In pancreatic beta-cells, ATP-sensitive potassium channels link changes in blood glucose concentration to insulin secretion. The β-cell KATP channel is characterised by pronounced channel inhibition in response to increased intracellular ATP concentration.
A lack of insulin secretion causes diabetes mellitus. Neonatal diabetes mellitus (NDM), however, is a rare disease which presents within the first six to nine months of life, and approximately half of these patients have KATP channel mutations.
In high glucose concentrations, ATP generated from glucose metabolism binds to KATP channels causing them to close, which leads to membrane depolarisation and insulin secretion. Mutant KATP channels found in neonatal diabetes patients are less sensitive to ATP inhibition and thus remain open when blood glucose rises, preventing their beta-cells from secreting insulin. In the past, patients with neonatal diabetes were dependent on lifelong insulin treatment for survival, but in recent years the preferred treatment has been oral sulphonylureas. In addition to improving their quality of life, this provides them with better glycaemic control and a lower risk of subsequent complications.
We investigate the effect of heterozygous activating mutations at residues G334 and C166 in Kir6.2 (KCNJ11), the pore-forming subunit of the channel, as well as the first known homozygous activating mutation: G324R. We confirm that these mutations lead to neonatal diabetes mellitus, and the data of these novel mutations and the mutations occurring at the same residues provide more evidence to support the strong correlation between greater loss of ATP sensitivity and more severe phenotype; that is, neonatal diabetes accompanied by neurological symptoms. Additionally, the success of sulphonylurea therapy in patients with Kir6.2 mutations reflects the in vitro response of the KATP channel with the same mutation to tolbutamide, and there is a threshold of 65-75% block required in order to cause insulin secretion.