Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic β-cell adenosine triphosphate-sensitive potassium channels
Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic β-cell adenosine triphosphate-sensitive potassium channels
复制标题
DOI：
10.1210/jc.2005-0158
复制
发表时间：
2005-07-01
影响因子：
5.8
通讯作者：
Dunne, MJ
中科院分区：
文献类型：
--
作者：
Hussain, K;Cosgrove, KE;Dunne, MJ
背景：贝克威斯-维德曼综合征（BWS）是一种先天性过度生长综合征，具有临床和遗传异质性。大约 50% 的 BWS 儿童会出现高胰岛素性低血糖，并且大多数婴儿会自行缓解。然而，在一小部分患者中，低血糖可能持续存在，可能需要胰腺切除术。这组患者持续性高胰岛素性低血糖的机制尚不清楚。 患者和方法：使用膜片钳技术对手术时获得的胰腺组织进行研究，我们研究了一名 BWS 和严重的医学上无反应的高胰岛素性低血糖患者的胰腺 β 细胞中 ATP 敏感的 K(+) (K(ATP)) 通道的电生理特性。 结果：发现持续性高胰岛素血症是由胰腺 β 细胞的 K(ATP) 通道。使用 SUR1 抗体进行的免疫荧光研究揭示了 BWS 细胞的核周染色模式，表明 SUR1 蛋白存在运输缺陷。分别编码 K(ATP) 通道两个亚基 SUR1 和 KIR6.2 的基因 ABCC8 和 KCNJ11 未发现突变。该患者 BWS 的遗传分析显示存在嵌合父本二倍体。结论：在这例 11p15 嵌合父本单亲二倍体 BWS 病例中，持续性高胰岛素血症是由于胰腺 β 细胞 K(ATP) 通道异常所致。 11p15 的嵌合父系单亲二体性导致 K(ATP) 通道的 SUR1 蛋白运输缺陷的机制仍有待阐明。
Background: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear.Patients and Methods: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia.Results: Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy.Conclusions: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.