From association to function: KCNJ11 and ABCC8

Abstract

ATP-sensitive potassium (KATP) channels regulate the secretion of insulin from pancreatic β-cells in response to glucose. These channels consist of the sulphonylurea receptor (SUR1, encoded by ABCC8) and the inwardly rectifying potassium channel (Kir6.2, encoded by KCNJ11) channel subunits. Loss-of-function mutations in ABCC8 or KCNJ11 cause familial hyperinsulinism, whereas activating mutations of these genes are the commonest cause of neonatal diabetes. Mutations in these genes have also recently been shown to cause maturity-onset diabetes of the young. Given the spectrum of diabetes that can be caused by mutations in KCNJ11 and ABCC8, they are excellent candidate genes for harbouring variants that predispose to later-onset diabetes, and a common haplotype of these genes has been robustly associated with an increased risk of type 2 diabetes. In this review, we discuss the role of ABCC8 and KCNJ11 variation in type 2 diabetes.