K(ATP) Channel Mutations and Neonatal Diabetes

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.