A variation at position -30 of the beta-cell glucokinase gene promoter is associated with reduced beta-cell function in middle-aged Japanese-American men

被引:67
作者
Stone, LM
Kahn, SE
Fujimoto, WY
Deeb, SS
Porte, D
机构
[1] UNIV WASHINGTON, DEPT MED, WASHINGTON, DC USA
[2] UNIV WASHINGTON, DEPT GENET, WASHINGTON, DC USA
关键词
D O I
10.2337/diabetes.45.4.422
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We sought to determine whether a G-->A variant at position -30) of the beta-cell promoter of the glucokinase (GCK) gene observed to be present more frequently in Japanese-American men with impaired glucose tolerance (IGT) than in Japanese-American men with normal glucose tolerance (NGT) is associated with impaired beta-cell function. We studied 125 unrelated Japanese-American men (aged 46-74 years; mean 61 +/- 0.5) who were nondiabetic by a 75-g oral glucose tolerance test (OGTT) (65 had NGT and 60 had IGT). The presence of the -30 beta-cell GCK gene promoter variant was determined by single-strand conformation polymorphism analysis. beta-cell function was assessed using the ratio of the incremental response in immunoreactive insulin (IRI) to that of glucose during the first 30 min of the OGTT (Delta IRI[30 min-0 min]/Delta glucose[30 min-0 min]) performed at baseline and at 5 years of follow-up. beta-cell function adjusted for basal IRI ([Delta IRI[30 min-0 min]/Delta glucose[30 min-0 min]]/basal IRI; the relative insulin response) was also evaluated. At baseline, the -30 beta-cell GCK gene promoter variant was present in 15.4% of subjects with NGT vs. 38.3% of subjects with IGT (P < 0.01). Fasting IRI did not differ between groups. At baseline, Delta IRI[30 min-0 min]/Delta glucose[30 min-0 min] was significantly lower in subjects with the promoter variant (57 x 10(-9) [35 x 10(-9) to 95 x 10(-9)] vs. 77 x 10(-9) [55 x 10(-9) to 128 x 10(-9)]; median [interquartile range]; P < 0.01) as was the relative insulin response (0.97 [0.70-1.24] vs. 1.37 [0.95-2.03]l/mmol;P < 0.0005). Similarly, at 5 years of follow-up, Delta IRI[30 min-0 min]/Delta glucose[30 min-0 min] and the relative insulin response were significantly reduced in the group with the variant. In the subgroups of subjects with IGT at baseline, IGT at 5 years, and NGT at 5 years, the relative insulin response was significantly lower in those with the variant. We conclude that the -30 beta-cell GCK gene promoter variant is associated with reduced beta-cell function in middle-aged Japanese-American men and may contribute to the high risk of abnormal glucose tolerance in this population.
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页码:422 / 428
页数:7
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