Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor‐1α gene mutations: evidence for pharmacogenetics in diabetes

ER Pearson, WG Liddell, M Shepherd… - Diabetic …, 2000 - Wiley Online Library
ER Pearson, WG Liddell, M Shepherd, RJ Corrall, AT Hattersley
Diabetic medicine, 2000Wiley Online Library
Introduction 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)‐1α gene are the commonest cause of MODY. Individual
patients with HNF‐1α 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‐1α mutations that show marked hypersensitivity to sulphonylureas. Case …
SUMMARY
Introduction  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)‐1α gene are the commonest cause of MODY. Individual patients with HNF‐1α 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‐1α mutations that show marked hypersensitivity to sulphonylureas.
Case reports  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‐1α 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‐1α 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.
Keywords  genetics, HNF‐1α, MODY, pharmacogenetics, sulphonylurea sensitivity
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