Abstract 529 Endocrinology & Diabetes III Platform, Sunday, 5/2

A form of congenital hyperinsulinism associated with hyperammonemia (HI/HA) has recently been linked to mutations in the gene for glutamate dehydrogenase (GDH). The defective GDH escapes normal inhibition by GTP resulting in excessive glutamate oxidation and increased insulin secretion. GDH is also allosterically activated by leucine, an amino acid which induces hypoglycemia in individuals with "leucine-sensitive hypoglycemia". We postulated that children with HI/HA would have exaggerated leucine acute insulin responses (AIRs) and that this test could differentiate HI/HA from other forms of congenital HI. We compared leucine AIRs in four HI/HA children, ages 2 months to 10 years, to a group of eight healthy adult controls and to two disease control groups, the first consisting of three children ages 4 to 12 years with HI due to sulfonylurea defects (SUR1), and the second composed of two children undergoing evaluation for suspected hypoglycemia (non-HI), ages 13 months and 3.5 years. The leucine AIR was performed using an intravenous bolus of L-leucine, 15 mg/kg over 1 minute. Plasma insulin levels were measured at -10, -5, 0, +1, +3, and +5 minutes. The leucine AIR was defined as the mean increase in insulin at 1 and 3 minutes. Blood glucose was monitored during the study, and when necessary, dextrose was infused to maintain glucose levels of 60-90 mg/dL. The control group had no response to leucine: AIR of 1 ± 1 µIU/mL (mean ± SEM, 95% CI of -2 to +4 µIU/mL). In contrast, HI/HA children briskly responded to leucine: AIR 38 ± 20 µIU/mL (p = 0.004), and their range of 9.1 to 98 µIU/mL did not overlap the 95% CI for controls. Both disease control groups exhibited little response to leucine: SUR1 AIR range was 0 to 7 µIU/mL, and non-HI AIR range was 3 to 5 µIU/mL. The leucine AIR is a safer and simpler means of investigating leucine sensitivity than the traditional oral or intravenous leucine tolerance tests. A positive leucine AIR appears to be specific for the HI/HA form of congenital HI. We speculate that GDH mutations may account for most previously reported cases of "leucine-sensitive hypoglycemia".