Emergency therapy of sulfonylurea overdoses with glucose is often unsatisfactory because glucose stimulates insulin release and initiates a need for escalating quantities of hypertonic glucose to maintain normoglycemia. We tested the hypothesis that octreotide, an analog of somatostatin, would reverse hyperinsulinemia induced by a sulfonylurea overdose. Eight normal subjects received glipizide (1.45 mg/kg) on three occasions. Within 3 h, all subjects became hypoglycemic (< 50 mg/dL) and were initially treated with 50% dextrose followed by 1) dextrose infusion, 2) octreotide (30 ng/kg.min, iv), or 3) diazoxide (300 mg, iv, every 4 h). Euglycemia (85 mg/dL) was maintained with supplementary dextrose in treatment limbs 2 and 3. Insulin concentrations were 4-5 times greater with dextrose alone or in combination with diazoxide than with octreotide (P < 0.01). Dextrose requirements during diazoxide or dextrose alone were not different, but were both greater than those during octreotide treatment (P < 0.0001). All therapies were stopped at 13 h. Glucose levels remained above 3.6 mmol/L (65 mg/dL) in six of eight subjects receiving octreotide for the remaining 4 h. Glucose fell to below 3.6 mmol/L within 1.5 h of stopping either dextrose or diazoxide in each subject. Overall, octreotide reduced and in four of eight subjects entirely eliminated the need for exogenous glucose after a large overdose of glipizide. We conclude that octreotide is safe and effective and should be strongly considered as a logical therapeutic alternative for this metabolic emergency.