Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence
Novel de novo mutation in sulfonylurea receptor 1 presenting as hyperinsulinism in infancy followed by overt diabetes in early adolescence
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DOI：
10.2337/db08-0159
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发表时间：
2008-07-01
期刊：
影响因子：
7.7
通讯作者：
Zangen, David H.
中科院分区：
文献类型：
--
作者：
Abdulhadi-Atwan, Maha;Bushmann, Jeremy;Zangen, David H.
目的：先天性高胰岛素血症，通常与新生儿严重低血糖相关，可能发展为糖尿病，通常在非胰腺切除术患者生命的第40年。我们的目的是对一名在婴儿期高胰岛素血症后出现明显糖尿病的10.5岁女孩的atp敏感K+通道进行基因分型。研究设计和方法：一名女性，年龄10.5岁，新发抗体阴性糖尿病（A1C 10.6%）。她出生时体重大于胎龄（5公斤），母亲为非糖尿病患者，经常出现低血糖发作，一直持续到3岁，最初接受静脉注射葡萄糖治疗，后来口服糖治疗。目前，她完全处于青春期，肥胖（BMI 30.2 kg/m(2)），患有部分控制的惊厥障碍（从1岁开始），学习成绩较差。连续监测72小时血糖水平为bb0 11.1 mmol/l，静脉葡萄糖耐量试验期间胰岛素分泌较低。对KCNJ11和ABCC8进行突变分析，鉴定出的突变在COSm6细胞中具有特征。结果：在患者的DNA中发现了一种新的、全新的杂合ABCC8磺酰脲受体（SUR） I突变（R370S），但在父母双方的DNA中均未发现。Kir6.2与突变体SUR1的共转染。突变蛋白在细胞表面有效表达，但对MgADP没有反应，导致通道活性最小。有趣的是，杂合通道（WT:R370S）对格列本脲反应良好，这一发现导致了磺脲类药物治疗的成功启动。结论：这种新的ABCC8突变与新生儿高胰岛素血症在10年内发展为胰岛素缺缺性糖尿病有关。与体外研究结果一致，患者对磺脲类药物治疗有反应。导致β细胞功能相对快速丧失的机制尚不清楚，但可能涉及突变诱导的与代谢需求增加相关的β细胞凋亡增加。
OBJECTIVE-Congenital hyperinsulinism, usually associated with severe neonatal hypoglycemia, may progress to diabetes, typically during the 4th decade of life in nonpancreatectomized patients. We aimed to genotype the ATP-sensitive K+ channel in a 10.5-year-old girl presenting with overt diabetes following hyperinsulinism in infancy.RESEARCH DESIGN AND METHODS-A female aged 10.5 years presented with new-onset, antibody-negative diabetes (A1C 10.6%). She was born large for gestational age (5 kg) to a nondiabetic mother and developed frequent hypoglycemic episodes, which persisted until age 3 years and responded initially to intravenous glucose and later to oral sweets. Currently, she is fully pubertal and obese (BMI 30.2 kg/m(2)), with a partially controlled convulsive disorder (since age 1 year) and poor school performance. Glucose levels were >11.1 mmol/l throughout 72 h of continuous glucose monitoring, with low insulin secretion during intravenous glucose tolerance testing. KCNJ11 and ABCC8 mutation analysis was performed, and the mutation identified was characterized in COSm6 cells.RESULTS-A novel, de novo heterozygous ABCC8 sulfonylurea receptor (SUR) I mutation (R370S) was identified in the patient's DNA but not in that of either parent. Cotransfection of Kir6.2 and mutant SUR1. demonstrate that the mutated protein is expressed efficiently at the cell surface but fails to respond to MgADP, resulting in minimal channel activity. Interestingly, the heterozygous channel (WT:R370S) responded well to glibenclamide, a finding that lead to the successful initiation of sulfonylurea therapy.CONCLUSIONS-This new ABCC8 mutation is associated with neonatal hyperinsulinism progressing within 10 years to insulinopenic diabetes. Consistent with in vitro findings, the patient responded to sulfonylurea treatment. The mechanism causing the relatively rapid loss in beta-cell function is not clear, but it may involve mutation-induced increased beta-cell apoptosis related to increased metabolic demand.