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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.
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The identification of risk factors for acute rejection (AR) may lead to strategies to improve success of kidney transplantation. Ectonucleotidases are ectoenzymes that hydrolyze extracellular nucleotides into nucleosides, modulating the purinergic signaling. Some members of the Ectonucleotidase family have been linked to transplant rejection processes. However, the association of Ectonucleotide Pyrophosphatase / Phosphodiesterase 1 (ENPP1) with AR has not yet been evaluated. The aim of this study was to evaluate the association between the K121Q polymorphism of ENPP1 gene and AR in kidney transplant patients. We analyzed 449 subjects without AR and 98 with AR from a retrospective cohort of kidney transplant patients from Southern Brazil. K121Q polymorphism was genotyped using allelic discrimination-real-time PCR. Cox regression analysis was used to evaluate freedom of AR in kidney transplant patients according to genotypes. Q allele frequency was 17.6% in recipients without AR and 21.9% in those with AR (P = 0.209). Genotype frequencies of the K121Q polymorphism were in Hardy-Weinberg equilibrium in non-AR patients (P = 0.70). The Q/Q genotype (recessive model) was associated with AR (HR = 2.83, 95% CI 1.08-7.45; P = 0.034) after adjusting for confounders factors. Our findings suggest a novel association between the ENPP1 121Q/Q genotype and AR in kidney transplant recipients.
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Rejeição de Enxerto/enzimologia , Rejeição de Enxerto/genética , Transplante de Rim/efeitos adversos , Diester Fosfórico Hidrolases/genética , Pirofosfatases/genética , Doença Aguda , Substituição de Aminoácidos , Brasil , Estudos de Casos e Controles , Estudos de Coortes , Frequência do Gene , Genes Recessivos , Estudos de Associação Genética , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Estudos RetrospectivosRESUMO
AIMS: The aim of this study was to investigate a miRNA expression profile in type 1 diabetes mellitus (T1DM) patients with DKD (cases) or without this complication (controls). METHODS: Expression of 48 miRNAs was screened in plasma of 58 T1DM patients (23 controls, 18 with moderate DKD, and 17 with severe DKD) using TaqMan Low Density Array cards (Thermo Fisher Scientific). Then, five of the dysregulated miRNAs were selected for validation in an independent sample of 10 T1DM controls and 19 patients with DKD (10 with moderate DKD and 9 with severe DKD), using RT-qPCR. Bioinformatic analyses were performed to explore the putative target genes and biological pathways regulated by the validated miRNAs. RESULTS: Among the 48 miRNAs investigated in the screening analysis, 9 miRNAs were differentially expressed between DKD cases and T1DM controls. Among them, the five most dysregulated miRNAs were chosen for validation in an independent sample. In the validation sample, miR-21-3p and miR-378-3p were confirmed to be upregulated in patients with severe DKD, while miR-16-5p and miR-29a-3p were downregulated in this group compared to T1DM controls and patients with moderate DKD. MiR-503-3p expression was not validated. Bioinformatic analyses indicate that the four validated miRNAs regulate genes from PI3K/Akt, fluid shear stress and atherosclerosis, AGE-RAGE, TGF-ß1, and relaxin signaling pathways. CONCLUSIONS: Our study found four miRNAs differentially expressed in patients with severe DKD, providing significant information about the biological pathways in which they are involved.
