GG-genotype in the promotor region of uncoupling-protein-1 gene is associated with lower level of dehydroepiandrosterone in type 2 diabetes

Summary:

The A → G (-3826) point mutation within the distal region of the uncoupling-protein-1 (UCP-1) promoter is possibly involved in the development of obesity, diabetes and related disorders. DHEAS has been found to stimulate expression of UCP-1-mRNA. The aim of our study was to evaluate the prevalence of the three UCP-1 genotypes in type 2 diabetic patients out of a population based sample. Possible associations of A → G mutation with serum levels of DHEAS and with obesity, diabetes and retinopathy were examined. - In 549 diabetic patients (312 males and 237 females) out of a population-based sample UCP-1 genotype was determined by genomic PCR and Bcl-I-RFLP analysis. Serum levels of DHEAS were measured by ELISA. - Genotype frequencies were: GG genotype, 4.4% (n = 24); AG genotype 37.3% (n = 205) and AA genotype 58.3% (n = 320). The genotype groups were comparable with respect to sex, BMI, HbA1c, systolic blood pressure (BP), retinopathy and also to serum levels of C-peptide, leptin and cortisol. Serum levels of DHEAS were lowest in GG-genotype as compared to AG and AA (GG: 1.8 ± 1.5 μmol/l, AG: 2.2 ± 1.8 μmol/l, AA: 2.6 ± 2.1 μmol/l; AA vs AG, AA vs GG: p < 0.05). In a multiple linear regression analysis, which controlled for age, C-peptide, cholesterol, systolic BP, BMI, and HbA_1c DHEAS was significantly negatively correlated with levels of cholesterol and positively with systolic BP only in females (p < 0.05). - Allelic frequency for G in diabetic subjects was 0.23 which was similar as compared to a non-diabetic population examined by us in an earlier study. GG-genotype was associated with low levels of DHEAS in diabetic patients but not with retinopathy. We suggest a role for UCP-1 polymorphism in the pathogenesis of obesity and arteriosclerosis. This hypothesis, however, needs further investigation.

Uncoupling protein-1 - DHEAS - diabetes mellitus

References

• 1 Clément K, Riuz J, Cassard-Doulcier A M, Bouillaud F, Ricquier D, Basdevant A, Guy-Grand B, Froguel P. Additive effect of A → G (- 3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the β3-adrenergic receptor gene on weight gain in morbid obesity.  Int J Obes Relat Metab Disord. 20 1062-1066 1996; 
• 2 Clore J N. Dehydroepiandrosterone and body fat.  Obes Res 4 ((Suppl)) 613S-616S 1995; 
• 3 Esterbauer H, Oberkofler H, Liu Y M, Breban D, Hell E, Krempler F, Patsch W. Uncoupling protein-1 mRNA expression in obese human subjects: the role of sequence variations at the uncoupling protein-1 gene locus.  J Lipid Res. 39 834-844 1998; 
• 4 Feldman H A, Johannes C B, McKinlay J B, Longcope C. Low dehydroepiandrosterone sulfate and heart disease in middle-aged men: cross sectional results from the Massachusetts Male Aging Study.  Ann Epidemiol. 8 217-228 1998; 
• 5 Fumeron F, Durack-Brown I, Cassard-Doulcier A M, Tuzet S, Bouillaud F, Melchior J C, Ricquier D, Apfelbaum M. Polymorphisms of uncoupling protein (UCP) and β3 adrenoreceptor genes in obese people submitted to a low caloric diet.  Int J Obes Relat Metab Disord. 20 1051-1054 1996; 
• 6 Kohner E M. Retinopathy Working Party . A protocol for screening for diabetic retinopathy in Europe.  Diabet Med. 8 263-267 1991; 
• 7 Lea-Currie Y R, Wen P, McIntosh M K. Dehydroepiandrosterone reduces proliferation and diferentiation of 3T3-L1 praeadipocytes.  Biochem Biophys Res Commun. 248 497-504 1998; 
• 8 Lea-Currie Y R, Wu S M, McIntosh M K. Effects of acute administration of dehydroepiandrosterone-sulfate on adipose tissue mass and cellularity in male rats.  Int J Obes Relat Metab Disord. 21 147-154 1997; 
• 9 Okamoto K. Distribution of dehydroepiandrosterone sulfate and relationships between its level and serum lipid levels in a rural japanese population.  J Epidemiol. 8 285-291 1998; 
• 10 Oppert J M, Vohl C M, Chagnon M, Dionne F T, Cassard-Doulcier A M, Ricquier D, Bouchard C. DNA polymorphism in the uncoupling protein (UCP) gene and human body fat.  Int J Obes Relat Metab Disord. 18 526-531 1994; 
• 11 Ricquier D, Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP.  Biochem J. 345 161-179 2000; 
• 12 Schaefer C, Friedman G, Ettinger B, Quesenberry C, Liu J, Haan M, Orentreich N, Vogelman J. Dehydroepiandrosterone sulfate (DHEAS), angina, and fatal ischemic heart disease. (Abstract).  Am J Epidemiol. 143 369 1996; 
• 13 Schäffler A, Palitzsch K-D, Watzlawek E, Drobnik W, Schwer H, Schölmerich J, Schmitz G. Frequency and significance of the AG (- 3826) polymorphism in the promoter gene of uncoupling protein-I with regard to metabolic parameters and adipocyte transcription factor binding in a large population-based Caucasian cohort.  Eur J Clin Invest. 29 770-779 1999; 
• 14 Schrauwen P, Walder K, Ravussin E. Human uncoupling proteins and obesity.  Obes Res. 7 97-105 1999; 
• 15 SPSS Inc .SPSS for Windows 95, V.7.5. SPSS Inc. Chicago 1997
• 16 Urhammer S A, Fridberg M, Sorensen T IA, Echwald S M, Andersen T, Tybjaerg-Hansen A, Clausen J O, Pedersen O. Studies of genetic variability of the uncoupling protein 1 gene in caucasian subjects with juvenile-onset obesity.  J Clin Endocrinol Metab. 82 4069-4074 1997; 
• 17 Walker K J, O'Dea K, Nicholson G C. Dietary composition affects regional body fat distribution and levvels of dehydroepiandrosterone sulphate (DHEAS) in pos-menopausal women with Type 2 diabetes.  Eur J Clin Nutr. 53 700-705 1999; 
• 18 Warden C. Genetics of uncoupling proteins in humans.  Int J Obes Relat Metab Disord 23 ((Suppl)) S46-S48 1999; 
• 19 Williams D P, Boyden T W, Pamenter R W, Lohmann T G, Going S B. Relationship of body fat percentage and fat distribution with dehydroepiandrosterone sulfate in premenopausal females.  Clin Endocrinol Metab. 77 80-85 1993;