Nitric oxide levels in patients with diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Altered serum nitric oxide (NO) levels in patients with diabetes mellitus (DM) have been reported by different studies; however, results are still controversial. Until this date, no meta-analysis evaluated the association of NO levels with DM. Thus, this paper describes a meta-analysis conducted to evaluate if there is a relationship between NO levels and type 1 DM (T1DM) or type 2 DM (T2DM). METHODS: A literature search was done to identify all studies that investigated NO levels between T1DM or T2DM patients (cases) and non-diabetic subjects (controls). Measurement of nitrate and nitrite (NOx - the stable NO products) were used to estimate NO concentrations because they closely reflect NO bioavailability. Weighted mean differences (WMD) of NOx levels between case and control samples were calculated for T1DM and T2DM groups. RESULTS: Thirty studies were eligible for inclusion in the meta-analysis (8 in T1DM samples and 22 in T2DM samples). NOx levels were increased in European T1DM patients compared with controls [random effect model (REM) WMD = 8.55, 95% CI 2.88 - 14.21]. No other ethnicity was evaluated in T1DM studies. NOx levels were also increased in both European (REM WMD = 18.76, 95% CI 1.67 - 35.85) and Asian (REM WMD = 18.41, 95% CI 8.01 - 28.81) T2DM patients, but not in Latin American patients compared with controls. CONCLUSIONS: This meta-analysis detected a significant increase in NOx levels in European T1DM patients as well as European and Asian T2DM patients. Further studies in other ethnicities are necessary to confirm these data.

Itraconazole in human medicine and veterinary practice.

Diagnosis and management of fungal infections are challenging in both animals and humans, especially in immunologically weakened hosts. Due to its broad spectrum and safety profile when compared to other antifungals, itraconazole (ITZ) has been widely used in the treatment and prophylaxis of fungal infections, both in human and veterinary medicine. The dose and duration of management depend on factors such as the type of fungal pathogen, the site of infection, sensitivity to ITZ, chronic stages of the disease, the health status of the hosts, pharmacological interactions with other medications and the therapeutic protocol used. In veterinary practice, ITZ doses generally vary between 3 mg/kg and 50 mg/kg, once or twice a day. In humans, doses usually vary between 100 and 400 mg/day. As human and veterinary fungal infections are increasingly associated, and ITZ is one of the main medications used, this review addresses relevant aspects related to the use of this drug in both clinics, including case reports and different clinical aspects available in the literature.

The presence of the -866A/55Val/Ins haplotype in the uncoupling protein 2 (UCP2) gene is associated with decreased UCP2 gene expression in human retina.

Uncoupling protein 2 (UCP2) is a mitochondrial transporter present in the inner membrane of mitochondria, and it uncouples substrate oxidation from ATP synthesis, thereby dissipating the membrane potential energy and consequently decreasing ATP production by mitochondrial respiratory chain. As a consequence of the uncoupling, UCP2 decreases the reactive oxygen species (ROS) formation by mitochondria. ROS overproduction is related to diabetic retinopathy (DR), a chronic complication of diabetes mellitus (DM). Recently, our group reported that the -866A/55Val/Ins haplotype (-866G/A, Ala55Val and Ins/Del polymorphisms) of the UCP2 gene was associated with increased risk for DR in patients with DM. The purpose of this study was to analyze the effect of this haplotype on UCP2 gene expression in human retina. In addition, MnSOD2 gene expression was also investigated according to different UCP2 haplotypes. This cross-sectional study included 188 cadaveric cornea donors. In a subset of 91 retinal samples differentiated according to the presence of the mutated UCP2 haplotype and risk alleles of the -866G/A and Ins/Del polymorphisms, UCP2 and MnSOD2 gene expressions were measured by semi-quantitative RT-qPCR. Mutated UCP2 haplotype carriers (homozygous + heterozygous) had a lower UCP2 gene expression than reference haplotype carriers (8.4 ± 7.6 vs. 18.8 ± 23.7 arbitrary units; P = 0.046). Accordingly, UCP2 gene expression was decreased in -866A carriers when compared with G/G carriers (P = 0.010). UCP2 gene expression did not differ between Ins allele carriers and Del/Del carriers (P = 0.556). Interestingly, subjects carrying the heterozygous UCP2 haplotype showed increased MnSOD2 gene expression (P = 0.025). This is the first report suggesting that the presence of the -866A/55Val/Ins haplotype is associated with decreased UCP2 gene expression in human retina. Possibly, MnSOD2 expression might influence the UCP2 effect in the protection against oxidative stress.

-866G/A and Ins/Del polymorphisms in UCP2 gene are associated with reduced short-term weight loss in patients who underwent Roux-en-Y gastric bypass.

BACKGROUND: Uncoupling protein 2 (UCP2) plays an important role in energy expenditure regulation. Previous studies have associated the common -866G/A (rs659366) and Ins/Del polymorphisms in the UCP2 gene with metabolic and obesity-related phenotypes. However, it is still unclear whether these polymorphisms influence weight loss after bariatric surgery. OBJECTIVES: To investigate whether UCP2 -866G/A and Ins/Del polymorphisms are associated with weight loss outcomes after bariatric surgery. SETTING: Longitudinal study in a university hospital. METHODS: We retrospectively evaluated 186 patients who underwent Roux-en-Y gastric bypass (RYGB) surgery for clinical and laboratory characteristics in the preoperative period, 6, 12, and 18 months after RYGB. The -866G/A (rs659366) polymorphism was genotyped using real-time PCR, while the Ins/Del polymorphism was genotyped by direct separation of PCR products in 2.5% agarose gels. RESULTS: Patients with the -866A/A genotype showed higher body mass index (BMI) after 6, 12, and 18 months of surgery and excess body weight after 6 and 12 months compared with G/G patients. They also showed lower excess weight loss (EWL%) after 6 and 12 months of surgery. Ins allele carriers (Ins/Ins + Ins/Del) had lower delta (Δ) BMI 12 months after surgery compared with Del/Del patients. Accordingly, patients carrying haplotypes with ≥2 risk alleles of these polymorphisms had higher BMI and excess weight and lower EWL% during follow-up. CONCLUSION: UCP2 -866A/A genotype is associated with higher BMI and excess weight and lower EWL% during an 18-month follow-up of patients who underwent RYGB, while the Ins allele seems to be associated with lower ΔBMI 12 months after surgery. Further studies are needed to confirm the associations of the -866G/A and Ins/Del polymorphisms with weight loss after bariatric surgery.

Polymorphisms of the UCP2 gene are associated with proliferative diabetic retinopathy in patients with diabetes mellitus.

BACKGROUND AND OBJECTIVE: Uncoupling protein 2 (UCP2) plays a role in controlling reactive oxygen species (ROS) production by mitochondria. As ROS overproduction is related to diabetic retinopathy (DR), UCP2 gene polymorphisms might be involved in the development of this complication. We investigated whether the -866G/A (rs659366), Ala55Val (rs660339) and 45 bp insertion/deletion (Ins/Del) polymorphisms in the UCP2 gene might be associated with proliferative DR (PDR). DESIGN AND METHODS: In this case-control study, we analysed 501 type 2 diabetic patients (242 patients with PDR and 259 subjects without any degree of DR) and 196 type 1 diabetic patients (85 cases with PDR and 111 without DR). Haplotypes constructed from the combination of the three UCP2 polymorphisms were inferred using a Bayesian statistical method. RESULTS: In the type 2 diabetic group, multivariate analyses confirmed that the haplotype [A Val Ins] was an independent risk factor for PDR when present in one [adjusted odds ratio (aOR) = 2.12; P = 0.006], at least one (aOR = 2.75; P = 0.00001), or two copies (aOR = 5.30; P = 0.00001), suggesting an additive model of inheritance. Nevertheless, in type 1 diabetic patients, the association of this haplotype with PDR was confirmed only when it was present in at least one (aOR = 2.68; P = 0.014) or two copies (aOR = 6.02; P = 0.005). CONCLUSIONS: The haplotype [A Val Ins] seems to be an important risk factor associated with PDR in both type 2 and 1 diabetic groups.