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Diabetes Mellitus Tipo 1/sangue , Nefropatias Diabéticas/sangue , MicroRNAs/sangue , Adolescente , Adulto , Estudos de Casos e Controles , Biologia Computacional/métodos , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , MicroRNAs/genética , Análise em Microsséries , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Adulto JovemRESUMO
AIMS: To investigate a miRNA expression profile in plasma of type 1 diabetes (T1DM) patients and control subjects and analyze the putative pathways involved. METHODS: Expressions of 48 miRNAs were analyzed in plasma of 33 T1DM patients and 26 age-and-gender-matched controls using Stem-loop RT-PreAmp PCR and TaqMan Low Density Arrays (Thermo Fisher Scientific). Five dysregulated miRNAs were then chosen for validation in an independent sample of 27 T1DM patients and 14 controls, using RT-qPCR. Bioinformatic analyses were performed to determine in which pathways these miRNAs are involved. RESULTS: Nine miRNAs were differentially expressed between recently-diagnosed T1DM patients (<5 years of diagnosis) and controls. No differences were observed between patients with ≥5â¯years of diagnosis and controls. After validation in an independent sample of T1DM patients, miR-103a-3p, miR-155-5p, miR-200a-3p, and miR-210-3p were confirmed as being upregulated in recently-diagnosed T1DM patients compared with controls or patients with ≥5â¯years of diagnosis. Moreover, miR-146a-5p was downregulated in recently-diagnosed T1DM patients compared with the other groups. These five miRNAs regulate several genes from innate immune system-, MAPK-, apoptosis-, insulin- and cancer-related pathways. CONCLUSION: Five miRNAs are dysregulated in recently-diagnosed T1DM patients and target several genes involved in pathways related to T1DM pathogenesis, thus representing potential T1DM biomarkers.
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Biologia Computacional/métodos , Diabetes Mellitus Tipo 1/genética , MicroRNAs/metabolismo , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Humanos , Masculino , Adulto JovemRESUMO
AIMS: Type 1 diabetes mellitus (T1DM) is characterized by severe autoimmune destruction of pancreatic beta-cells. The triggering of autoimmunity against beta-cells is probably caused by a combination of environmental and genetic risk factors. Even though much is known about the genetic of T1DM, more information is needed to completely unravel this tangled disease. MicroRNAs (miRNAs) are a class of small noncoding RNAs molecules that negatively regulate gene expression by inducing target mRNA cleavage or by inhibiting protein translation. Abnormal miRNA expressions have been described in autoimmune diseases and T1DM. Polymorphisms in genes codifying miRNAs may alter the expression of the corresponding miRNA and, thus, confer susceptibility for a given disease. Therefore, the aim of this study was to investigate whether polymorphisms in genes encoding miR-155, miR-146a, and miR-375 are associated with T1DM. METHODS: Frequencies of the miRNA-146a rs2910164, miRNA-155 rs767649 and miRNA-375 rs6715345 polymorphisms were analyzed in 490 T1DM patients and in 469 nondiabetic subjects. RESULTS: The miR-146a rs2910164 and miR-155 rs767649 polymorphisms were associated with protection for T1DM, and the strongest association was observed for the dominant model [odds ratio (OR) = 0.557 95% CI 0.355-0.874 and OR = 0.508, 95% CI 0.265-0.973, respectively, after adjustment for age, ethnicity, and risk HLA loci]. However, miR-375 rs6715345 frequencies did not differ between cases and controls. CONCLUSION: MiR-146a rs2910164 and miR-155 rs767649 polymorphisms were associated with protection for T1DM.
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Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/prevenção & controle , Estudos de Associação Genética/métodos , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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.
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Diabetes Mellitus , Óxido Nítrico/sangue , Adolescente , Adulto , Criança , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Humanos , Adulto JovemRESUMO
BACKGROUND AND AIMS: Diabetic kidney disease (DKD) is the leading cause of end stage renal disease worldwide and is associated with increased cardiovascular mortality. The endothelin system has been implicated in the pathogenesis of arterial hypertension and renal dysfunction. In the present study, the association of DKD with polymorphisms in ET-1 (EDN1) and ETRA (EDNRA) genes was analyzed in patients with type 2 diabetes mellitus (T2DM). METHODS: A case-control study was conducted in 548 white T2DM patients. Patients with proteinuria or on dialysis were considered cases and patients with normoalbuminuria were considered controls. Two polymorphisms in the EDN1 gene (rs1800541 and rs57072783) and five in EDNRA gene (rs6842241; rs4835083; rs4639051; rs5333 and rs5343) were genotyped and haplotype analyses were performed. RESULTS: The presence of rs57072783 T allele (TT/TG vs. GG) or rs1800541 G allele (GG/GT vs. TT) protected against DKD (OR = 0.69, 95 % CI 0.48-0.99, P = 0.049; and OR = 0.60, 95 % CI 0.41-0.88, P = 0.009, respectively). However in multivariate analyses, only the rs1800541 G allele remained independently associated with DKD (P = 0.046). CONCLUSIONS: The present study shows that ET-1 could be involved in the pathogenesis of DKD in patients with T2DM.
