Postprandial and postabsorptive glucose metabolism was studied in a 3-yr-old girl with leprechaunism by substrate and hormonal measurements and by quantifying hepatic glucose output during continuous infusion of D-[6-6-2H2]-glucose. Hepatic glucogen content and the activity of glycogen synthase and phosphorylase were also measured in the post-prandial state on a separate occasion. During the 4-h postprandial state, plasma glucose, alanine, lactate, beta-hydroxybutyrate, and glycerol were normal, as were hepatic glycogen, glycogen synthase, phosphorylase, and hepatic glucose output of 7.5 mg kg-1 min-1. Intravenous injection of glucagon (30 micrograms kg-1) caused an immediate almost 3-fold rise in glucose production consistent with brisk glycogenolysis. During the 8- to 12-h postabsorptive state, however, the patient had elevated levels of glycerol (330-508 microM) and beta-hydroxybutyrate (3291-3801 microM) and decreased levels of glucose 24-29 mg/dl) and alanine (121-135 microM) consistent with a much longer period of fasting in the normal child. Furthermore, hepatic glucose output was reduced to 3.9 mg kg-1 min-1, and iv glucagon injection failed to increase this rate; both of these observations are consistent with a hepatic state generally found only later in fasting in the normal child. From these observations we conclude that the hypoglycemia reported in the leprechaunism syndrome is due to an accelerated fasting state secondary to insulin resistance. As with long-fasted, glycogen-depleted normal children, gluconeogenesis alone is often not capable of adequately meeting the child's large noninsulin-dependent cerebral glucose requirements.