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 micromol/l, AG: 2.2+/-1.8 micromol/l, AA: 2.6+/-2.1 micromol/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 HbA1c 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.