Two genetic forms of hyperinsulinemic hypoglycemia caused by dysregulation of glutamate dehydrogenase.

Glutamate dehydrogenase (GDH) has recently been shown to be involved in two genetic disorders of hyperinsulinemic hypoglycemia in children. These include the hyperinsulinism/hyperammonemia syndrome caused by dominant activating mutations of GLUD1 which interfere with inhibitory regulation by GTP and hyperinsulinism due to recessive deficiency of short-chain 3-hydroxy-acyl-CoA dehydrogenase (SCHAD, encoded by HADH1). The clinical manifestations of the abnormalities in pancreatic ß-cell insulin regulation include fasting hypoglycemia, as well as protein-sensitive hypoglycemia. The latter is due to abnormally increased sensitivity of affected children to stimulation of insulin secretion by the amino acid, leucine. In patients with GDH activating mutations, mild hyperammonemia occurs in both the basal and protein-fed state, possibly due to increased renal ammoniagenesis. Some patients with GDH activating mutations appear to be at unusual risk of developmental delay and generalized epilepsy, perhaps reflecting consequences of increased GDH activity in the brain. Studies of these two disorders have been carried out in mouse models to define the mechanisms of insulin dysregulation. In SCHAD deficiency, the activation of GDH is due to loss of a direct inhibitory protein-protein interaction between SCHAD and GDH. These two novel human disorders demonstrate the important role of GDH in insulin regulation and illustrate unexpectedly important reasons for the unusually complex allosteric regulation of GDH.