UCP2, IL18, and miR-133a-3p are dysregulated in subcutaneous adipose tissue of patients with obesity.

The aim of this study was to compare the expression of UCP2, NLRP3, IL1B, IL18, and miR-133a-3p in subcutaneous adipose tissue (SAT) of 61 patients divided according to BMI: Group 1 (n = 8; BMI<25.0 kg/m2), Group 2 (n = 24; BMI 30.0-39.9 kg/m2), and Group 3 (n = 29; BMI≥40.0 kg/m2). SAT biopsies were obtained from individuals who underwent bariatric surgery or elective abdominal surgery. Gene expressions were quantified using qPCR. Bioinformatics analyses were employed to investigate target genes and pathways related to miR-133a-3p. UCP2 and miR-133a-3p expressions were decreased in SAT of Groups 2 and 3 while IL18 was increased compared to Group 1. NLRP3 and IL1B expressions did not differ between groups; however, NLRP3 was positively correlated with waist circumference and excess weight. Bioinformatics analysis demonstrated that UCP2 and NLRP3 are targets of miR-133a-3p. In conclusion, UCP2 and miR-133a-3p expressions are downregulated in patients with obesity, while IL18 is upregulated. NRLP3 is correlated with waist circumference and weight excess.

Improvement of human pancreatic islet quality after co-culture with human adipose-derived stem cells.

The aim of this study was to investigate whether co-culture of human islets with adipose-derived stem cells (ASCs) can improve islet quality and to evaluate which factors play a role in the protective effect of ASCs against islet dysfunction. Islets and ASCs were cultured in three experimental groups for 24 h, 48 h, and 72 h: 1) indirect co-culture of islets with ASC monolayer (Islets/ASCs); 2) islets alone; and 3) ASCs alone. Co-culture with ASCs improved islet viability and function in all culture time-points analyzed. VEGFA, HGF, IL6, IL8, IL10, CCL2, IL1B, and TNF protein levels were increased in supernatants of islet/ASC group compared to islets alone, mainly after 24 h. Moreover, VEGFA, IL6, CCL2, HIF1A, XIAP, CHOP, and NFKBIA genes were differentially expressed in islets from the co-culture condition compared to islets alone. In conclusion, co-culture of islets with ASCs promotes improvements in islet quality.

Interaction of HSD11B1 and H6PD polymorphisms in subjects with type 2 diabetes are protective factors against obesity: a cross-sectional study.

BACKGROUND: The enzyme 11-beta hydroxysteroid dehydrogenase type 1 (HSD11B1) converts inactive cortisone to active cortisol in a process mediated by the enzyme hexose-6-phosphate dehydrogenase (H6PD). The generation of cortisol from this reaction may increase intra-abdominal cortisol levels and contribute to the physiopathogenesis of obesity and metabolic syndrome (MetS). The relationship of HSD11B1 rs45487298 and H6PD rs6688832 polymorphisms with obesity and MetS was studied. We also studied how HSD11B1 abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) gene expression is related to body fat distribution. METHODS: Rates of obesity and MetS features were cross-sectionally analyzed according to these polymorphisms in 1006 Brazilian white patients with type 2 diabetes (T2DM). Additionally, HSD11B1 expression was analyzed in VAT and SAT in a different cohort of 28 participants with and without obesity who underwent elective abdominal operations. RESULTS: Although polymorphisms of the two genes were not individually associated with MetS features, a synergistic effect was observed between both. Carriers of at least three minor alleles exhibited lower BMI compared to those with two or fewer minor alleles adjusting for gender and age (27.4 ± 4.9 vs. 29.3 ± 5.3 kg/m2; P = 0.005; mean ± SD). Obesity frequency was also lower in the first group (24.4% vs. 41.6%, OR = 0.43, 95% CI 0.21-0.87; P = 0.019). In the second cohort of 28 subjects, HSD11B1 gene expression in VAT was inversely correlated with BMI (r = - 0.435, P = 0.034), waist circumference (r = - 0.584, P = 0.003) and waist-to-height ratio (r = - 0.526, P = 0.010). CONCLUSIONS: These polymorphisms might interact in the protection against obesity in T2DM individuals. Obese individuals may have decreased intra-abdominal VAT HSD11B1 gene expression resulting in decreasing intra-abdominal cortisol levels as a compensatory mechanism against central and general adiposity.