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INTRODUCTION: Irisin has recently been described as a novel myokine, which reduces visceral obesity and improves glucose metabolism in mice. Thus, polymorphisms in the gene encoding irisin, fibronectin type III domain containing 5 (FNDC5), may be associated with type 2 diabetes mellitus (T2DM) and related disorders. However, to date, no study has investigated the association between FNDC5 polymorphisms and susceptibility to T2DM. OBJECTIVE: To investigate the association of FNDC5 rs3480 (A/G) and rs1746661 (G/T) polymorphisms, alone or in combination, with T2DM and its clinical features. METHODS: We analyzed 1006 T2DM patients and 434 nondiabetic subjects. Polymorphisms were genotyped by real-time PCR using TaqMan MGB probes. Haplotypes constructed from the combination of rs1746661 and rs3480 polymorphisms were inferred using the Phase 2.1 program. RESULTS: Genotype, allele and haplotype frequencies of rs1746661 and rs3480 polymorphisms did not differ significantly between nondiabetic subjects and T2DM patients. Women with T2DM carrying the G allele of rs3480 showed increased HbA1c levels compared with A/A carriers, adjusted for age. The T allele of rs1746661 was associated with increased systolic blood pressure, total cholesterol and LDL-cholesterol and decreased HDL-cholesterol in women with T2DM, adjusted for covariates. Moreover, prevalence of hypercholesterolemia was higher in women carrying the T allele of rs1746661 than in G/G carriers (72.4% vs. 58.7%, OR=2.010, 95% CI=1.210-3.390), but it was not significantly different in men. CONCLUSIONS: These results indicate that, although not associated with T2DM, the G allele of rs3480 appears to be associated with increased HbA1c, while the T allele of rs1746661 appears to be associated with higher systolic blood pressure and dyslipidemia in women with T2DM.
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Pressão Sanguínea/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Fibronectinas/genética , Fibronectinas/fisiologia , Lipídeos/sangue , Envelhecimento , Colesterol/sangue , Feminino , Frequência do Gene , Genótipo , Hemoglobinas Glicadas/metabolismo , Heterozigoto , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético/genética , Caracteres SexuaisRESUMO
BACKGROUND: A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association. METHODS: 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. RESULTS: Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33-2.15, p<0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23-8.59, p<0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21-7.21, p=0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02-4.50, p=0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. CONCLUSION: Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D.
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Diabetes Mellitus Tipo 1/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Genes Dominantes , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
PURPOSE: We tested the hypothesis that tumor necrosis factor (TNF) gene polymorphisms are associated with diabetic retinopathy (DR) in Caucasians with type 2 diabetes mellitus. METHODS: In a case-control study, the -238G>A (rs361525), -308G>A (rs1800629), and -857C>T (rs1799724) polymorphisms of the TNF gene were genotyped in 745 outpatients with type 2 diabetes, including 331 subjects without DR, 246 with nonproliferative DR (NPDR), and 168 with proliferative DR (PDR). RESULTS: Genotype and allele frequencies of the -238G>A, -308G>A, and -857C>T polymorphisms in subjects with NPDR were not significantly different from those of subjects without DR (P > 0.05 for all comparisons). However, the A allele of the -308G>A polymorphism was more frequent in subjects with PDR than in those with no DR (18.1% vs. 11.5%, corrected P = 0.035). Multivariate logistic regression analysis showed that the -308A allele was independently associated with an increased risk of PDR, under a dominant model (adjusted odds ratio [aOR], 1.82; 95% confidence interval [CI], 1.11-2.98). The combined analysis of the three polymorphisms also showed that haplotypes containing the -308A allele were associated with an increased risk of PDR (aOR, 2.36; 95% CI, 1.29-4.32). CONCLUSIONS: This study detected, for the first time to our knowledge, an independent association of the -308G>A polymorphism in the TNF gene with PDR in Caucasian Brazilians with type 2 diabetes. This finding suggests that TNF is a potential susceptibility gene for PDR.
