Decreased Fasting and Oral Glucose Stimulated C-peptide in Nondiabetic Subjects With Sequence Variants in the Sulfonylurea Receptor 1 Gene

Abstract

The high-affinity sulfonylurea receptor 1 (SUR1) plays an important role in regulating insulin secretion. In the Québec 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 reaction–restriction fragment-length polymorphism analysis. Phenotypes measured were 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 skinfold thicknesses. In ND subjects, exon 18 Thr759(ACC→ACT) T allele carriers (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 noncarriers (T^–). Also, in those with the cT/tC haplotype (from both IVS15-3c→t and 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%) were lower than that in cT^– subjects. In overweight individuals (BMI >25 kg/m²), 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 results suggest that the T and cT allele variants are associated with lower insulin secretion parameters, particularly in female and overweight subjects, adding evidence to the role of SUR1 sequence variants in decreased insulin secretion.