MicroRNAs and diabetic kidney disease: Systematic review and bioinformatic analysis.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. Emerging evidence has suggested a role for miRNAs in the development of diabetic kidney disease (DKD), indicating that miRNAs may represent potential biomarkers of this disease. However, results are still inconclusive. Therefore, we performed a systematic review of the literature on the subject, followed by bioinformatic analysis. PubMed and EMBASE were searched to identify all studies that compared miRNA expressions between patients with DKD and diabetic patients without this complication or healthy subjects. MiRNA expressions were analyzed in kidney biopsies, urine/urinary exosomes or total blood/plasma/serum. MiRNAs consistently dysregulated in DKD patients were submitted to bioinformatic analysis to retrieve their putative target genes and identify potentially affected pathways under their regulation. As result, twenty-seven studies were included in the systematic review. Among 151 dysregulated miRNAs reported in these studies, 6 miRNAs were consistently dysregulated in DKD patients compared to controls: miR-21-5p, miR-29a-3p, miR-126-3p, miR-192-5p, miR-214-3p, and miR-342-3p. Bioinformatic analysis indicated that these 6 miRNAs are involved in pathways related to DKD pathogenesis, such as apoptosis, fibrosis, and extracellular matrix accumulation. In conclusion, six miRNAs seem to be dysregulated in patients with different stages of DKD, constituting potential biomarkers of this disease.

Role of Innate Immunity in Preeclampsia: A Systematic Review.

Innate immune system dysfunction has been known to be a key player in preeclampsia (PE). Activation of the maternal innate immunity may be triggered by invading microorganisms or endogenous ligands, which are detected by different pattern recognition receptors (PRRs). Although some studies have linked PRR activation to PE, it is still unclear if dysregulated PRR expression is associated with the development of this complication. Therefore, we conducted a systematic review of the literature, searching articles that evaluated associations of PRRs with PE. Twenty-six studies met the inclusion criteria: 20 of them analyzed PRR expressions and 6 studies investigated the association between PRR polymorphisms and PE. Among the PRRs, only few studies analyzed retinoic acid-inducible gene I-like helicase (RLH) and/or toll-like receptor (TLR)-1, 5, 6, 7, 8, and 9 expressions in immune cells or placentas from women with PE and controls; thus, it is inconclusive if these PRRs are involved in PE. Results from the 10 studies that analyzed TLR-2 expressions in women with PE and controls are also contradictory. The majority of the studies that investigated TLR-3 and -4 expressions indicate that these PRRs are increased in placenta or immune cells from women with PE compared to pregnant control woman. To date, polymorphisms in TLR-2, - 3, and - 4 and nucleotide-binding oligomerization domain-like receptor 2 genes do not seem to be associated with PE development. No study has evaluated the association between polymorphisms in genes codifying other TLRs or RLHs genes. In conclusion, available data in literature support a role for TLR-3 and TLR-4 in the pathogenesis of PE.

MicroRNA expression profiles and type 1 diabetes mellitus: systematic review and bioinformatic analysis.

