Closure of ATP-sensitive K(+) channels (K(ATP) channels) in response to 
metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin 
release from pancreatic beta-cells. Heterozygous gain-of-function mutations in 
the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in 
approximately 47% of patients diagnosed with permanent diabetes at <6 months of 
age. There is a striking genotype-phenotype relationship with specific Kir6.2 
mutations being associated with transient neonatal diabetes, permanent neonatal 
diabetes alone, and a novel syndrome characterized by developmental delay, 
epilepsy, and neonatal diabetes (DEND) syndrome. All mutations appear to cause 
neonatal diabetes by reducing K(ATP) channel ATP sensitivity and increasing the 
K(ATP) current, which inhibits beta-cell electrical activity and insulin 
secretion. The severity of the clinical symptoms is reflected in the ATP 
sensitivity of heterozygous channels in vitro with wild type > transient 
neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. 
Sulfonylureas still close mutated K(ATP) channels, and many patients can 
discontinue insulin injections and show improved glycemic control when treated 
with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 
mutations can cause neonatal diabetes has enabled a new therapeutic approach and 
shed new light on the structure and function of the Kir6.2 subunit of the K(ATP) 
channel.