title: Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1alpha gene mutations: evidence for pharmacogenetics in diabetes.
abstract: BACKGROUND
  Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominantly inherited, early-onset, non-insulin-dependent diabetes. Mutations in the hepatocyte nuclear factor (HNF)-1alpha gene are the commonest cause of MODY. Individual patients with HNF-1alpha mutations have been reported as being unusually sensitive to the hypoglycaemic effects of sulphonylurea therapy. We report three patients, attending a single clinic, with HNF-1alpha mutations that show marked hypersensitivity to sulphonylureas.
  
  
  METHODS
  In cases 1 and 2 there were marked changes in HbA1c on cessation (4.4% and 5.8%, respectively) and reintroduction (5.0% and 2.6%) of sulphonylureas. Case 3 had severe hypoglycaemic symptoms on the introduction of sulphonylureas despite poor glycaemic control and was shown with a test dose of 2.5 mg glibenclamide to have symptomatic hypoglycaemia (blood glucose 2 mmol/l) after 4 h despite eating.
  
  
  CONCLUSIONS
  HNF-1alpha MODY diabetic subjects are more sensitive to sulphonylureas than Type 2 diabetic subjects and this is seen in different families, with different mutations and may continue up to 13 years from diagnosis. This is an example of pharmacogenetics, with the underlying aetiological genetic defect altering the pharmacological response to treatment. The present cases suggest that in HNF-1alpha MODY patients: (i) sulphonylureas can dramatically improve glycaemic control and should be considered as initial treatment for patients with poor glycaemic control on an appropriate diet; (ii) hypoglycaemia may complicate the introduction of sulphonylureas and therefore very low doses of short acting sulphonylureas should be used initially; and (iii) cessation of sulphonylureas should be undertaken cautiously as there may be marked deterioration in glycaemic control.
authors.affiliation: Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, UK.
authors.forename: E R
authors.initials: ER
authors.lastname: Pearson
authors.forename: W G
authors.initials: WG
authors.lastname: Liddell
authors.forename: M
authors.initials: M
authors.lastname: Shepherd
authors.forename: R J
authors.initials: RJ
authors.lastname: Corrall
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002747:Chlorpropamide / Q000627:therapeutic use*; D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005905:Glyburide / Q000627:therapeutic use*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D009687:Nuclear Proteins; D017354:Point Mutation; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007004:Hypoglycemic Agents; D007328:Insulin; D009687:Nuclear Proteins; D013453:Sulfonylurea Compounds; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D008687:Metformin; D005905:Glyburide; D002747:Chlorpropamide