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.