Molecular mechanisms of congenital hyperinsulinism.
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, UCP2 and HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically unresponsive CHI. Mutations in GLUD1 and HADH lead 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 in HNF4A and HNF1A lead 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.
Genetics and Genomic MedicineUCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UKDepartment of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS, 30 Guilford Street, London WC1N 1EH, UK.
Sofia A
SA
Rahman
Genetics and Genomic MedicineUCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UKDepartment of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS, 30 Guilford Street, London WC1N 1EH, UK.
Azizun
A
Nessa
Genetics and Genomic MedicineUCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UKDepartment of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS, 30 Guilford Street, London WC1N 1EH, UK Genetics and Genomic MedicineUCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UKDepartment of Paediatric EndocrinologyGreat Ormond Street Hospital for Children NHS, 30 Guilford Street, London WC1N 1EH, UK Khalid.Hussain@ucl.ac.uk.
Khalid
K
Hussain
D000818:Animals; D044903:Congenital Hyperinsulinism / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008954:Models, Biological
D007328:Insulin
KATP channels; congenital hyperinsulinism; development; genetics; glucose; human; hypoglycaemia; insulin