Mutations in the glucokinase gene of the fetus result in reduced birth weight
Mutations in the glucokinase gene of the fetus result in reduced birth weight
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DOI：
10.1038/953
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发表时间：
1998-07-01
期刊：
影响因子：
30.8
通讯作者：
Ellard, S
中科院分区：
文献类型：
--
作者：
Hattersley, AT;Beards, F;Ellard, S
低出生体重和胎儿瘦弱与儿童期和成年期的非胰岛素依赖型糖尿病 (NIDDM) 以及胰岛素抵抗相关 (1-6)。有人提出，这种关联是胎儿对宫内环境做出反应的编程结果(7,8)。另一种解释是，相同的遗传影响会改变子宫内生长和成人葡萄糖耐量。胎儿胰岛素分泌对母体血糖的反应在胎儿生长中起着关键作用，而成人胰岛素分泌是葡萄糖耐量的主要决定因素。我们假设，由葡萄糖激酶基因杂合突变引起的胰腺葡萄糖感知缺陷(9)，除了导致出生后高血糖之外，还可能降低胎儿生长和出生体重。在 58 个后代中，如果父母之一患有葡萄糖激酶突变，则胎儿遗传葡萄糖激酶突变会导致出生体重平均减少 533 克（P=0.002）。在 21 个因存在葡萄糖激酶突变而不一致的同胞对中，有 19 个兄弟姐妹的出生体重较低，平均差异为 521 克（P=0.0002）。葡萄糖激酶突变导致的母亲高血糖导致出生体重平均增加 601 克（P=0.001）。母体和胎儿葡萄糖激酶突变对出生体重的影响是相加的。我们认为出生体重的这些变化反映了胎儿胰岛素分泌的变化，胎儿胰岛素分泌的变化直接受到胎儿基因型的影响，并通过母体高血糖间接受到母体基因型的影响。这一观察结果表明，胎儿生长的变化可用于评估改变胰岛素分泌或胰岛素作用的基因的作用。
Low birth weight and fetal thinness have been associated with non-insulin dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and adulthood(1-6). It has been proposed that this association results from fetal programming in response to the intrauterine environment(7,8). An alternative explanation is that the same genetic influences alter both intrauterine growth and adult glucose tolerance. Fetal insulin secretion in response to maternal glycaemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. We hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene(9), could reduce fetal growth and birth weight in addition to causing hyperglycaemia after birth. In 58 offspring, where one parent has a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P=0.002). In 19 of 21 sibpairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P=0.0002). Maternal hyperglycaemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P=0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. We propose that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycaemia, by the maternal genotype. This observation suggests that variation in fetal growth could be used in the assessment of the role of genes which modify either insulin secretion or insulin action.