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.
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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 |
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