A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects.
It was reported that the common -866G/A polymorphism in the promoter of the human uncoupling protein-2 (UCP2) gene, which enhances its trascriptional activity, is associated with increased mRNA levels in human adipocytes and reduced risk of obesity. Studies in knockout mice and beta-cells indicate that UCP2 may play a role in beta-cell function. In this study, we addressed the question of whether the common -866G/A polymorphism in UCP2 gene contributes to the variation of insulin secretion in humans by genotyping 301 nondiabetic subjects who underwent an oral glucose tolerance test. Glucose-stimulated insulin secretion estimated by several indexes of beta-cell function was significantly lower in carriers of the -866A/A genotype compared with -866A/G or -866G/G according to the dosage of the A allele (P = 0.002-0.05). To investigate directly whether the UCP2 -866G/A polymorphism affects human islet function, pancreatic islets isolated from two -866G/G homozygous, seven -866G/A heterozygous, and one -866A/A homozygous nondiabetic donors were studied. Islets from -866A/A homozygous had lower insulin secretion in response to glucose stimulation as compared with -866G/G and -866G/A carriers. These results indicate that the common -866G/A polymorphism in the UCP2 gene may contribute to the biological variation of insulin secretion in humans.
Sesti
Giorgio
G
Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Graecia, Via Tommaso Campanella, 115 11800 Catanzaro, Italy. sesti@unicz.it
Cardellini
Marina
M
Marini
Maria Adelaide
MA
Frontoni
Simona
S
D'Adamo
Monica
M
Del Guerra
Silvia
S
Lauro
Davide
D
De Nicolais
Pierluigi
P
Sbraccia
Paolo
P
Del Prato
Stefano
S
Gambardella
Sergio
S
Federici
Massimo
M
Marchetti
Piero
P
Lauro
Renato
R
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007473:Ion Channels; D008055:Lipids / Q000097:blood; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D024101:Mitochondrial Proteins; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D000071246:Uncoupling Protein 2
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D007473:Ion Channels; D008055:Lipids; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D000071246:Uncoupling Protein 2; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse