title: Diabetes in very young children and mutations in the insulin-secreting cell potassium channel genes: therapeutic consequences.
abstract: ATP-sensitive potassium (KATP) channels regulate the flux of K+ ions across the cell membranes and couple cell metabolism to electrical activity. These channels are octameric complexes of 4 pore-forming Kir and 4 regulatory sulphonylurea receptor (SUR) subunits. The KATP channels play multiple physiological roles in the glucose metabolism regulation, especially in the pancreatic Beta-cells where they regulate insulin secretion, in response to increases in ATP concentration. Several studies have reported activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the pancreatic KATP channel, in patients with permanent neonatal diabetes mellitus for 30-50% of the cases. These mutations result in reduced ATP sensitivity of the KATP channels compared with the wild types. The level of channel activity defect 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, developmental delay, muscle weakness and mild dysmorphic features. The very recently elucidated mutations in the ABCC8 gene, encoding the second KATP channel subunit, SUR1, account for transient neonatal diabetes mellitus as well as permanent neonatal diabetes mellitus cases. In vitro studies showed no attenuation of ATP sensitivity but an increase in the opening probability of the channel through interaction of the mutated SUR1 subunit on Kir6.2. Sulphonylureas close KATP channels by binding with high affinity to SUR suggesting they could replace insulin in these patients. Subsequently, more than 60 patients have been reported as successfully switched from insulin subcutaneous injections to oral sulphonylurea therapy, with an improvement in their glycated hemoglobin. The transfer from insulin injections to oral glibenclamide therapy seems highly effective and safe for most patients, and should be performed in accordance with the legal rules for the use of such a drug, specially in children, in each country.
authors.affiliation: Clinique des Maladies du Développement, Unité d'Endocrinologie, Diabétologie et Gynécologie Pédiatrique, Hôpital Necker-Enfants Malades, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Flechtner
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.forename: Raphael
authors.initials: R
authors.lastname: Scharfmann
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001692:Biological Transport; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007223:Infant; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008954:Models, Biological; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D005947:Glucose; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human