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

The A -->G (-3826) point mutation within the distal region of the uncouplin g-protein-1 (UCP-1) promoter is possibly involved in the development of obe sity diabetes and related disorders. DHEAS has been found to stimulate expr ession of UCP-1-mRNA. The aim of our study was to evaluate the prevalence o f 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 o f DHEAS and with obesity, diabetes and retinopathy were examined.- In 549 d iabetic patients (312 males and 237 females) out of a population-based samp le UCP-1 genotype was determined by genomic PCR and Bcl-I-RFLP analysis. Se rum 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 55.3% (n = 320). The genotype groups were comparable with respect to sex, BMI, H bA1c, systolic blood pressure (BP), retinopathy and also to serum levels of C-peptide, leptin and cortisol. Serum levels of DHEAS were lowest in GG-ge notype as compared to AG and AA (GG: 1.8 +/-1.5 mu mol/l, AG: 2.2 +/-1.8 mu mol/l, AA: 2.6 +/-2.1 mu mol/l; AA vs AG, AA vs GG: p<0.05). In a multiple linear regression analysis, which controlled for age, C-peptide, cholester ol, systolic BP, BMI, and HbA(1c), DHEAS was significantly negatively corre lated with levels of cholesterol and positively with systolic BP only in fe males (p<0.05). - Allelic frequency for G in diabetic subjects was 0.23 whi ch was similar as compared to a non-diabetic population examined by us in a n earlier study GG-genotype was associated with low levels of DHEAS in diab etic patients but not with retinopathy. We suggest a role for UCP-1 polymor phism in the pathogenesis of obesity and arteriosclerosis. This hypothesis, however, needs further investigation.