1 Molecular Mechanisms of Congenital Hyperinsulinism 1

ABSTRACT 20 Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin 21 secretion from pancreatic β-cells is unregulated and inappropriate for the level of blood 22 glucose. The inappropriate insulin secretion drives glucose into the insulin sensitive tissues, 23 such as the muscle, liver and adipose tissue leading to severe hyperinsulinaemic 24 hypoglycaemia (HH). At a molecular level, genetic abnormalities in 9 different genes 25 (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2, HADH) have been 26 identified which cause CHI. Autosomal recessive and dominant mutations in 27 ABCC8/KCNJ11 are the commonest cause of medically-unresponsive CHI. Mutations in 28 GLUD1 and HADH lead to leucine-induced HH and these two genes encode for the key 29 enzymes (glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase) 30 which play a key role in amino acid and fatty acid regulation of insulin secretion, 31 respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in 32 the newborn period and maturity onset diabetes later in life. This state of the art review 33 provides an update on the molecular basis of CHI. 3