title: Lack of glibenclamide response in a case of permanent neonatal diabetes caused by incomplete inactivation of glucokinase.
abstract: BACKGROUND
  Hypoglycaemic drugs that close the KATP channel have been tested in patients with permanent neonatal diabetes due to glucokinase mutations (PNDM-GCK). From the results obtained, it has been suggested that this treatment may be beneficial in patients carrying GCK mutations with mild kinetic defects. The aim of this study was to evaluate the kinetic analysis of glucokinase activity as a predictive factor for response to sulphonylureas in PNDM-GCK.
  
  
  METHODS
  The clinical characteristics of two siblings with PNDM born to non-consanguineous parents are described. Mutation analysis of KCNJ11, INS and GCK genes was done by sequencing. A comprehensive functional characterisation of GCK mutation was undertaken. Glibenclamide treatment was assayed for 16 weeks in one child. Response to treatment was evaluated by means of fasting glycaemia, C-peptide and HbA1c levels.
  
  
  RESULTS
  Compound heterozygous GCK mutations (p.Ile19Asn and p.Ser441Trp) were identified. Functional analysis of GCK(p.Ile19Asn) indicated that this mutant retained more than 70% of wild-type catalytic activity in vitro, with a slight increase of thermolability. This mutation did not impair the interaction with the glucokinase regulatory protein, and the enzymatic activity of the GCK(p.Ile19Asn) mutant is restored to wild-type levels in the presence of GCK allosteric activator LY2121260. However, glibenclamide treatment of the patient on a reduced dose of insulin did not reduce HbA1c levels, and C-peptide increased only very slightly.
  
  
  CONCLUSIONS
  Hypoglycaemic drugs acting on the KATP channel might not be useful in the treatment of PNDM-GCK, even in patients carrying GCK mutations with mild kinetic defects.
authors: Servicio de Bioquímica y Genética Molecular. Hospital Clínic. Departamento de Ciencias Fisiológicas I. Facultad de Medicina., Universidad de Barcelona, Barcelona, Spain.
authors: Josep
authors: J
authors: Oriola
authors: Francisca
authors: F
authors: Moreno
authors: Angel
authors: A
authors: Gutiérrez-Nogués
authors: Sara
authors: S
authors: León
authors: Carmen-María
authors: CM
authors: García-Herrero
authors: Olivier
authors: O
authors: Vincent
authors: María-Angeles
authors: MA
authors: Navas