UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations

Kapoor, RR; Flanagan, SE; James, CT; McKiernan, J; Thomas, AM; Harmer, SC; Shield, JP; ... Hussain, K; + view all (2011) Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations. Diabetologia , 54 (10) pp. 2575-2583. 10.1007/s00125-011-2207-4. Green open access

[thumbnail of art%3A10.1007%2Fs00125-011-2207-4.pdf]
Preview
PDF
art%3A10.1007%2Fs00125-011-2207-4.pdf

Download (530kB)

Abstract

Dominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (K-ATP) channel mutations causing HH in the proband.We studied the phenotype of 30 mutation carriers (14 children and 16 adults) from nine families with dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel missense mutations were examined by reconstituting the K-ATP channel in human embryonic kidney 293 (HEK293) cells and evaluating the effect of drugs and metabolic poisoning on the channels using the Rb-86 flux assay.The mutant channels all showed a lack of Rb-86 efflux on exposure to the channel agonist diazoxide or metabolic inhibition. In the families, dominant ABCC8/KCNJ11 mutations were associated with increased birthweight (median + 1.56 SD score [SDS]). Fourteen children had HH and five adults were reported with HH or hypoglycaemic episodes (63%). Progression from hypoglycaemia to diabetes mellitus occurred in two individuals. Eight adults had a history of gestational diabetes in multiple pregnancies or were diabetic (diagnosed at a median age of 31 years). Within these families, none of the 19 adults who were not carriers of the ABCC8/KCNJ11 mutation was known to be diabetic.The phenotype associated with dominant ABCC8/KCNJ11 mutations ranges from asymptomatic macrosomia to persistent HH in childhood. In adults, it may also be an important cause of dominantly inherited early-onset diabetes mellitus.

Type: Article
Title: Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s00125-011-2207-4
Publisher version: http://dx.doi.org/10.1007/s00125-011-2207-4
Language: English
Additional information: The final publication is available at Springer.com: http://dx.doi.org/10.1007/s00125-011-2207-4
Keywords: Diabetes mellitus, Hyperinsulinism, Hypoglycaemia, KATP channels, K-ATP CHANNELS, SULFONYLUREA RECEPTOR, CONGENITAL HYPERINSULINISM, FAMILIAL HYPERINSULINISM, INSULIN-SECRETION, INFANCY, TRAFFICKING, IDENTIFICATION, GENE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
URI: https://discovery.ucl.ac.uk/id/eprint/1311457
Downloads since deposit
81Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item