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DNA/genética , Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/genética , Polimorfismo Genético , Fator de Necrose Tumoral alfa/genética , População Branca , Adulto , Brasil/epidemiologia , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/metabolismo , Retinopatia Diabética/etnologia , Retinopatia Diabética/metabolismo , Feminino , Seguimentos , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Different dietary interventions have been identified as potential modifiers of adiponectin concentrations, and they may be influenced by lipid intake. We identified studies investigating the effect of dietary lipids (type/amount) on adiponectin concentrations in a systematic review with meta-analysis. A literature search was conducted until July 2013 using databases such as Medline, Embase and Scopus (MeSH terms: 'adiponectin', 'dietary lipid', 'randomized controlled trials (RCT)'). Inclusion criteria were RCT in adults analysing adiponectin concentrations with modification of dietary lipids. Among the 4930 studies retrieved, fifty-three fulfilled the inclusion criteria and were grouped as follows: (1) total dietary lipid intake; (2) dietary/supplementary n-3 PUFA; (3) conjugated linoleic acid (CLA) supplementation; (4) other dietary lipid interventions. Diets with a low fat content in comparison to diets with a high-fat content were not associated with positive changes in adiponectin concentrations (twelve studies; pooled estimate of the difference in means: -0·04 (95% CI -0·82, 0·74) µg/ml). A modest increase in adiponectin concentrations with n-3 PUFA supplementation was observed (thirteen studies; 0·27 (95% CI 0·07, 0·47) µg/ml). Publication bias was found by using Egger's test (P= 0·01) and funnel plot asymmetry. In contrast, CLA supplementation reduced the circulating concentrations of adiponectin compared with unsaturated fat supplementation (seven studies; -0·74 (95% CI -1·38, -0·10) µg/ml). However, important sources of heterogeneity were found as revealed by the meta-regression analyses of both n-3 PUFA and CLA supplementation. Results of new RCT would be necessary to confirm these findings.
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Adiponectina/sangue , Gorduras na Dieta/administração & dosagem , Regulação para Cima , Adiponectina/agonistas , Adulto , Dieta com Restrição de Gorduras , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/uso terapêutico , Suplementos Nutricionais/efeitos adversos , Regulação para Baixo , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Ácidos Linoleicos Conjugados/efeitos adversos , Ácidos Linoleicos Conjugados/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos TestesRESUMO
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.
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Índice de Massa Corporal , Predisposição Genética para Doença , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Obesidade/genética , Alelos , Estudos de Associação Genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Proteína Desacopladora 1 , Proteína Desacopladora 2 , Proteína Desacopladora 3RESUMO
There is a very well known correlation between diabetes and cardiovascular disease but many health care professionals are just concerned with glycemic control, ignoring the paramount importance of controlling other risk factors involved in the pathogenesis of serious cardiovascular diseases. This Position Statement from the Brazilian Diabetes Society was developed to promote increased awareness in relation to six crucial topics dealing with diabetes and cardiovascular disease: Glicemic Control, Cardiovascular Risk Stratification and Screening Coronary Artery Disease, Treatment of Dyslipidemia, Hypertension, Antiplatelet Therapy and Myocardial Revascularization. The issue of what would be the best algorithm for the use of statins in diabetic patients received a special attention and a new Brazilian algorithm was developed by our editorial committee. This document contains 38 recommendations which were classified by their levels of evidence (A, B, C and D). The Editorial Committee included 22 specialists with recognized expertise in diabetes and cardiology.
