A Common Polymorphism in the Promoter of UCP2 Contributes to the Variation in Insulin Secretion in Glucose-Tolerant Subjects
- Giorgio Sesti1,
- Marina Cardellini2,
- Maria Adelaide Marini2,
- Simona Frontoni3,
- Monica D’Adamo2,
- Silvia Del Guerra4,
- Davide Lauro2,
- Pierluigi De Nicolais1,
- Paolo Sbraccia2,
- Stefano Del Prato4,
- Sergio Gambardella3,
- Massimo Federici2,
- Piero Marchetti4 and
- Renato Lauro2
- 1Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Græcia, Catanzaro, Italy
- 2Laboratory of Molecular Medicine, University of Rome-Tor Vergata, Rome, Italy
- 3Department of Internal Medicine, University of Rome-Tor Vergata, Rome, Italy
- 4Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
Abstract
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 β-cells indicate that UCP2 may play a role in β-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 β-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.
Footnotes
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Address correspondence and reprint requests to Giorgio Sesti, MD, Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro-Magna Græcia, Via Tommaso Campanella, 115 88100 Catanzaro, Italy. E-mail: sesti{at}unicz.it.
Received for publication 25 November 2002 and accepted in revised form 22 January 2003.
CIR, corrected insulin response; FGIR, fasting glucose to insulin ratio; FIRI, fasting insulin resistance index; HBSS, Hanks’ balanced salt solution; HOMA, homeostasis model assessment; OGTT, oral glucose tolerance test; QUICKI, quantitative insulin sensitivity check index; UCP2, uncoupling protein-2.
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