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

  1. S. John Weisnagel1,
  2. Tuomo Rankinen2,
  3. André Nadeau3,
  4. D.C. Rao4,
  5. Yvon C. Chagnon1,
  6. Louis Pérusse1 and
  7. Claude Bouchard2
  1. 1Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada
  2. 2Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana
  3. 3Diabetes Research Unit, Laval University Health Center, Ste-Foy, Québec, Canada
  4. 4Division of Biostatistics and Departments of Psychiatry and Genetics, Washington University Medical School, St. Louis, Missouri

    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.

    Footnotes

    • 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: john.weisnagel{at}kin.msp.ulaval.ca.

      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.

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