Singh R, Pearson E R, Clark P M, Hattersley A T
Department of Molecular Medicine, Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, and Division of Medicine and Therapeutics, Ninewells Hospital, Dundee, UK.
Diabetologia. 2007 Mar;50(3):620-4. doi: 10.1007/s00125-006-0541-8. Epub 2007 Jan 10.
AIMS/HYPOTHESIS: There is strong evidence that maternal diabetes while offspring are in utero results in offspring beta cell dysfunction and diabetes or glucose intolerance. Offspring born to mothers with a mutation in the glucokinase gene (GCK) are a good model for studying exposure to moderate hyperglycaemia, as mutation carriers have fasting hyperglycaemia throughout life including during pregnancy. We assessed the long term effects of exposure to maternal hyperglycaemia in utero on beta cell function and glucose tolerance in adult offspring.
We studied 86 adult offspring (mean age 40 years), 49 born to glucokinase mothers (exposed to hyperglycaemia in utero) and 37 born to glucokinase fathers (controls). We measured glucose tolerance during an OGTT and beta cell function using early insulin response (EIR); we also measured anthropometric data including birthweight.
Offspring of glucokinase mothers had a higher birthweight by 450 g (p<0.001), but no evidence of deterioration in glucose tolerance (2-h glucose 9.1 vs 8.6 mmol/l p=0.50) or reduced beta cell function (log EIR 1.40 vs 1.26, p=0.11) compared with offspring born to glucokinase fathers.
CONCLUSIONS/INTERPRETATION: The marked increase in birthweight shows that offspring born to affected mothers were exposed to increased glycaemia in utero. Despite this, there was no evidence of altered beta cell function or glucose tolerance. As previous human examples of marked programming by hyperglycaemia in utero have been in genetically predisposed offspring, we propose that our finding reflects the lack of genetic predisposition in the offspring to progressive beta cell dysfunction.
目的/假设：有充分证据表明，子代在子宫内时母亲患糖尿病会导致子代β细胞功能障碍以及糖尿病或葡萄糖耐量异常。母亲携带葡萄糖激酶基因（GCK）突变的子代是研究暴露于中度高血糖情况的良好模型，因为突变携带者一生都存在空腹高血糖，包括孕期。我们评估了子宫内暴露于母亲高血糖对成年子代β细胞功能和葡萄糖耐量的长期影响。
我们研究了86名成年子代（平均年龄40岁），其中49名是葡萄糖激酶母亲的子代（子宫内暴露于高血糖），37名是葡萄糖激酶父亲的子代（对照组）。我们通过口服葡萄糖耐量试验（OGTT）测量葡萄糖耐量，并使用早期胰岛素反应（EIR）评估β细胞功能；我们还测量了包括出生体重在内的人体测量数据。
与葡萄糖激酶父亲的子代相比，葡萄糖激酶母亲的子代出生体重高450克（p<0.001），但没有证据表明葡萄糖耐量恶化（2小时血糖9.1 vs 8.6 mmol/L，p = 0.50）或β细胞功能降低（log EIR 1.40 vs 1.26，p = 0.11）。
结论/解读：出生体重的显著增加表明，患病母亲的子代在子宫内暴露于更高的血糖水平。尽管如此，没有证据表明β细胞功能或葡萄糖耐量发生改变。由于之前子宫内高血糖显著编程的人类实例均为具有遗传易感性的子代，我们认为我们的发现反映了子代缺乏发生进行性β细胞功能障碍的遗传易感性。
