Zaidi F K, Wareham N J, McCarthy M I, Holdstock J, Kalloo-Hosein H, Krook A, Swinn R A, O'Rahilly S
Department of Medicine, University of Cambridge, UK.
Diabet Med. 1997 Mar;14(3):228-34. doi: 10.1002/(SICI)1096-9136(199703)14:3<228::AID-DIA330>3.0.CO;2-N.
A commonly occurring sequence variant in the islet-specific promoter of the glucokinase gene (-30 G to A) has been variably reported to be associated with reduced insulin secretory responses to oral glucose. The effect of this promoter variant may be subtle and only become apparent under conditions of beta-cell 'stress'. As late pregnancy is a time of increased insulin secretory demand, we have examined whether this common genetic variant was associated with impairment of insulin secretory responses to oral glucose in 92 women in the third trimester of pregnancy. The three women who were homozygous for the variant sequence had a markedly diminished 30' insulin incremental response to oral glucose (10.4, 11.4, and 17.2 pmol insulin mmol-1 glucose, respectively) compared to either heterozygous (49.3 (37.6-64.6 pmol insulin mmol-1 glucose)) (p < 0.002) or homozygous wild-type (51.4 (40.9-64.7 pmol insulin mmol-1 glucose)) (p < 0.002) Mann-Whitney U test) women. In a subset of 35 British Caucasian women with gestational diabetes, no mutations resulting in a change of amino acid sequence were detected by molecular scanning of all exons of the glucokinase gene. In summary, in a cohort of 35 British Caucasian women with gestational diabetes neither missense nor nonsense glucokinase mutations were found. However, in women in the third trimester of pregnancy, homozygosity for a common polymorphic variant in the islet-specific promoter of the glucokinase gene was associated with a highly significant reduction of early insulin secretory responsiveness to oral glucose. Under the conditions of increased secretory demand represented by late pregnancy, a promoter variant in the glucokinase gene may influence the early insulin secretory response to oral glucose.
葡萄糖激酶基因的胰岛特异性启动子中常见的序列变异（-30 G突变为A），不同研究报告显示其与口服葡萄糖后胰岛素分泌反应降低有关。这种启动子变异的影响可能较为细微，只有在β细胞“应激”条件下才会显现。由于妊娠晚期胰岛素分泌需求增加，我们研究了这一常见基因变异是否与92名妊娠晚期女性口服葡萄糖后的胰岛素分泌反应受损有关。与杂合子（49.3（37.6 - 64.6 pmol胰岛素 mmol⁻¹葡萄糖））（p < 0.002）或纯合野生型（51.4（40.9 - 64.7 pmol胰岛素 mmol⁻¹葡萄糖））（p < 0.002，曼-惠特尼U检验）女性相比，三名该变异序列纯合子女性口服葡萄糖后30分钟的胰岛素增量反应明显降低（分别为10.4、11.4和17.2 pmol胰岛素 mmol⁻¹葡萄糖）。在35名患有妊娠期糖尿病的英国白种女性亚组中，通过对葡萄糖激酶基因所有外显子进行分子扫描，未检测到导致氨基酸序列改变的突变。总之，在35名患有妊娠期糖尿病的英国白种女性队列中，未发现葡萄糖激酶的错义或无义突变。然而，在妊娠晚期女性中，葡萄糖激酶基因的胰岛特异性启动子中一种常见多态性变异的纯合性与口服葡萄糖后早期胰岛素分泌反应的显著降低有关。在妊娠晚期所代表的分泌需求增加的条件下，葡萄糖激酶基因的启动子变异可能会影响口服葡萄糖后的早期胰岛素分泌反应。
