K_ATP Channel Mutations and Neonatal Diabetes

Abstract

Since the discovery of the K_ATP channel in 1983, numerous studies have revealed its physiological functions. The K_ATP channel is expressed in various organs, including the pancreas, brain and skeletal muscles. It functions as a "metabolic sensor" that converts the metabolic status to electrical activity. In pancreatic beta-cells, the K_ATP channel regulates the secretion of insulin by sensing a change in the blood glucose level and thus maintains glucose homeostasis. In 2004, heterozygous gain-of-function mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the K_ATP channel, were found to cause neonatal diabetes. In some mutations, diabetes is accompanied by severe neurological symptoms [developmental delay, epilepsy, neonatal diabetes (DEND) syndrome]. This review focuses on mutations of Kir6.2, the pore-forming subunit and sulfonylurea receptor (SUR) 1, the regulatory subunit of the K_ATP channel, which cause neonatal diabetes/DEND syndrome and also discusses the findings of the pathological mechanisms that are associated with neonatal diabetes, and its neurological features.