The Uncoupling Protein 2 Ala55Val Polymorphism Is Associated with Diabetes Mellitus: The CARDIA Study Xinhua Yu, 1 David R. Jacobs, Jr., 1,2* Pamela J. Schreiner, 1 Myron D. Gross, 3 Michael W. Steffes, 3 and Myriam Fornage 4 Background: Uncoupling proteins (UCPs) reduce ATP generation with concomitant increased release of heat. The activities of UCPs have been related to obesity and energy metabolism. Methods: We investigated the association of the com- monly observed UCP2 Ala55Val (V) polymorphism with diabetes mellitus and impaired fasting glucose (IFG) among 3684 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Results: The V frequency was 45% in blacks and 42% in whites. Those with the Val/Val (VV) genotype had a higher incidence of diabetes than those having the Ala/Ala (AA) genotype (5.8% vs 3.3%; P  0.02). Simi- larly, the incidences of diabetes in participants without abdominal obesity were 2.8% and 1.0% (P  0.03) in the VV and AA groups, and 12.4% and 8.3% (P  0.15) in participants with abdominal obesity. The incidence of IFG was higher in VV vs AA only in those without abdominal obesity (12.9% vs 9.2%). These trends per- sisted in minimally and fully adjusted models, and in strata of blacks and whites and men and women. The homeostasis model assessment for insulin resistance was highest in VV in the combined group of those with IFG or untreated diabetes, but not in those with normal fasting glucose. Conclusion: The VV genotype of the UCP2 polymor- phism was positively related to diabetes. It may involve increased insulin resistance in those with impaired glucose homeostasis. © 2005 American Association for Clinical Chemistry The etiology of type 2 diabetes relates to peripheral insulin resistance and a decrease in insulin secretion. In addition, it involves multiple dietary, hormonal, biochem- ical, and genetic factors, many of which are associated with obesity and may reflect energy usage and metabolic efficiency. Uncoupling proteins (UCPs) 5 comprise a complex of several related proteins that may significantly regulate energy utilization. UCP, as a proton transporter, uncou- ples the proton-motive force (diminishing the proton gradient across the inner mitochondrial membrane), de- creasing formation of both ATP and reactive oxygen species (ROS) with the release of chemical energy as heat. UCP2, one of 5 known human homologs (1, 2 ), is located on chromosome 11 (1), a site linked to lower resting metabolic rate (3). Work in model systems and in animals suggests that increased expression of UCP2 decreases glucose-stimulated insulin secretion and thus impairs glucose homeostasis and increases the risk of diabetes mellitus (4–6). In contrast, elimination of the UCP2 gene in diabetes-prone rodents decreases the risk of diabetes (7). Variation in UCP activity may influence the production of ATP and ROS in humans. A common UCP2 polymor- phism involves a C-to-T substitution in exon 4 at position 1 Division of Epidemiology, School of Public Health, University of Minne- sota, Minneapolis, MN. 2 Department of Nutrition, University of Oslo, Oslo, Norway. 3 Department of Laboratory Medicine, Medical School, University of Minnesota, Minneapolis, MN. 4 Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX. *Address correspondence to this author at: University of Minnesota, Division of Epidemiology, School of Public Health, 1300 South 2nd St., Suite 300, Minneapolis, MN 55454. Fax 612-624-0315; e-mail jacobs@epi.umn.edu. Received November 3, 2004; accepted May 20, 2005. Previously published online at DOI: 10.1373/clinchem.2004.044859 5 Nonstandard abbreviations: UCP, uncoupling protein; ROS, reactive oxygen species; CARDIA, Coronary Artery Risk Development in Young Adults study; BMI, body mass index; FAM, 6-carboxyfluorescein; TAMRA, 6-carboxytetramethylrhodamine; IFG, impaired fasting glucose; HOMA, ho- meostasis model assessment; OR, odds ratio; and NFG, normal fasting glucose. Clinical Chemistry 51:8 1451–1456 (2005) Lipids, Lipoproteins, and Cardiovascular Risk Factors 1451 Downloaded from https://academic.oup.com/clinchem/article/51/8/1451/5629922 by guest on 11 June 2022