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Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor‐1α gene mutations: evidence for pharmacogenetics in diabetes
Author(s) -
Pearson E. R.,
Liddell W. G.,
Shepherd M.,
Corrall R. J.,
Hattersley A. T.
Publication year - 2000
Publication title -
diabetic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.474
H-Index - 145
eISSN - 1464-5491
pISSN - 0742-3071
DOI - 10.1046/j.1464-5491.2000.00305.x
Subject(s) - medicine , endocrinology , diabetes mellitus , glibenclamide , pharmacogenetics , sulfonylurea , gliclazide , hepatocyte nuclear factors , type 2 diabetes , genetic testing , gene , genotype , genetics , gene expression , biology
SUMMARYIntroduction 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 HbA 1c 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