Acute insulin response tests for the differential diagnosis of congenital hyperinsulinism
Acute insulin response tests for the differential diagnosis of congenital hyperinsulinism
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DOI：
10.1210/jc.2002-020378
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发表时间：
2002-10-01
影响因子：
5.8
通讯作者：
Otonkoski, T
中科院分区：
文献类型：
--
作者：
Huopio, H;Jääskeläinen, J;Otonkoski, T
编码β细胞ATP敏感性钾通道（K-ATP）通道的两个亚基（SUR 1和Kir6.2）的基因突变是先天性高胰岛素血症（CHI）的主要原因。在这项研究中，K-ATP通道基因进行了筛选，以人口为基础的研究，包括所有验证的芬兰CHI患者（n = 43）在27年的时间。发现了7种不同的突变，占所有病例的60%。通过在能够参加这些研究的CHI患者中测定对钙（n = 18）、葡萄糖（n = 12）和甲苯磺丁脲（n = 11）的急性（1-3分钟）血浆胰岛素和C肽反应，在体内研究了主要错义突变的功能后果。与无KATP通道突变的患者相比，SUR 1-E1506 K突变患者的C肽和胰岛素对钙的反应显著更高。具有SUR 1-V187 D突变的患者显示对甲苯磺丁脲的反应降低，但出乎意料地对钙刺激没有显示任何反应。1例Kir6.2-（-54）/K67 N突变的复合杂合子患者对钙治疗有反应，但对甲苯磺丁脲也有反应。总之，我们的结果表明，在钙测试中的阳性反应是指示K-ATP通道突变，但所有的突变不能用这种方法来确定。根据基因型的不同，SUR 1突变患者对甲苯磺丁脲的胰岛素反应受到不同程度的损害。钙和甲苯磺丁脲试验的组合是检测CHI患者K-ATP通道功能障碍的有用工具。然而，我们的研究结果也表明了这些反应的复杂性和解释的困难。
Mutations in genes encoding the two subunits of the beta-cell ATP-sensitive potassium channel (K-ATP) channel (SUR1 and Kir6.2) are the major cause of congenital hyperinsulinism (CHI). In this study, the K-ATP channel genes were screened in a population-based study that included all verified Finnish CHI patients (n = 43) in a 27-yr period. Seven different mutations were identified, which accounted for 60% of all cases. The functional consequences of the major missense mutations were studied in vivo, by determining acute (1-3 min) plasma insulin and C-peptide responses to calcium (n = 18), glucose (n = 12), and tolbutamide (n = 11) in those CHI patients who were able to take part in these studies. C-peptide and insulin responses to calcium were significantly higher in the patients with SUR1-E1506K mutation, compared with patients without KATP channel mutations. The patients with SUR1-V187D mutation showed a reduced response to tolbutamide but unexpectedly did not show any response to calcium stimulation. A compound heterozygous patient with Kir6.2-(-54)/K67N mutations responded to calcium but also to tolbutamide. In conclusion, our results show that a positive response in the calcium test is indicative of a K-ATP channel mutation, but all mutations cannot be identified with this method. The insulin response to tolbutamide in patients with SUR1 mutations is impaired to different extents, depending on the genotype. The combination of calcium and tolbutamide tests is a useful tool for the detection of CHI patients with K-ATP channel dysfunction. Our results, however, also demonstrate the complexity of these responses and the difficulties in their interpretation.