Molecular mechanisms of congenital hyperinsulinism

Abstract

Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic b-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.

Hiperinsulinismo congénito del recién nacido: A propósito de un caso clínico

“…Histopathology describes adenomatous hyperplasia of the pancreas, which may be diffuse or focal, although a third atypical form has been identified, which mixes healthy and abnormal islets 11 . The molecular mechanism is different in each case 3,4,7 . The diffuse form is related to autosomal recessive inheritance and the focal is usually sporadic and has a lower risk of recurrence 11 .…”

“…Currently, it is possible to know the histological type with the use of the genetic study and PET/CT 3,6 . Genetic alteration has been identified in 50% of HC patients, corresponding to mutations of nine genes related to insulin secretion 3,4,7,11 . 36% are "channelopathies", which alter the functioning of the β-cell K ATP sensitive channel.…”

“…Of these, the ABCC8 gene encodes for the sulfonylurea receptor (SUR1) and the KCNJ11 encodes for the Kir 6.2 subunit. They cause permanent closure of the channel, producing a continuous depolarization of the β-cell and uncontrolled secretion of insulin 7 . Channelopathies (ABCC8 and KCNJ11) are usually recessive conditions, generating more severe HC.…”

“…Channelopathies (ABCC8 and KCNJ11) are usually recessive conditions, generating more severe HC. They are more resistant to medical treatment than dominant ones, which have an unaffected allele 3,7 . Focal lesions require the succession of two events: a recessive K ATP sensitive mutation of paternal origin, followed by the postzygotic loss of heterogeneity of the 11p15.1 region.…”

“…HC is characterized by inadequate and unregulated insulin production when blood glucose levels are low 6 . Insulin secretion by pancreatic β cells is controlled to maintain fasting glucose normally between 63 and 99 mg/dl 7 . The importance of early diagnosis and treatment lies in neurological damage secondary to hypoglycemic states, which may be permanent [1][2][3]8 .…”