Growing evidence indicates that microRNAs (miRNAs) have a key role in processes involved in type 1 diabetes mellitus (T1DM) pathogenesis, including immune system functions and beta-cell metabolism and death. Although dysregulated miRNA profiles have been identified in T1DM patients, results are inconclusive; with only few miRNAs being consistently dysregulated among studies. Thus, we performed a systematic review of the literature on the subject, followed by bioinformatic analysis, to point out which miRNAs are dysregulated in T1DM-related tissues and in which pathways they act. PubMed and EMBASE were searched to identify all studies that compared miRNA expressions between T1DM patients and non-diabetic controls. Search was completed in August, 2017. Those miRNAs consistently dysregulated in T1DM-related tissues were submitted to bioinformatic analysis, using six databases of miRNA-target gene interactions to retrieve their putative targets and identify potentially affected pathways under their regulation. Thirty-three studies were included in the systematic review: 19 of them reported miRNA expressions in human samples, 13 in murine models and one in both human and murine samples. Among 278 dysregulated miRNAs reported in these studies, 25.9% were reported in at least 2 studies; however, only 48 of them were analyzed in tissues directly related to T1DM pathogenesis (serum/plasma, pancreas and peripheral blood mononuclear cells (PBMCs)). Regarding circulating miRNAs, 11 were consistently dysregulated in T1DM patients compared to controls: miR-21-5p, miR-24-3p, miR-100-5p, miR-146a-5p, miR-148a-3p, miR-150-5p, miR-181a-5p, miR-210-5p, miR-342-3p, miR-375 and miR-1275. The bioinformatic analysis retrieved a total of 5867 validated and 2979 predicted miRNA-target interactions for human miRNAs. In functional enrichment analysis of miRNA target genes, 77 KEGG terms were enriched for more than one miRNA. These miRNAs are involved in pathways related to immune system function, cell survival, cell proliferation and insulin biosynthesis and secretion. In conclusion, eleven circulating miRNAs seem to be dysregulated in T1DM patients in different studies, being potential circulating biomarkers of this disease.

Current role of the NLRP3 inflammasome on obesity and insulin resistance: A systematic review.

NLRP3 inflammasome activation seems to be a culprit behind the chronic inflammation characteristic of obesity and insulin resistance (IR). Nutrient excess generates danger-associated molecules that activate NLRP3 inflammasome-caspase 1, leading to maturation of IL-1ß and IL-18, which are proinflammatory cytokines released by immune cells infiltrating the adipose tissue (AT) from obese subjects. Although several studies have reported an association of the NLRP3 inflammasome with obesity and/or IR; contradictory results were also reported by other studies. Therefore, we conducted a systematic review to summarize results of studies that evaluated the association of the NLRP3 with obesity and IR. Nineteen studies were included in the review. These studies focused on NLRP3 expression/polymorphism analyses in AT. Overall, human studies indicate that obesity and IR are associated with increased NLRP3 expression in AT. Studies in obese mice corroborate this association. Moreover, high fat diet (HFD) increases Nlrp3 expression in murine AT while calorie-restricted diet decreases its expression. Hence, Nlrp3 blockade in mice protects against HFD-induced obesity and IR. NLRP3 rs10754558 polymorphism is associated with risk for T2DM in Chinese Han populations. In conclusion, available studies strongly points for an association between NLRP3 inflammasome and obesity/IR.

GLIS3 rs7020673 and rs10758593 polymorphisms interact in the susceptibility for type 1 diabetes mellitus.

AIMS: The transcription factor Gli-similar 3 (GLIS3) plays a key role in the development and maintenance of pancreatic beta cells as well as in the regulation of Insulin gene expression in adults. Accordingly, genome-wide association studies identified GLIS3 as a susceptibility locus for type 1 diabetes mellitus (T1DM) and glucose metabolism traits. Therefore, the aim of this study was to replicate the association of the rs10758593 and rs7020673 single nucleotide polymorphisms (SNPs) in the GLIS3 gene with T1DM in a Brazilian population. METHODS: Frequencies of the rs7020673 (G/C) and rs10758593 (A/G) SNPs were analyzed in 503 T1DM patients (cases) and in 442 non-diabetic subjects (controls). Haplotypes constructed from the combination of these SNPs were inferred using a Bayesian statistical method. RESULTS: Genotype and allele frequencies of rs7020673 and rs10758593 SNPs did not differ significantly between case and control groups. However, the frequency of ≥3 minor alleles of the analyzed SNPs in haplotypes was higher in T1DM patients compared to non-diabetic subjects (6.2 vs. 1.6%; P = 0.001). The presence of ≥3 minor alleles remained independently associated with risk of T1DM after adjustment for T1DM high-risk HLA DR/DQ haplotypes, age and ethnicity (OR = 3.684 95% CI 1.220-11.124). Moreover, levels of glycated hemoglobin seem to be higher in T1DM patients with rs10758593 A/A genotype than patients carrying the G allele of this SNP (P = 0.038), although this association was not kept after Bonferroni correction. CONCLUSIONS: Our results indicate that individually the rs7020673 and rs10758593 SNPs are not significantly associated with T1DM but seem to interact in the predisposition for this disease.

rs1888747 polymorphism in the FRMD3 gene, gene and protein expression: role in diabetic kidney disease.

