Permanent neonatal diabetes (PNDM) is diagnosed in the first three months of 
life and is a major management problem as patients require lifelong insulin 
injections. Recently, activating mutations in the KCNJ11 gene which encodes the 
Kir6.2 subunit of the KATP channels in the pancreatic beta-cells were found to 
be an important cause of PNDM. The mutated KATP channels do not close in the 
presence of adenosine triphosphate (ATP) so the beta-cell membrane is 
hyperpolarized and insulin secretion does not occur. Some patients have DEND 
syndrome (developmental delay, epilepsy and neonatal diabetes) with the 
neurological features arising from mutated KATP channels in muscle, nerve and 
brain. Defining a genetic aetiology has not only given insights into clinical 
classification and disease mechanism, but has also influenced treatment. 
Sulphonylureas, by binding the sulphonylurea receptor, can close the KATP 
channel. This has led to patients who were insulin-dependent being able to 
discontinue insulin injections and achieve excellent control with sulphonylurea 
tablets. In this article we discuss the work that established Kir6.2 mutations 
as a common cause of neonatal diabetes, the clinical features, the underlying 
mechanism and the impact on patient treatment.