Decreased Fasting and Oral Glucose Stimulated C-peptide in Nondiabetic Subjects With Sequence Variants in the Sulfonylurea Receptor 1 Gene
- S. John Weisnagel1,
- Tuomo Rankinen2,
- André Nadeau3,
- D.C. Rao4,
- Yvon C. Chagnon1,
- Louis Pérusse1 and
- Claude Bouchard2
- 1Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada
- 2Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana
- 3Diabetes Research Unit, Laval University Health Center, Ste-Foy, Québec, Canada
- 4Division of Biostatistics and Departments of Psychiatry and Genetics, Washington University Medical School, St. Louis, Missouri
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.
- CP30, OGTT C-peptide area above basal in first 30 min
- CPEP, fasting plasma C-peptide
- CPtot, OGTT C-peptide area above basal over 180 min
- GLU, fasting plasma glucose
- IN30, OGTT insulin area above basal in first 30 min
- INS, fasting plasma insulin
- IRI, immunoreactive insulin
- ND, nondiabetic
- OGTT, oral glucose tolerance test
- PCR, polymerase chain reaction
- PI, proinsulin
- QFS, Québec Family Study
- sum of six skinfold thicknesses
- SUR1, sulfonylurea receptor 1
- WC, waist circumference
Address correspondence and reprint requests to S. John Weisnagel, M.D., FRCPC, Physical Activity Sciences Laboratory, Kinesiology, PEPS 0234, Laval University, Ste-Foy, Québec, Canada G1K 7P4. E-mail:.
Received for publication 4 May 2000 and accepted in revised form 7 December 2000.
Additional information can be found in an online appendix at www.diabetes.org/diabetes/appendix.asp.