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 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.
Physical Activity Sciences Laboratory, Laval University, Ste-Foy, Québec, Canada. john.weisnagel@kin.msp.ulaval.ca
S J
SJ
Weisnagel
T
T
Rankinen
A
A
Nadeau
D C
DC
Rao
Y C
YC
Chagnon
L
L
Pérusse
C
C
Bouchard
D018528:ATP-Binding Cassette Transporters; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood*; D005215:Fasting / Q000097:blood*; D005260:Female; D014644:Genetic Variation; D005947:Glucose / Q000494:pharmacology*; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug / Q000235:genetics*; D012016:Reference Values; D064233:Sulfonylurea Receptors
C577507:ABCC8 protein, human; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D005947:Glucose