Pheochromocytoma, a neuroendocrine tumor, is often associated with hyperglycemia. To investigate the underlying pathogenetic mechanisms, five patients (3 women and 2 men, aged 49+/-2.5, mean+/-SD) with benign adrenal pheochromocytoma were studied with an oral glucose tolerance test (OGTT) and the euglycaemic clamp technique. They were studied preoperatively without taking any medication (stage I), after taking an alpha adrenergic receptor blocking agent (stage II), after taking both an alpha and a beta adrenergic receptor blocking agent (stage III), and after surgical removal of the tumor (stage IV). Before any treatment, fasting blood glucose levels and glucose levels during the OGTT were pathologic in all patients. In all patients, mean glucose levels of the OGTTs performed at the three preoperative stages of the study were significantly higher than those of the OGTT performed postoperatively (ANOVA, alpha<0.05). Insulin levels during the OGTTs performed preoperatively peaked at 90 min while postoperatively they peaked at 60 min. No statistically significant difference was found among mean insulin levels during the OGTTs performed at all stages of the study. The clamp-based insulin sensitivity index (SI) improved progressively from stage I to IV of the study (ANOVA, alpha<0.05) (SIs of stages I, II, III, and IV were, respectively, 3.23+/-0.9 (mean+/-SE), 3.79+/-0.7, 4.67+/-0.3, 6.38+/-1 (10(-4) dl/kg x min per microU/ml)). In conclusion, the pheochromocytoma-associated metabolic alterations of glucose homeostasis improved substantially only after removal of the tumor. The administration of alpha and beta adrenergic receptor blocking agents resulted in a slight but statistically significant improvement in glucose utilization whereas it completely normalized the cardiovascular manifestations of the disease. Thus, it is possible that either the dose of the adrenergic receptor blocking agent needed to control cardiovascular manifestations of pheochromocytoma is different than that needed for glucose metabolism normalization, or that other pheochromocytoma-associated factors may influence directly and/or indirectly carbohydrate homeostasis.