The concept of leucine sensitive hypoglycemia, introduced by Cochrane in 1960, has been largely superseded by the recognition of congenital hyperinsulinism and its association, in some infants, with exaggarated insulin responses to amino acid secretogogues. We have identified a family with a syndrome of hyperinsulinism plus hyperammonemia (HI/HA) in which attacks of hypoglycemia occur after protein-containing meals. The index patient, a 5 yr old girl, presented at 9 mos of age with staring spells and was discovered to have hypoglycemia due to hyperinsulinism. Her 2 yr old sister was normoglycemic after a 14 hr fast at 4 mos of age, but also developed symptoms of hypoglycemia at 9 mos old and was diagnosed with hyperinsulinism. In both girls, fasting hypoglycemia was controlled with diazoxide, 10 mg/kg/d, but they continue to have symptomatic hypoglycemia 1-2 hr following high protein meals. Their father presented with similar staring spells at 1 yr old; he was diagnosed with “leucine sensitive hypoglycemia”. He was treated with diet alone and continues to have symptomatic hypoglycemia, especially after protein loads, 1-2 times a week. Our recent demonstration of dominantly-expressed mutations of glutamate dehydrogenase (GDH) in patients with HI/HA syndrome prompted reassessment of this family. Plasma ammonium concentrations in the three affecteds were 80-100 μmol/L vs. 35 μmol/L in the unaffected mother. All three affected had a single missense mutation that changed a serine to a proline at amino acid 448 of the mature GDH enzyme. This mutation is associated with a two-fold reduction in enzyme responsiveness to GTP, an important allosteric inhibitor of GDH. HI/HA patients with GDH mutations differ from the more common recessive defects of the β-cell sulfonylurea receptor: in addition to hyperammonemia they are not LGA at birth, have milder fasting hypoglycemia, and respond to diazoxide. The GDH mutation in this family seems particularly to induce sensitivity to protein loads, consistent with evidence that leucine stimulates insulin secretion by allosterically activating GDH to increase rates of glutamate oxidation.
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Glutamate dehydrogenase: Structure of a hyperinsulinism mutant, corrections to the atomic model, and insights into a regulatory site
Proteins: Structure, Function, and Bioinformatics (2019)