The metabolic effects of chronic hypercortisolaemia were studied by administration of tetracosactrin-depot, 1 mg I.M. daily for 36-60 hr to normal subjects. Partial insulin and glucagon deficiency were induced at the end of the period by infusion of somatostatin, 100 micrograms/h for 210 min. Tetracosactrin alone induced a three fold rise in basal serum cortisol levels and fasting blood glucose concentration rose from 5.2 +/- 0.2 to 7.2 +/- 0.2 mmole/l (p less than 0.01) with a rise in fasting serum insulin from 5.2 +/- 1.2 to 13.1 +/- 1.9 mU/l (p less than 0.02). Concentrations of the gluconeogenic precursors lactate, pyruvate and alanine were also raised, but non-esterified fatty acid, glycerol and ketone body levels were unchanged. Somatostatin infusion caused a 30%-50% decrease in serum insulin and a 20%-60% decrease in plasma glucagon concentrations both before and after tetracosactrin administration. A similar rise in blood glucose concentration, relative to the saline control, occurred over the period of somatostatin infusion both with and without elevated cortisol levels. However, prior tetracosactrin administration caused a 100% greater rise in blood ketone body concentrations during infusion of somatostatin than was seen in the euadrenal state, despite similar plasma NEFA concentrations. Hypercortisolaemia causes hyperglycaemia and elevated gluconeogenic precursor concentrations but the associated rise in serum insulin concentrations limits lipolysis and ketosis. In insulin deficiency, a ketotic effort of glucocorticoid excess is evident which may be independent of lipolysis and occurs despite concurrent glucagon deficiency. These catabolic actions of cortisol are likely to be of major importance in the metabolic response to stress.