A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans.
Obesity is frequently associated with type 2 diabetes. We previously observed an association of a functional G/A polymorphism in the uncoupling protein 2 (UCP2) promoter with obesity. The wild-type G allele was associated with reduced adipose tissue mRNA expression in vivo, reduced transcriptional activity in vitro, and increased risk of obesity. On the other hand, studies in animal and cell culture models identified pancreatic beta-cell UCP2 expression as a main determinant of the insulin secretory response to glucose. We therefore ascertained associations of the -866G/A polymorphism with beta-cell function and diabetes risk in obesity. We show here that the pancreatic transcription factor PAX6 preferentially binds to and more effectively trans activates the variant than the wild-type UCP2 promoter allele in the beta-cell line INS1-E. By studying 39 obese nondiabetic humans, we observed genotype differences in beta-cell function; wild-type subjects displayed a greater disposition index (the product of insulin sensitivity and acute insulin response to glucose) than subjects with the variant allele (P < 0.03). By comparing obese subjects with and without type 2 diabetes, we observed genotype-associated differences in diabetes prevalence that translated into a twofold age-adjusted risk reduction in wild-type subjects. Thus, the more common UCP2 promoter G allele, while being conducive for obesity, affords relative protection against type 2 diabetes.
Krempler
Franz
F
Department of Internal Medicine, Krankenhaus Hallein, Hallein, Austria.
Esterbauer
Harald
H
Weitgasser
Raimund
R
Ebenbichler
Christoph
C
Patsch
Josef R
JR
Miller
Karl
K
Xie
Mingqiang
M
Linnemayr
Veronika
V
Oberkofler
Hannes
H
Patsch
Wolfgang
W
D000273:Adipose Tissue / Q000378:metabolism; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006801:Humans; D007473:Ion Channels; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D024101:Mitochondrial Proteins; D015999:Multivariate Analysis; D009765:Obesity / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D000071246:Uncoupling Protein 2
D001786:Blood Glucose; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D012333:RNA, Messenger; D014280:Triglycerides; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D002784:Cholesterol