RESUMO
Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuron-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function, and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain, and other human tissues, and we identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1, and Rbfox2, were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-ßH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, whereas silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose-induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival, and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.
Assuntos
Células Secretoras de Insulina/citologia , Proteínas de Ligação a RNA/metabolismo , Processamento Alternativo , Animais , Apoptose , Linhagem Celular , Sobrevivência Celular , Células Cultivadas , Proteína Semelhante a ELAV 4/genética , Proteína Semelhante a ELAV 4/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Proteínas de Ligação a RNA/genética , RatosRESUMO
Primary aldosteronism (PA) is a group of disorders in which aldosterone is excessively produced. These disorders can lead to hypertension, hypokalemia, hypervolemia and metabolic alkalosis. The prevalence of PA ranges from 5% to 12% around the globe, and the most common causes are adrenal adenoma and adrenal hyperplasia. The importance of PA recognition arises from the fact that it can have a remarkably adverse cardiovascular and renal impact, which can even result in death. The aldosterone-to-renin ratio (ARR) is the election test for screening PA, and one of the confirmatory tests, such as oral sodium loading (OSL) or saline infusion test (SIT), is in general necessary to confirm the diagnosis. The distinction between adrenal hyperplasia (AH) or aldosterone-producing adenoma (APA) is essential to select the appropriate treatment. Therefore, in order to identify the subtype of PA, imaging exams such as computed tomography or magnetic ressonance imaging, and/or invasive investigation such as adrenal catheterization must be performed. According to the subtype of PA, optimal treatment - surgical for APA or pharmacological for AH, with drugs like spironolactone and amiloride - must be offered.
Assuntos
Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/terapia , HumanosRESUMO
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.
Assuntos
Diabetes Mellitus , Óxido Nítrico/sangue , Adolescente , Adulto , Criança , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Humanos , Adulto JovemRESUMO
The majority of liver grafts destined for transplantation originate from brain dead donors. However, significantly better posttransplantation outcomes are achieved when organs from living donors are used, suggesting that brain death (BD) causes irreversible damage to the liver tissue. Recently, glucagon-like peptide-1 (GLP1) analogues were shown to possess interesting hepatic protection effects in different liver disease models. We hypothesized that donor treatment with the GLP1 analogue exendin-4 (Ex-4) could alleviate BD-induced liver damage. A rat model of BD was employed in order to estimate BD-induced liver damage and Ex-4's potential protective effects. Liver damage was assessed by biochemical determination of circulating hepatic markers. Apoptosis in the hepatic tissue was assessed by immunoblot and immunohistochemistry using an antibody that only recognizes the active form of caspase-3. Gene expression changes in inflammation and stress response genes were monitored by quantitative real-time polymerase chain reaction. Here, we show that Ex-4 administration to the brain dead liver donors significantly reduces levels of circulating aspartate aminotransferase and lactate dehydrogenase. This was accompanied by a remarkable reduction in hepatocyte apoptosis. In this model, BD caused up-regulation of tumor necrosis factor and stress-related genes, confirming previous findings in clinical and animal studies. In conclusion, treatment of brain dead rats with Ex-4 reduced BD-induced liver damage. Further investigation is needed to determine the molecular basis of the observed liver protection. After testing in a randomized clinical trial, the inclusion of GLP1 analogues in organ donor management might help to improve organ quality, maximize organ donation, and possibly increase liver transplantation success rates.
Assuntos
Hepatopatias/prevenção & controle , Transplante de Fígado , Peptídeos/administração & dosagem , Peçonhas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Morte Encefálica/metabolismo , Caspase 3/biossíntese , Caspase 3/genética , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Exenatida , Regulação da Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/administração & dosagem , Immunoblotting , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/patologia , Hepatopatias/genética , Hepatopatias/metabolismo , Masculino , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Purpose: The plasma kallikrein-kinin system is activated during vascular injury caused by diabetic retinopathy (DR), being involved in hyperpermeability and inflammation. Bradykinin B1 receptor (B1R) is expressed in human retina, and its levels are increased in murine models of diabetes. Experimental studies reveal that B1R antagonists ameliorate retinal injury caused by diabetes in rodents. Thus, the aim of this study was to investigate the association between the rs12050217A/G polymorphism in the BDKRB1 gene, the gene that codifies B1R, and DR in type 2 diabetes mellitus (T2DM) patients. Methods: We analyzed 636 T2DM patients and 443 non-diabetic subjects. T2DM patients were categorized by the presence of non-proliferative DR (NPDR, n = 267), proliferative DR (PDR, n = 197), and absence of DR (n = 172). The BDKRB1 rs12050217A/G polymorphism was genotyped by real-time PCR using TaqMan MGB probes. Results: The genotype frequencies of the BDKRB1 rs12050217A/G polymorphism are in Hardy-Weinberg equilibrium and did not differ between T2DM patients and non-diabetic subjects (P > 0.05). The presence of the genotypes containing the rs12050217 G allele was less frequent in patients with PDR when compared to patients with NPDR and without DR (32.0%, 41.9%, and 43.0%, P = 0.045, respectively). Interestingly, the presence of G allele was associated with ~40% protection for PDR, which was confirmed after correction for the presence of hypertension, ethnicity, age, HDL, and gender (odds ratio = 0.616, 95% confidence interval 0.385-0.986, P = 0.043). Conclusion: For the first time, we showed that BDKRB1 rs12050217 G allele is associated with protection for the advanced stage of DR in T2DM patients; however, further studies are needed to confirm this finding.
