Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation
Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation
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DOI：
10.2337/diabetes.53.8.2164
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发表时间：
2004-08-01
期刊：
影响因子：
7.7
通讯作者：
Laakso, M
中科院分区：
文献类型：
--
作者：
Cuesta-Muñoz, AL;Huopio, H;Laakso, M
葡萄糖激酶（GK）是一种糖酵解关键酶，在胰腺P细胞中作为葡萄糖传感器发挥作用，在那里它控制葡萄糖刺激的胰岛素分泌（GSIS）。葡萄糖激酶基因（GCK）中的杂合失活突变可导致轻度糖尿病（年轻人成熟型糖尿病[MODY]2），而激活突变与轻度家族性高胰岛素血症性低血糖相关。我们描述了第一例严重的持续性高胰岛素血症性低血糖症，由于“从头”突变GCK（Y214 C）。一名女婴提出了低血糖癫痫发作，因为第一天出生后，以及与不适当的高胰岛素血症。严重的低血糖持续存在，甚至在二氮嗪和胰腺次全切除术治疗后，导致不可逆的脑损伤。胰腺组织学显示异常大和功能亢进的胰岛。该突变位于蛋白质的推定变构激活剂结构域中。纯化的重组谷胱甘肽S转移酶融合蛋白GK-Y214 C的功能研究表明，其对葡萄糖的亲和力增加了6倍，降低了协同性，并增加了k（cat）。GK-Y214 C的相对活性指数为130，通过数学建模预测的GSIS阈值为0.8 mmol/l，而野生型酶为5 mmol/l。总之，我们已经确定了一个从头GCK激活突变，导致异常严重的高胰岛素血症性低血糖。这些发现表明，GCK突变引起的临床表型的范围从完全胰岛素缺乏症到极端高胰岛素血症不等。
Glucokinase (GK) is a glycolytic key enzyme that functions as a glucose sensor in the pancreatic P-cell, where it governs glucose-stimulated insulin secretion (GSIS). Heterozygous inactivating mutations in the glucokinase gene (GCK) cause a mild form of diabetes (maturity-onset diabetes of the young [MODY]2), and activating mutations have been associated with a mild form of familial hyperinsulinemic hypoglycemia. We describe the first case of severe persistent hyperinsulinemic hypoglycemia due to a "de novo" mutation in GCK (Y214C). A baby girl presented with hypoglycemic seizures since the first postnatal day as well as with inappropriate hyperinsulinemia. Severe hypoglycemia persisted even after treatment with diazoxide and subtotal pancreatectomy, leading to irreversible brain damage. Pancreatic histology revealed abnormally large and hyperfunctional islets. The mutation is located in the putative allosteric activator domain of the protein. Functional studies of purified recombinant glutathionyl Stransferase fusion protein of GK-Y214C showed a sixfold increase in its affinity for glucose, a lowered cooperativity, and increased k(cat). The relative activity index of GK-Y214C was 130, and the threshold for GSIS predicted by mathematical modeling was 0.8 mmol/l, compared with 5 mmol/l in the wild-type enzyme. In conclusion, we have identified a de novo GCK activating mutation that causes hyperinsulinemic hypoglycemia of exceptional severity. These findings demonstrate that the range of the clinical phenotype caused by GCK mutations varies from complete insulin deficiency to extreme hyperinsulinemia.