Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1α gene mutations:: evidence for pharmacogenetics in diabetes
Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor-1α gene mutations:: evidence for pharmacogenetics in diabetes
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DOI：
10.1046/j.1464-5491.2000.00305.x
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发表时间：
2000-07-01
影响因子：
3.5
通讯作者：
Hattersley, AT
中科院分区：
文献类型：
--
作者：
Pearson, ER;Liddell, WG;Hattersley, AT
前言青年成熟型糖尿病(MODY)以常染色体显性遗传、早发性、非胰岛素依赖型糖尿病为特征。肝细胞核因子-1α基因突变是MODY最常见的原因。有报道称，携带HNF-1α突变的个体患者对磺脲类药物的降糖作用异常敏感。我们报告了三名患者，在一次临床中，HNF-1α突变对磺胺类药物表现出明显的超敏反应。病例1和2的病例报告在停止(4.4%和5.8%)和重新引入(5.0%和2.6%)磺脲类药物时HBA(1c)有显著变化。例3服用磺脲类药物后出现严重的低血糖症状，但血糖控制不佳，服药4h后仍出现症状性低血糖(血糖2 mm ol/L)。结论人神经营养因子-1α-MODY糖尿病患者比2型糖尿病患者对磺脲类药物更敏感，这种现象可见于不同的家系，基因突变不同，从确诊之日起可持续13年。这是药物遗传学的一个例子，潜在的病因学遗传缺陷改变了对治疗的药理学反应。目前的病例表明，在HNF-1αMODY患者中：(I)磺脲类药物可显著改善血糖控制，应考虑作为血糖控制不良患者的初始治疗，但应适当饮食；(Ii)低血糖可能会使磺脲类药物的引入复杂化，因此最初应使用极小剂量的短效磺脲类药物；(Iii)应谨慎停止磺脲类药物，因为血糖控制可能会明显恶化。
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)-1 alpha gene are the commonest cause of MODY. Individual patients with HNF-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha 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.