Stress-induced diabetic ketoacidosis is characterized by an elevation in stress hormone concentration. Whether metabolic decompensation induces or results from the secretion of stress hormones has not been examined. Our study examined the temporal relationship between the onset of stress (pyrogen-induced shaking chills and fever); the elevation in stress hormone concentation; and the rise in plasma glucose, ketone bodies, and nonesterified fatty acid concentration. Insulin deficiency, which may itself induce stress hormone secretion, was prevented by the continuous infusion of insulin (0.01 U/kg.h). Pyrogen administration induced malaise and fever in all diabetic volunteers and the rapid endogenous secretion of all stress hormones. The rise in plasma GH, catecholamines, and cortisol preceded the rise in plasma nonesterified fatty acid and ketone body concentrations by at least 30 min. The rise in plasma glucagon concentration preceded the rise in plasma glucose concentration by at lease 1 h. Thus, these studies support a primary role for stress hormones in initiating metabolic decompensation in stressed diabetic man.