BACKGROUND: We carried out a case-control study in patients with type 2 diabetes mellitus (T2DM) to evaluate the association between seven single nucleotide polymorphisms (SNPs) previously described to be linked to diabetic kidney disease (DKD) in type 1 diabetes mellitus (T1DM). Additionally, we evaluated gene and protein expression related to the polymorphism associated with DKD. METHODS: The association study included 1098 T2DM patients (718 with DKD and 380 without DKD). Out of the 13 polymorphisms associated with DKD in a previous study with T1DM, seven were chosen for evaluation in this sample: rs1888747, rs9521445, rs39075, rs451041, rs1041466, rs1411766 and rs6492208. The expression study included 91 patients who underwent nephrectomy. Gene expression was assessed by RT-qPCR and protein expression in kidney samples was quantified by western blot and it localization by immunohistochemistry. RESULTS: The C/C genotype of rs1888747 SNP was associated with protection for DKD (OR = 0.6, 95 % CI 0.3-0.9; P = 0.022). None of the other SNPs were associated with DKD. rs1888747 is located near FRMD3 gene. Therefore, FRMD3 gene and protein expression were evaluated in human kidney tissue according to rs1888747 genotypes. Gene and protein expression were similar in subjects homozygous for the C allele and in those carrying the G allele. CONCLUSIONS: Replication of the association between rs1888747 SNP and DKD in a different population suggests that this link is not the result of chance. rs1888747 SNP is located at the FRMD3 gene, which is expressed in human kidney. Therefore, this gene is a candidate gene for DKD. However, in this study, no rs1888747 genotype or specific allele effect on gene and/or protein expression of the FRMD3 gene was demonstrated.

Meta-analysis reveals the association of common variants in the uncoupling protein (UCP) 1-3 genes with body mass index variability.

BACKGROUND: The relationship between uncoupling protein (UCP) 1-3 polymorphisms and susceptibility to obesity has been investigated in several genetic studies. However, the impact of these polymorphisms on obesity is still under debate, with contradictory results being reported. Until this date, no meta-analysis evaluated the association of UCP polymorphisms with body mass index (BMI) variability. Thus, this paper describe a meta-analysis conducted to evaluate if the -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3) polymorphisms are associated with BMI changes. METHODS: A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and BMI. Weighted mean differences (WMD) were calculated for different inheritance models. RESULTS: Fifty-six studies were eligible for inclusion in the meta-analysis. Meta-analysis results showed that UCP2 55Val/Val genotype was associated with increased BMI in Europeans [Random Effect Model (REM) WMD 0.81, 95% CI 0.20, 1.41]. Moreover, the UCP2 Ins allele and UCP3-55T/T genotype were associated with increased BMI in Asians [REM WMD 0.46, 95% CI 0.09, 0.83 and Fixed Effect Model (FEM) WMD 1.63, 95% CI 0.25, 3.01]. However, a decreased BMI mean was observed for the UCP2-866 A allele in Europeans under a dominant model of inheritance (REM WMD -0.18, 95% CI -0.35, -0.01). There was no significant association of the UCP1-3826A/G polymorphism with BMI mean differences. CONCLUSIONS: The meta-analysis detected a significant association between the UCP2-866G/A, Ins/Del, Ala55Val and UCP3-55C/T polymorphisms and BMI mean differences.

Associations between UCP1 -3826A/G, UCP2 -866G/A, Ala55Val and Ins/Del, and UCP3 -55C/T polymorphisms and susceptibility to type 2 diabetes mellitus: case-control study and meta-analysis.