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BACKGROUND: Adiponectin is a major regulator of glucose and lipid homeostasis by its insulin sensitizer properties. Since decreased insulin sensitivity is linked to metabolic syndrome (MS), decreased adiponectin levels may be related to its development. The purpose of the study was to investigate the relationship between adiponectin levels and MS. METHODS: Firstly, we cross-sectionally examined subjects with or without MS submitted to an oral glucose tolerance test at Hospital de Clínicas de Porto Alegre (n = 172). A replication analysis was performed in subjects (n = 422) undergoing cardiac angiography at Hospital São Paulo. Subchronic inflammation (US-CRP), coagulation marker (fibrinogen), insulin sensitivity and resistance (Matsuda ISI and HOMA-IR) were estimated. Plasma total and high molecular weight (HMW) adiponectin were measured. RESULTS: Total and HMW adiponectin levels were lower in MS subjects (P < 0.05). Total adiponectin levels were lower in the presence of high waist circumference, low HDL-cholesterol and elevated triglyceride criteria in both samples and by elevated blood pressure and glucose criteria in Porto Alegre. HMW adiponectin levels were lower in the presence of low HDL-cholesterol, elevated triglycerides, and glucose criteria. Total adiponectin levels were positively related with HDL-cholesterol and ISI Matsuda, negatively related with waist circumference, glucose, triglycerides, HOMA-IR, and US-CRP and not related with blood pressure. While adjusting for sex and age, increased adiponectin levels remained associated with a reduced prevalence ratio for MS in both cohorts (P = 0.001). CONCLUSIONS: Adiponectin levels decreased with increasing number of MS criteria, and it is in part determined by its relationship with HDL, triglycerides and abdominal adiposity.
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BACKGROUND: We investigated whether the -3826A/G polymorphism (rs1800592) of the uncoupling protein 1 gene (UCP1) and the Trp64Arg polymorphism (rs4994) of the ß3-adrenergic receptor gene (ADRB3) are associated with type 2 diabetes mellitus (T2DM) and features of metabolic syndrome in a Brazilian-Caucasian population. METHODS: Both polymorphisms were genotyped in 1015 T2DM patients and 561 nondiabetic subjects. The combined effect of both polymorphisms on T2DM and metabolic syndrome-related parameters was analyzed according to a triallelic inheritance pattern, by which at least three minor alleles from two loci are necessary for trait manifestation. RESULTS: UCP1 -3826A/G and ADRB3 Trp64Arg polymorphisms were not associated with T2DM (P>0.05). Patients carrying the ADRB3 64Arg allele had higher fasting plasma glucose and high-density lipoprotein cholesterol (HDL-C) than patients with the Trp64Trp genotype (P=0.0001 and P=0.015, respectively). The 64Arg allele was also associated with protection against overweight/obesity (body mass index ≥ 25 kg/m(2); odds ratio [OR]=0.598; P=0.014). Interestingly, prevalence of overweight/obesity was lower among carriers of at least three minor alleles of the -3826A/G and ADRB3 Trp64Arg polymorphisms than among patients with fewer than three minor alleles (54.5% vs. 79.1%; OR=0.288; P=0.007, respectively). Subjects with at least three minor alleles also had higher HDL-C levels (P=0.018). CONCLUSIONS: UCP1 -3826A/G and ADRB3 Trp64Arg polymorphisms may have a combined effect in the modulation of overweight/obesity and HDL-C levels in type 2 diabetes mellitus (T2DM) Caucasian-Brazilian patients.