Assuntos
Retinopatia Diabética/genética , Proteínas de Ligação ao GTP/genética , Polimorfismo de Nucleotídeo Único , Receptor B1 da Bradicinina/genética , Adulto , Idoso , Alelos , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Feminino , Frequência do Gene , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Systemic inflammation associated with brain death (BD) decreases islet yield and quality, negatively affecting outcomes of human islet transplantation. A recent study from our group showed an increased expression of uncoupling protein-2 (UCP2) in pancreas from rats with BD as compared with controls. UCP2 is located in the mitochondrial inner membrane and regulates production of reactive oxygen species and glucose-stimulated insulin secretion. It has been suggested that UCP2 also plays a role in ß cell apoptosis, but these findings remain controversial. METHODS: We have presently performed a case-control study to assess UCP2 expression in pancreas from BD donors (cases) and subjects who underwent pancreatectomy (controls). We next investigated the role of Ucp2 in cytokine-induced apoptosis of rat insulin-producing INS-1E cells. RESULTS: UCP2 gene expression was higher in pancreas from BD donors compared with controls (1.73 ± 0.93 vs 0.75 ± 0.66; fold change, P < 0.05). Ucp2 knockdown (80% at the protein and messenger RNA levels) reduced by 30% cytokine-induced apoptosis and nitric oxide production in INS-1E cells. This protection was associated with decreased expression of cleaved (activated) caspases 9 and 3, suggesting that Ucp2 knockdown interferes with cytokine triggering of the intrinsic apoptotic pathway. Moreover, both messenger RNA and protein concentrations of the antiapoptotic protein Bcl-2 were increased after Ucp2 knockdown in INS-1E cells. CONCLUSIONS: These data suggest that UCP2 has an apoptotic effect in ß cells via regulation of the intrinsic pathway of apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Morte Encefálica/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Interferon gama/farmacologia , Transplante de Pâncreas/métodos , Transdução de Sinais/efeitos dos fármacos , Doadores de Tecidos , Fator de Necrose Tumoral alfa/farmacologia , Proteína Desacopladora 2/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Morte Encefálica/patologia , Estudos de Casos e Controles , Linhagem Celular , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Óxido Nítrico/metabolismo , Pancreatectomia , Estudos Prospectivos , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Superóxido Dismutase/metabolismo , Fatores de Tempo , Transfecção , Proteína Desacopladora 2/genética , Regulação para CimaRESUMO
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.
Assuntos
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
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.
Assuntos
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
Islet quality loss after isolation from brain-dead donors still hinders the implementation of human islet transplantation for treatment of type 1 diabetes. In this scenario, systemic inflammation elicited by donor brain death (BD) is among the main factors influencing islet viability and functional impairment. Exendin-4 is largely recognized to promote anti-inflammatory and cytoprotective effects on ß-cells. Therefore, we hypothesized that administration of exendin-4 to brain-dead donors might improve islet survival and insulin secretory capabilities. Here, using a rat model of BD, we demonstrate that exendin-4 administration to the brain-dead donors increases both islet viability and glucose-stimulated insulin secretion. In this model, exendin-4 treatment produced a significant decrease in interleukin-1ß expression in the pancreas. Furthermore, exendin-4 treatment increased the expression of superoxide dismutase-2 and prevented BD-induced elevation in uncoupling protein-2 expression. Such observations were accompanied by a reduction in gene expression of two genes often associated with endoplasmic reticulum (ER) stress response in freshly isolated islets from treated animals, C/EBP homologous protein and immunoglobulin heavy-chain binding protein. As ER stress response has been shown to be triggered by and to participate in cytokine-induced ß-cell death, we suggest that exendin-4 might exert its beneficial effects through alleviation of pancreatic inflammation and oxidative stress, which in turn could prevent islet ER stress and ß-cell death. Our findings might unveil a novel strategy to preserve islet quality from brain-dead donors. After testing in the human pancreatic islet transplantation setting, this approach might sum to the ongoing effort to achieve consistent and successful single-donor islet transplantation.
Assuntos
Anti-Inflamatórios/farmacologia , Ilhotas Pancreáticas/fisiologia , Peptídeos/farmacologia , Peçonhas/farmacologia , Animais , Apoptose , Morte Encefálica/patologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citoproteção , Exenatida , Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Insulina/metabolismo , Secreção de Insulina , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Canais Iônicos/genética , Canais Iônicos/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Masculino , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Ratos Wistar , Estresse Fisiológico , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteína Desacopladora 2RESUMO
Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with "brittle T1DM", who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre - Rio Grande do Sul, Brazil.
Assuntos
Separação Celular/métodos , Diabetes Mellitus Tipo 1/terapia , Arquitetura de Instituições de Saúde/normas , Transplante das Ilhotas Pancreáticas/tendências , Ilhotas Pancreáticas , Brasil , Humanos , Insulina/uso terapêutico , Transplante das Ilhotas Pancreáticas/economia , