Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes.
Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes.
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DOI：
10.1007/s00125-016-3921-8
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发表时间：
2016-06
期刊：
影响因子：
8.2
通讯作者：
Hattersley AT
中科院分区：
文献类型：
--
作者：
Babiker T;Vedovato N;Patel K;Thomas N;Finn R;Männikkö R;Chakera AJ;Flanagan SE;Shepherd MH;Ellard S;Ashcroft FM;Hattersley AT
由于钾通道突变而患有糖尿病的患者可以从胰岛素转移到磺脲类药物，这一发现彻底改变了永久性新生儿糖尿病患者的管理。突变的体外特征在多大程度上可以预测成功转移尚不清楚。我们的目的是确定与KCNJ 11（编码内向整流钾通道Kir6.2）突变导致的永久性新生儿糖尿病患者成功从胰岛素转换为磺脲类药物相关的因素。我们回顾性分析了127例因KCNJ 11突变而试图改用磺脲类药物的新生儿糖尿病患者的临床资料。当患者在磺脲类药物治疗期间完全停用胰岛素时，我们认为转移成功。所有不成功的转移均接受≥0.8 mg kg−1 day−1格列本脲（或等效药物）治疗>4周。突变Kir6.2/SUR 1通道对甲苯磺丁脲的体外反应在爪蟾卵母细胞中进行了评估。对于一些特定的突变，并非所有携带突变的个体都能够成功转移;因此，我们研究了哪些临床特征可以预测成功转移。总之，127例患者中有112例（88%）成功从胰岛素转换为磺脲类药物，HbA 1c从胰岛素组的8.2%（66 mmol/mol）改善至磺脲类药物组的5.9%（41 mmol/mol）（p = 0.001）。突变对甲苯磺丁脲的体外反应决定了转移的可能性：对于p.C166Y、p.I296L、p.L164P或p.T293N突变，甲苯磺丁脲阻断的程度<63%，并且没有具有这些突变的患者成功转移。然而，大多数具有甲苯磺丁脲阻断>73%的突变的个体确实成功转移。少数携带这些突变但不能转移的患者的糖尿病持续时间比那些成功转移的患者更长（18.2 vs 3.4年，p = 0.032）。转移前HbA 1c（p = 0.87）、年龄别体重z评分（SD评分; p = 0.12）或性别（p = 0.17）无差异。对于大多数KCNJ 11患者来说，从胰岛素转移是成功的，并且最好通过特定突变的体外反应和糖尿病的持续时间来预测。了解特定的突变和糖尿病病程可以帮助预测是否有可能成功转移到磺脲类药物。这一结果支持了6个月以下新生儿糖尿病患者的早期基因检测和早期治疗。本文的在线版本（doi：10.1007/s 00125 -016-3921-8）包含同行评审但未经编辑的补充材料，可供授权用户使用。
The finding that patients with diabetes due to potassium channel mutations can transfer from insulin to sulfonylureas has revolutionised the management of patients with permanent neonatal diabetes. The extent to which the in vitro characteristics of the mutation can predict a successful transfer is not known. Our aim was to identify factors associated with successful transfer from insulin to sulfonylureas in patients with permanent neonatal diabetes due to mutations in KCNJ11 (which encodes the inwardly rectifying potassium channel Kir6.2). We retrospectively analysed clinical data on 127 patients with neonatal diabetes due to KCNJ11 mutations who attempted to transfer to sulfonylureas. We considered transfer successful when patients completely discontinued insulin whilst on sulfonylureas. All unsuccessful transfers received ≥0.8 mg kg−1 day−1 glibenclamide (or the equivalent) for >4 weeks. The in vitro response of mutant Kir6.2/SUR1 channels to tolbutamide was assessed in Xenopus oocytes. For some specific mutations, not all individuals carrying the mutation were able to transfer successfully; we therefore investigated which clinical features could predict a successful transfer. In all, 112 out of 127 (88%) patients successfully transferred to sulfonylureas from insulin with an improvement in HbA1c from 8.2% (66 mmol/mol) on insulin, to 5.9% (41 mmol/mol) on sulphonylureas (p = 0.001). The in vitro response of the mutation to tolbutamide determined the likelihood of transfer: the extent of tolbutamide block was <63% for the p.C166Y, p.I296L, p.L164P or p.T293N mutations, and no patients with these mutations successfully transferred. However, most individuals with mutations for which tolbutamide block was >73% did transfer successfully. The few patients with these mutations who could not transfer had a longer duration of diabetes than those who transferred successfully (18.2 vs 3.4 years, p = 0.032). There was no difference in pre-transfer HbA1c (p = 0.87), weight-for-age z scores (SD score; p = 0.12) or sex (p = 0.17). Transfer from insulin is successful for most KCNJ11 patients and is best predicted by the in vitro response of the specific mutation and the duration of diabetes. Knowledge of the specific mutation and of diabetes duration can help predict whether successful transfer to sulfonylureas is likely. This result supports the early genetic testing and early treatment of patients with neonatal diabetes aged under 6 months. The online version of this article (doi:10.1007/s00125-016-3921-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.