The molecular mechanisms and pharmacotherapy of ATP-sensitive potassium channel gene mutations underlying neonatal diabetes

Pharmgenomics Pers Med. 2010:3:145-61. doi: 10.2147/PGPM.S6969. Epub 2010 Nov 24.


Neonatal diabetes mellitus (NDM) is a monogenic disorder caused by mutations in genes involved in regulation of insulin secretion from pancreatic β-cells. Mutations in the KCNJ11 and ABCC8 genes, encoding the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel Kir6.2 and SUR1 subunits, respectively, are found in ∼50% of NDM patients. In the pancreatic β-cell, K(ATP) channel activity couples glucose metabolism to insulin secretion via cellular excitability and mutations in either KCNJ11 or ABCC8 genes alter K(ATP) channel activity, leading to faulty insulin secretion. Inactivation mutations decrease K(ATP) channel activity and stimulate excessive insulin secretion, leading to hyperinsulinism of infancy. In direct contrast, activation mutations increase K(ATP) channel activity, resulting in impaired insulin secretion, NDM, and in severe cases, developmental delay and epilepsy. Many NDM patients with KCNJ11 and ABCC8 mutations can be successfully treated with sulfonylureas (SUs) that inhibit the K(ATP) channel, thus replacing the need for daily insulin injections. There is also strong evidence indicating that SU therapy ameliorates some of the neurological defects observed in patients with more severe forms of NDM. This review focuses on the molecular and cellular mechanisms of mutations in the K(ATP) channel that underlie NDM. SU pharmacogenomics is also discussed with respect to evaluating whether patients with certain K(ATP) channel activation mutations can be successfully switched to SU therapy.

Keywords: ABCC8; ATP-sensitive potassium channels; KCNJ11; neonatal diabetes.