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HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/genética , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Obesidade/genética , Sobrepeso/genética , Receptores Adrenérgicos beta 3/genética , Idoso , Alelos , Glicemia , Brasil , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/etnologia , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo Genético , Fatores de Risco , Inquéritos e Questionários , Proteína Desacopladora 1 , População BrancaRESUMO
OBJECTIVE: The aim of this study was to investigate the association between the rs7903146 (C/T) polymorphism in the TCF7L2 gene and type 2 diabetes mellitus, in a Southern-Brazilian population. MATERIALS AND METHODS: The TCF7L2 rs7903146 polymorphism was genotyped in 953 type 2 diabetic patients and 535 non-diabetic subjects. All subjects were white. The polymorphism was genotyped by Real-Time PCR using TaqMan MGB probes (Life Technologies). Odds ratios (OR) and 95% confidence intervals (CI) were calculated for additive, recessive and dominant inheritance models. RESULTS: Genotype and allele frequencies of the rs7903146 polymorphism differed significantly between type 2 diabetic patients and non-diabetic subjects (P = 0.001 and P = 0.0001, respectively). The frequency of the minor allele was 38% in type 2 diabetes group and 31% in non-diabetic subjects, and this allele was significantly associated with type 2 diabetes risk (OR = 1.42, 95% CI 1.15 - 1.76 for the dominant model of inheritance). Moreover, the T/T genotype was associated with a higher risk for type 2 diabetes (OR = 1.83, 95% CI 1.3-2.5) than the presence of only one copy of the T allele (OR = 1.31, 95% CI 1.1-1.6). Both results were adjusted for age and gender. CONCLUSIONS: Our results confirm the association between the TCF7L2 rs7903146 polymorphism and increase risk for type 2 diabetes in Southern-Brazil.
Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Fatores Etários , Idoso , Alelos , Glicemia , Índice de Massa Corporal , Brasil/etnologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Genótipo , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Fatores Sexuais , População Branca/genéticaRESUMO
BACKGROUND: To investigate gene expression of podocyte-specific proteins in urine of diabetes and prediabetes subjects and the association of these proteins with albuminuria. METHODS: Fifteen controls, 19 prediabetes, and 67 diabetes subjects were included. Messenger RNA of nephrin, podocin, podocalyxin, synaptopodin, TRPC6, alpha-actinin-4, and TGF-ß1 were measured using RT-PCR. Podocyte marker expression was correlated with albuminuria, glycemic control, and renal function. The diagnostic performance of the genes used to detect increased albuminuria was assessed using ROC curves and Poisson regressions. RESULTS: Podocyte marker expression was significantly higher in diabetic subjects. Urinary nephrin was correlated with increasing levels of albuminuria; risk of albuminuria increased by 20% for every one-unit increase in the log10 of nephrin mRNA. Nephrinuria was found in 53%, 71%, and 90% of normo-, micro-, and macroalbuminuric diabetes subjects, respectively (p = 0.023). Urinary nephrin, podocalyxin, TRPC6, podocin, and alpha actinin-4 were correlated with glycemic control and albuminuria but not with renal function. CONCLUSIONS: Diabetes subjects had higher urinary mRNA levels of podocyte proteins than nondiabetic subjects, even the normoalbuminuric patients. Nephrinuria was correlated with diabetic nephrophathy stage and predicted pathological albuminuria. Urinary mRNA levels of podocyte markers of prediabetic subjects did not differ from controls.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/metabolismo , Podócitos/metabolismo , Proteinúria/metabolismo , Proteoma/metabolismo , RNA Mensageiro/urina , Adulto , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS/HYPOTHESIS: Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. METHODS: We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Génétique de la Néphropathie Diabétique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. RESULTS: The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. CONCLUSIONS/INTERPRETATION: CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney.
Assuntos
Catalase/genética , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/genética , Frequência do Gene , Falência Renal Crônica/enzimologia , Falência Renal Crônica/genética , Estresse Oxidativo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Bélgica , Brasil , Catalase/metabolismo , Estudos Transversais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Feminino , Seguimentos , França , Variação Genética , Taxa de Filtração Glomerular , Humanos , Incidência , Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Medição de Risco , Fatores de RiscoRESUMO
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.