The effect of adrenalectomy (ADX) on glucose tolerance and insulin secretion was examined in conscious mice made obese by a single injection of gold thioglucose (GTG). To facilitate such a study a chronic jugular catheter was implanted into the mice at the time of performing the ADX or sham-ADX. One week after ADX, the body weight (GTG-obese+sham-ADX, 35.6 +/- 0.6 g; GTG-obese+ADX, 33.1 +/- 0.6 g; P < 0.05) and glycogen content of the liver (GTG-obese+sham-ADX, 2.4 +/- 0.2 mumol/liver; GTG-obese+ADX, 1.6 +/- 0.1 mumol/liver; P < 0.05) of GTG-injected mice were reduced. Plasma glucose concentrations, in both the overnight fasted state and in response to an intravenous glucose load were also reduced following ADX of GTG-obese mice, but not to the level of the sham-ADX control mice. However, ADX completely normalized plasma insulin concentrations in both the basal state and also in response to a glucose load, as indicated by the finding that the integrated insulin secretory response of the ADX GTG-obese mice was not different from that of sham-ADX control mice (control+sham-ADX, 192 +/- 5 min.microU/ml; GTG-obese+ADX, 196 +/- 10 min.microU/ml). The effects of ADX on carbohydrate metabolism were not restricted to GTG-injected mice, as ADX of control mice decreased fasting plasma glucose levels and reduced liver glycogen and plasma insulin concentrations. The normalization of insulin release in ADX GTG-obese mice occurred while these mice were still obese and glucose intolerant. This suggests that the decreased insulin release was not due solely to an ADX-induced improvement in insulin sensitivity and/or weight loss. Removal of central glucocorticoid effects on the parasympathetic stimulation of insulin release may play a role in the reduced insulin release observed after ADX of obese and control mice, although peripheral effects of glucocorticoid deficiency on glycogen synthesis in the liver may also influence whole animal glucose homeostasis.