Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations.
Extremes of clinical and enzymatic phenotypes in children with hyperinsulinism caused by glucokinase activating mutations.
复制标题
由葡萄糖激酶激活突变引起的高胰岛素血症儿童的临床和酶表型的极端情况。
DOI：
10.2337/db08-1792
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发表时间：
2009-06
期刊：
影响因子：
7.7
通讯作者：
Stanley CA
中科院分区：
文献类型：
--
作者：
Sayed S;Langdon DR;Odili S;Chen P;Buettger C;Schiffman AB;Suchi M;Taub R;Grimsby J;Matschinsky FM;Stanley CA
据报道，葡萄糖激酶的杂合子激活突变可在少数家庭中引起高胰岛素血症所致的低血糖。我们报告了三个新的葡萄糖激酶高胰岛素血症突变的儿童，他们表现出与酶动力学显着不同的临床表型谱。对突变株进行直接测序，并将突变株表达为谷胱甘肽S-转移酶-葡糖激酶融合蛋白。酶的动力学分析包括稳定性、活性指数的测定、对葡糖激活剂药物的反应以及葡糖激活剂调节蛋白的作用。CHILD 1有INS454A突变，CHILD 2有W99L突变，CHILD 3有M197I突变。二氮嗪治疗对CHILD 3有效，但对CHILD 1无效，对CHILD 2只有部分有效。突变的葡萄糖激酶ins454A、W99L和M197I酶在三个儿童中的表达显示出一系列高相对活性指数(分别为26、8.9和3.1；野生型=1.0)。INS454A对葡糖激酶调节蛋白抑制和药物RO0281675激活的变构反应减弱，但不受M197I突变的影响。INS454A比M197I突变和W99L突变的中间突变更严重地降低了葡萄糖刺激的胰岛素释放阈值(分别为1.1、3.5和2.2mmoL/L；野生型=5.0mmoL/L)。这些结果证实了葡萄糖激酶作为胰腺β细胞葡萄糖感受器的有效性，并表明在葡萄糖激酶高胰岛素血症中，对二氮卓的反应因基因而异，导致低血糖，这可能比之前认为的更难控制。
Heterozygous activating mutations of glucokinase have been reported to cause hypoglycemia attributable to hyperinsulinism in a limited number of families. We report three children with de novo glucokinase hyperinsulinism mutations who displayed a spectrum of clinical phenotypes corresponding to marked differences in enzyme kinetics. Mutations were directly sequenced, and mutants were expressed as glutathionyl S-transferase–glucokinase fusion proteins. Kinetic analysis of the enzymes included determinations of stability, activity index, the response to glucokinase activator drug, and the effect of glucokinase regulatory protein. Child 1 had an ins454A mutation, child 2 a W99L mutation, and child 3 an M197I mutation. Diazoxide treatment was effective in child 3 but ineffective in child 1 and only partially effective in child 2. Expression of the mutant glucokinase ins454A, W99L, and M197I enzymes revealed a continuum of high relative activity indexes in the three children (26, 8.9, and 3.1, respectively; wild type = 1.0). Allosteric responses to inhibition by glucokinase regulatory protein and activation by the drug RO0281675 were impaired by the ins454A but unaffected by the M197I mutation. Estimated thresholds for glucose-stimulated insulin release were more severely reduced by the ins454A than the M197I mutation and intermediate in the W99L mutation (1.1, 3.5, and 2.2 mmol/l, respectively; wild type = 5.0 mmol/l). These results confirm the potency of glucokinase as the pancreatic β-cell glucose sensor, and they demonstrate that responsiveness to diazoxide varies with genotype in glucokinase hyperinsulinism resulting in hypoglycemia, which can be more difficult to control than previously believed.