title: Diabetes and hypoglycaemia in young children and mutations in the Kir6.2 subunit of the potassium channel: therapeutic consequences.
abstract: ATP-sensitive potassium channels (K(ATP)) couple cell metabolism to electrical activity by regulating potassium movement across the membrane. These channels are octameric complex with two kind of subunits: four regulatory sulfonylurea receptor (SUR) embracing four poreforming inwardly rectifying potassium channel (Kir). Several isoforms exist for each type of subunits: SUR1 is found in the pancreatic beta-cell and neurons, whereas SUR2A is in heart cells and SUR2B in smooth muscle; Kir6.2 is in the majority of tissues as pancreatic beta-cells, brain, heart and skeletal muscle, and Kir6.1 can be found in smooth vascular muscle and astrocytes. The K(ATP) channels play multiple physiological roles in the glucose metabolism regulation, especially in beta-cells where it regulates insulin secretion, in response to an increase in ATP concentration. They also seem to be critical metabolic sensors in protection against metabolic stress as hypo or hyperglycemia, hypoxia, ischemia. Persistent hyperinsulinemic hypoglycaemia (HI) of infancy is a heterogeneous disorder which may be divided into two histopathological forms (diffuse and focal lesions). Different inactivating mutations have been implicated in both forms: the permanent inactivation of the K(ATP) channels provokes inappropriate insulin secretion, despite low ATP. Diazoxide, used efficiently in certain cases of HI, opens the K(ATP) channels and therefore overpass the mutation effect on the insulin secretion. Conversely, several studies reported sequencing of KCNJ11, coding for Kir6.2, in patients with permanent neonatal diabetes mellitus and found different mutations in 30 to 50% of the cases. More than 28 heterozygous activating mutations have now been identified, the most frequent mutation being in the aminoacid R201. These mutations result in reduced ATP-sensitivity of the K(ATP) channels compared with the wild-types and the level of channel block is responsible for different clinical features: the "mild" form confers isolated permanent neonatal diabetes whereas the severe form combines diabetes and neurological symptoms such as epilepsy, deve-lopmental delay, muscle weakness and mild dimorphic features. Sulfonylureas close K(ATP) channels by binding with high affinity to SUR suggesting they could replace insulin in these patients. Subsequently, more than 50 patients have been reported as successfully and safely switched from subcutaneous insulin injections to oral sulfonylurea therapy, with an improvement in their glycated hemoglobin. We therefore designed a protocol to transfer and evaluate children who have insulin treated neonatal diabetes due to KCNJ11 mutation, from insulin to sulfonylurea. The transfer from insulin injections to oral glibenclamide therapy seems highly effective for most patients and safe. This shows how the molecular understan-ding of some monogenic form of diabetes may lead to an unexpected change of the treatment in children. This is a spectacular example by which a pharmacogenomic approach improves the quality of life of our young diabetic patients in a tremendous way.
authors.affiliation: Clinique des Maladies du Développement, Unité d'Endocrinologie, Diabétologie et Gynécologie Pédiatrique, Hôpital Necker-Enfants malades, 149, rue de Sèvres, Paris, France. isabelle.flechtner@nck.aphp.fr
authors.forename: I
authors.initials: I
authors.lastname: Flechtner
authors.forename: P
authors.initials: P
authors.lastname: de Lonlay
authors.forename: M
authors.initials: M
authors.lastname: Polak
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D003920:Diabetes Mellitus / Q000235:genetics*; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics; D007003:Hypoglycemia / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology; D000099161:Kcnj11 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel