Diurnal concentrations of glucose, the major regulatory hormones, and selected biochemistries were measured serially throughout a 25-h period in 38 healthy type I diabetic patients, 25 patients with acute ketoacidosis, and 20 normal subjects. Poor glucose control, meal intolerance, and hypercortisolemia were the dominant abnormalities in the healthy diabetic subjects. Ketonemia due to elevated plasma beta-hydroxybutyrate concentrations without ketonuria (nitroprusside reaction) was a frequent finding in a group of poorly controlled diabetic subjects. In the patients with acute ketoacidosis, the dominant abnormalities were overproduction of epinephrine and cortisol. High glucagon and growth hormone concentrations were documented in about one-half of these patients. We conclude that (1) the hyperglycemia, meal intolerance, and abnormal ketone body metabolism seen in these patients are caused by inadequacies in their insulin regimens; (2) ketone body underutilization contributes to diabetic ketosis; (3) epinephrine and cortisol overproduction are important components of acute ketoacidosis; and (4) the complex hormone-metabolic interactions in type I diabetes can best be explained by a multihormonal hypothesis with the primary defect being loss of beta-cell function.