Pearson Ewan R, Starkey Bryan J, Powell Roy J, Gribble Fiona M, Clark Penny M, Hattersley Andrew T
Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, UK.
Lancet. 2003 Oct 18;362(9392):1275-81. doi: 10.1016/S0140-6736(03)14571-0.
Type 2 diabetes shows evidence of underlying heterogeneity. No studies have assessed whether different causes for diabetes change the response to oral hypoglycaemic therapy. In a few cases, patients with diabetes caused by mutations in the hepatocyte nuclear factor 1alpha (HNF-1alpha) gene have been described as sensitive to the hypoglycaemic effects of sulphonylureas. We aimed to see whether the glycaemic response to the sulphonylurea gliclazide and the biguanide metformin differed in HNF-1alpha diabetes and type 2 diabetes, and to investigate the mechanism for differences in sulphonylurea sensitivity.
We did a randomised crossover trial of glicazide and metformin in 36 patients, either with diabetes caused by HNF-1alpha mutations or type 2 diabetes, who were matched for body-mass index and fasting plasma glucose. The primary outcome was reduction in fasting plasma glucose. Analysis was by intention to treat. We assessed possible mechanisms for sulphonylurea sensitivity through insulin sensitivity, insulin secretory response to glucose and tolbutamide, and tolbutamide clearance.
Patients with HNF-1alpha diabetes had a 5.2-fold greater response to gliclazide than to metformin (fasting plasma glucose reduction 4.7 vs 0.9 mmol/L, p=0.0007) and 3.9-fold greater response to gliclazide than those with type 2 diabetes (p=0.002). Patients with HNF-1alpha diabetes had a strong insulin secretory response to intravenous tolbutamide despite a small response to intravenous glucose, and were more insulin sensitive than those with type 2 diabetes. Sulphonylurea metabolism was similar in both patient groups.
The cause of hyperglycaemia changes the response to hypoglycaemic drugs; HNF-1alpha diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1alpha deficiency, which show that the beta-cell defect is upstream of the sulphonylurea receptor. Definition of the genetic basis of hyperglycaemia has implications for patient management.
2型糖尿病存在潜在异质性的证据。尚无研究评估不同病因导致的糖尿病是否会改变口服降糖治疗的反应。在少数病例中，已描述由肝细胞核因子1α（HNF-1α）基因突变引起的糖尿病患者对磺脲类药物的降糖作用敏感。我们旨在观察HNF-1α糖尿病和2型糖尿病患者对磺脲类药物格列齐特和双胍类药物二甲双胍的血糖反应是否存在差异，并研究磺脲类药物敏感性差异的机制。
我们对36例由HNF-1α基因突变引起的糖尿病患者或2型糖尿病患者进行了格列齐特和二甲双胍的随机交叉试验，这些患者的体重指数和空腹血糖相匹配。主要结局是空腹血糖的降低。分析采用意向性治疗。我们通过胰岛素敏感性、胰岛素对葡萄糖和甲苯磺丁脲的分泌反应以及甲苯磺丁脲清除率评估磺脲类药物敏感性的可能机制。
HNF-1α糖尿病患者对格列齐特的反应比对二甲双胍的反应大5.2倍（空腹血糖降低4.7 vs 0.9 mmol/L，p = 0.0007），对格列齐特的反应比对2型糖尿病患者大3.9倍（p = 0.002）。尽管HNF-1α糖尿病患者对静脉注射葡萄糖的反应较小，但对静脉注射甲苯磺丁脲有强烈的胰岛素分泌反应，并且比2型糖尿病患者更具胰岛素敏感性。两组患者的磺脲类药物代谢相似。
高血糖的病因会改变对降糖药物的反应；HNF-1α糖尿病对磺脲类药物具有显著敏感性。这种药物遗传学效应与HNF-1α缺乏模型一致，该模型表明β细胞缺陷位于磺脲类药物受体的上游。高血糖遗传基础的定义对患者管理具有重要意义。
