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).
Hyperinsulinemia associated with non-ketotic hypoglycemia is observed in patients with mutated β-oxidation enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase (HADHSC).
Autosomal recessive mutations in the HADHSC gene (encoding the enzyme short-chain L-3-hydroxyacyl-CoA dehydrogenase) have been linked to defects in fatty acid oxidation and hyperinsulinism.
In contrast to focal islet-cell hyperplasia, always sporadic to our knowledge, diffuse hyperinsulinism is a heterogeneous disorder involving several genes, various mechanisms of pathogenic mutations and different transmissions: (i) channelopathy involving the genes encoding the sulphonylurea receptor (SUR1) or the inward-rectifying potassium channel (Kir6.2) in recessively inherited HI or more rarely dominantly inherited HI; (ii) metabolic disorders implicating the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) enzyme inrecessively inherited HI, the glucokinase gene (GK), the glutamate dehydrogenase gene (GLUD1) when hyperammonemia is associated, dominant exercise-induced HI with still-unknown mechanism, and more recently the human insulin receptor gene in dominantly inherited hyperinsulinism.