Decreased fasting and oral glucose stimulated C-peptide in nondiabetic subjects with sequence variants in the sulfonylurea receptor 1 gene

The high-affinity sulfonylurea receptor 1 (SUR1) plays an important role in regulating insulin secretion. In the Quebec Family Study, we genotyped 731 individuals (685 nondiabetic [ND] subjects) for the SUR1 gene IVS15-3c-->t and exon 18 Thr759(ACC-->ACT) polymorphisms using polymerase chain reactio n-restriction fragment-length polymorphism analysis. Phenotypes measured we re fasting plasma glucose (GLU), fasting plasma insulin (INS), and fasting C-peptide (CPEP), as well as oral glucose tolerance test (OGTT) responses; they were adjusted for age, sex, waist circumference, and the sum of six sk infold thicknesses. In ND subjects, exon 18 Thr759(ACC-->ACT) T allele carr iers (T+) had lower CPEP (P = 0.022, -12.8%) and acute C-peptide responses (area above basal in first 30 min [CP30]) (P = 0.051, -12.4%) than noncarri ers (T-). Also, in those with the cT/tC haplotype (from both IVS15-3c-->t a nd exon 18 Thr759[ACC-->ACT] polymorphisms), CPEP (P = 0.005, -21.2%), CP30 (P = 0.034, -19.2%), and total C-peptide responses (P = 0.016, -20.2%) wer e lower than that in cT(-) subjects. In overweight individuals (BMI >25 kg/ m(2)), differences between carriers and noncarriers of the T or cT alleles were greater for GLU (P = 0.023-0.034), CPEP (P = 0.021-0.015), acute OGTT insulin response (P = 0.014-0.019), and CP30 (P = 0.034-0.019). These resul ts suggest that the T and cT allele variants are associated with lower insu lin secretion parameters, particularly in female and overweight subjects, a dding evidence to the role of SUR1 sequence variants in decreased insulin s ecretion.