercise duration there is a progressive shift from muscle glycogen to blood glucose. Blood glucose concentration declines to hypoglycemic levels (i.e., 2.5 mmol/L) in well-trained cyclists after approximately h of exercise and this appears to cause muscle fatigue by reducing the contribution of blood glucose to oxidative metabolism. Carbohydrate feeding throughout exercise delays fatigue by 30-60 min, apparently by maintaining blood glucose concentration and the rate of carbohydrate oxidation necessary to exercise strenuously. Carbohydrate feedings do not spare muscle glycogen utilization. Very little muscle glycogen is used for energy during the 3-4-h period of prolonged exercise when fed carbohydrate, suggesting that blood glucose is the predominant carbohydrate source. At this time, exogenous glucose disposal exceeds 1 g/min (i.e., 16 mg.kg-1.min-1) as evidenced by the observation that intravenous glucose infusion at this rate is required to maintain blood glucose at 5 mmol/L. However, at this time these cyclist cannot exercise more intensely than 74% of maximal O2 consumption, suggesting a limit to the rate at which blood glucose can be used for energy. It is important to realize that carbohydrate supplementation during exercise delays fatigue by 30-60 min, but does not prevent fatigue. In conclusion, fatigue during prolonged strenuous exercise is often due to inadequate carbohydrate oxidation. This is partly a result of hypoglycemia, which limits carbohydrate oxidation and causes muscle fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)