| The pathophysiology of type 2 diabetes mellitus (T2DM) includes two interrelated defects: impaired insulin action and failure of pancreatic β-cell to compensate through increasing insulin secretion for the enhanced insulin demand. As a proton carrier in mitochondria inner membrane, UCP-2 can transport H+ from outside to inside of mitochondria inner membrane and decrease electro-chemical gradient of the two sides of membrane during oxidative process, the result is that oxidative process is uncoupled and ATP production is compromised. Recent studies have indicated that UCP-2 could affect the function of ( cell. Increased expression of UCP-2 could decrease insulin secretion. Chromosome 11q13, where uncoupling protein 2 locates, was found to be linked to T2DM and hyperinsulinemia, but no conformed relation to T2DM was found with variations in its coding region and therefore, may be not related to T2DM. A common variation of -866G/A in its promoter has been found to be related to the expression of UCP-2 and the insulin level of the A/A carrier was lower and less insulin was produced under glucose challenge. -866G/A polymorphism has been found related to T2DM in Westerners. There is no report for the -866G/A polymorphism in Chinese T2DM until now.Objective To analyze the UCP-2 -866G/A polymorphism in non-diabetics and T2DM subjects and to study its relationship to the development of T2DM.Methods 125 patients with T2DM (60 men and 65 women, mean age 61.4±13.3 yrs) and 80 non-diabetic subjects with fasting glucose less than 6.0mmol/L (50 men and 30 women, mean age 60.4±10.1 yrs) were selected. Genomic DNA was isolated from peripheral blood cells according to standard procedures. Sense and anti-sense primers were designed according to the sequence of UCP-2 promoter, 369bp fragments of polymerase chain reaction spanning the -866G/A nucleotide was amplified. The products were digested with restriction enzyme Mlu I for three hours. The genotypes were read after separation of the digested products with 1% agarose gel electrophoresis. Different distribution in genotypes between diabetic and non-diabetic subjects was analyzed; the islet function for different genotype was also studied. Multivariate Logistic regression was taken between genotypes (1 was designed to GG and GA, 2 to AA) and present of type 2 diabetes mellitus.Results1. The frequency of -866G/A polymorphism was GG 47.5%, GA 35%, AA 17.5%; the frequency of allele was G 65% and A 35% in non-diabetes, the distribution was in Hardy-Weinberg equilibration. The frequency of -866G/A polymorphism was GG 36%, GA 32.8%, AA 31.2%; the frequency of allele was G 52.4%, A 47.6% in T2DM. The frequency of AA genotype and the frequency of allele A were significantly higher in diabetes than in non-diabetes ((2=7.414, P=0.023 and (2=6.331, P=0.014, respectively). 2. The mean C peptide value in non-diabetes subject was GG 1.44±0.64mmol/l, GA 1.86±1.37mmol/l, and AA 0.59±0.35mmol/l. There was no significant difference between GG and GA genotype. But there was significant difference between AA and GA/GG. The insulin levels among all of groups were not significantly different.3 .The mean C peptide value in T2DM subjects was GG 0.87±0.8mmol/l, GA 0.91±0.71mmol/l, AA 0.57±0.71mmol/l. There was no significant difference among all of groups.4.Multivariate Logistic regression analysis showed that -866G/A polymorphism, TC and TG were positively and significantly related to T2DM. The partial regression coefficients were 1.49, 1.15, and 0.93, respectively.Conclusions The frequency of -866G/A genotypes in UCP-2 promoter was found to be significantly different between non-diabetes subjects and diabetic patients. Lower ( cell function, as indicated with the C peptide value, in subjects with AA genotype was observed. Therefore, the UCP-2 -866G/A polymorphism might contribute to the development of T2DM. |
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