Molecular mechanisms of congenital hyperinsulinism

Abstract

Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic β-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin-sensitive tissues, such as the muscle, liver and adipose tissue, leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in nine different genes (ABCC8,KCNJ11,GLUD1,GCK,HNF4A,HNF1A,SLC16A1,UCP2andHADH) have been identified which cause CHI. Autosomal recessive and dominant mutations inABCC8/KCNJ11are the commonest cause of medically unresponsive CHI. Mutations inGLUD1andHADHlead to leucine-induced HH, and these two genes encode the key enzymes glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase which play a key role in amino acid and fatty acid regulation of insulin secretion respectively. Genetic abnormalities inHNF4AandHNF1Alead to a dual phenotype of HH in the newborn period and maturity onset-diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.