BACKGROUND: Some studies have reported associations between five uncoupling protein (UCP) 1-3 polymorphisms and type 2 diabetes mellitus (T2DM). However, other studies have failed to confirm the associations. This paper describes a case-control study and a meta-analysis conducted to attempt to determine whether the following polymorphisms are associated with T2DM: -3826A/G (UCP1); -866G/A, Ala55Val and Ins/Del (UCP2) and -55C/T (UCP3). METHODS: The case-control study enrolled 981 T2DM patients and 534 nondiabetic subjects, all of European ancestry. A literature search was run to identify all studies that investigated associations between UCP1-3 polymorphisms and T2DM. Pooled odds ratios (OR) were calculated for allele contrast, additive, recessive, dominant and co-dominant inheritance models. Sensitivity analyses were performed after stratification by ethnicity. RESULTS: In the case-control study the frequencies of the UCP polymorphisms did not differ significantly between T2DM and nondiabetic groups (P>0.05). Twenty-three studies were eligible for the meta-analysis. Meta-analysis results showed that the Ala55Val polymorphism was associated with T2DM under a dominant model (OR = 1.27, 95% CI 1.03-1.57); while the -55C/T polymorphism was associated with this disease in almost all genetic models: allele contrast (OR = 1.17, 95% CI 1.02-1.34), additive (OR = 1.32, 95% CI 1.01-1.72) and dominant (OR = 1.18, 95% CI 1.02-1.37). However, after stratification by ethnicity, the UCP2 55Val and UCP3 -55C/T alleles remained associated with T2DM only in Asians (OR = 1.25, 95% CI 1.02-1.51 and OR = 1.22, 95% CI 1.04-1.44, respectively; allele contrast model). No significant association of the -3826A/G, -866G/A and Ins/Del polymorphisms with T2DM was observed. CONCLUSIONS: In our case-control study of people with European ancestry we were not able to demonstrate any association between the UCP polymorphisms and T2DM; however, our meta-analysis detected a significant association between the UCP2 Ala55Val and UCP3 -55C/T polymorphisms and increased susceptibility for T2DM in Asians.

The UCP1 -3826A/G polymorphism is associated with diabetic retinopathy and increased UCP1 and MnSOD2 gene expression in human retina.

PURPOSE: Uncoupling protein 1 (UCP1) reduces mitochondrial production of reactive oxygen species (ROS). ROS overproduction is related to diabetic retinopathy (DR), a chronic complication of diabetes mellitus (DM). Therefore, deleterious polymorphisms in the UCP1 gene are candidate risk factors for DR. We investigated the relationships between the UCP1 -3826A/G polymorphism and risk of DR and UCP1 gene expression in human retina. Considering that superoxide dismutase-2 (MnSOD2) enzyme is the first line of defense against oxidative stress in mitochondria, we also analyzed MnSOD2 gene expression in retinal samples according to different UCP1 -3826A/G genotypes. METHODS: In a case-control study, frequencies of -3826A/G polymorphisms were analyzed in 257 type 1 DM patients (154 cases with DR and 103 controls without DR). In a cross-sectional study comprising cadaveric cornea donors, UCP1 and MnSOD2 gene expressions were evaluated in 107 retinal samples differentiated according to different -3826A/G genotypes. RESULTS: In the type 1 DM group, multivariate analysis confirmed that the G/G genotype was an independent risk factor for DR (OR = 3.503; P = 0.043). In cornea donors, G allele carriers had higher UCP1 cDNA and protein concentrations than A/A carriers (P = 0.034 and P = 0.039, respectively). Interestingly, G allele carriers exhibited increased MnSOD2 expression (P = 0.001). CONCLUSIONS: This study suggests that the -3826A/G polymorphism is associated with DR in type 1 DM patients. This is the first report demonstrating UCP1 gene expression in human retinas and indicates that the -3826A/G polymorphism influences its expression. In addition, the -3826G allele was associated with increased MnSOD2 expression; thus, suggesting that this allele could be a marker of oxidative stress.