Endocrine Abstracts

Background: The pancreatic β-cell K_ATP channel plays a key role in glucose stimulated insulin secretion and is encoded by the genes ABCC8 and KCNJ11. Recessive mutations in ABCC8/KCNJ11 cause severe medically unresponsive HH. Recently, dominant mutations in these genes have been described that cause mild, medically responsive HH. Controversy exists on whether these dominant ABCC8/KCNJ11 mutations predispose to diabetes mellitus in adulthood or not.

Aim: To characterise the phenotype of the dominantly inherited ABCC8/KCNJ11 mutations causing HH and study the prevalence of diabetes mellitus in the adult mutation carriers.

Methods: We studied the phenotype of ten families (fourteen patients with HH) with nine different dominant ABCC8/KCNJ11 mutations. Functional consequences of six novel mutations were examined by reconstituting the K_ATP channel in HEK293 cells and evaluating the effect of drugs (diazoxide, glibenclamide) and metabolic poisoning on the channels using Rb⁸⁶ flux assay.

Results: HH was diagnosed at a median age of 1 day. The median birth weight was 4303 g at a median gestational age of 40 weeks. 12/14 probands responded to diazoxide, while the remaining two had transient HH that resolved spontaneously. Of the sixteen adult mutation carriers identified, only five have persisting or past symptoms of hypoglycaemia. Five adult mutation carriers have developed young onset diabetes mellitus, at a median age of 38 years whilst three others have developed gestational diabetes. When activated, wild-type K_ATP channels showed significant Rb+ efflux whereas mutant K_ATP channels showed no Rb+ efflux thus confirming the pathogenicity of the mutations.

Conclusions: Dominant mutations in ABCC8/KCNJ11 cause a varying phenotype ranging from asymptomatic macrosomia to medically responsive HH in childhood. In adults, it may be an important cause of dominantly inherited early onset diabetes mellitus.