Homozygosity for a Common Polymorphism in the Islet-specific Promoter of the Glucokinase Gene is Associated with a Reduced Early Insulin Response to Oral Glucose in Pregnant Women
✍ Scribed by Zaidi, F.K.; Wareham, N.J.; McCarthy, M.I.; Holdstock, J.; Kalloo-Hosein, H.; Krook, A.; Swinn, R.A.; O’ Rahilly, S.
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 81 KB
- Volume
- 14
- Category
- Article
- ISSN
- 0742-3071
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✦ Synopsis
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 Ͻ Ͻ 0.002) or homozygous wild-type (51.4 (40.9-64.7 pmol insulin mmol -1 glucose)) (p Ͻ Ͻ Ͻ 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.
KEY WORDS Gestational diabetes Insulin secretion Glucokinase
Glucose intolerance Molecular scanning of insulin secretion to rise in compensation for the Abbreviations: GDM gestational diabetes, SSCP single-stranded conforcriteria. 5 Female members of MODY pedigrees are often mation polymorphism, NIDDM non-insulin dependent diabetes, BMI body mass index, OGTT oral glucose tolerance test, MODY maturity-undiagnosed until pregnancy, when diabetes is detected onset diabetes of the young by routine screening. 6 Three previous studies of the Correspondence to: Professor Stephen O'Rahilly, Departments of glucokinase mutations in women with GDM have Medicine and Clinical Biochemistry