title: Acute insulin responses to leucine in children with the hyperinsulinism/hyperammonemia syndrome.
abstract: Mutations of glutamate dehydrogenase cause the hyperinsulinism/hyperammonemia syndrome by desensitizing glutamate dehydrogenase to allosteric inhibition by GTP. Normal allosteric activation of glutamate dehydrogenase by leucine is thus uninhibited, leading us to propose that children with hyperinsulinism/hyperammonemia syndrome will have exaggerated acute insulin responses to leucine in the postabsorptive state. As hyperglycemia increases beta-cell GTP, we also postulated that high glucose concentrations would extinguish abnormal responsiveness to leucine in hyperinsulinism/hyperammonemia syndrome patients. After an overnight fast, seven hyperinsulinism/hyperammonemia syndrome patients (aged 9 months to 29 yr) had acute insulin responses to leucine performed using an iv bolus of L-leucine (15 mg/kg) administered over 1 min and plasma insulin measurements obtained at -10, -5, 0, 1, 3, and 5 min. The acute insulin response to leucine was defined as the mean increase in insulin from baseline at 1 and 3 min after an iv leucine bolus. The hyperinsulinism/hyperammonemia syndrome group had excessively increased insulin responses to leucine (mean +/- SEM, 73 +/- 21 microIU/ml) compared with the control children and adults (n = 17) who had no response to leucine (1.9 +/- 2.7 microU/ml; P < 0.05). Four hyperinsulinism/hyperammonemia syndrome patients then had acute insulin responses to leucine repeated at hyperglycemia (blood glucose, 150-180 mg/dl). High blood glucose suppressed their abnormal baseline acute insulin responses to leucine of 180, 98, 47, and 28 microU/ml to 73, 0, 6, and 19 microU/ml, respectively. This suppression suggests that protein-induced hypoglycemia in hyperinsulinism/hyperammonemia syndrome patients may be prevented by carbohydrate loading before protein consumption.
authors.affiliation: Division of Endocrinology, The Children's Hospital of Philadelphia, and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kelly
authors.forename: D
authors.initials: D
authors.lastname: Ng
authors.forename: R J
authors.initials: RJ
authors.lastname: Ferry
authors.forename: A
authors.initials: A
authors.lastname: Grimberg
authors.forename: S
authors.initials: S
authors.lastname: Koo-McCoy
authors.forename: P S
authors.initials: PS
authors.lastname: Thornton
authors.forename: C A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D000641:Ammonia / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003981:Diazoxide; D005260:Female; D005969:Glutamate Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D022124:Hyperammonemia / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D006946:Hyperinsulinism / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D007223:Infant; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007930:Leucine; D008297:Male; D017354:Point Mutation; D013577:Syndrome
chemical_list: D001786:Blood Glucose; D007328:Insulin; D000641:Ammonia; D005969:Glutamate Dehydrogenase; D007930:Leucine; D003981:Diazoxide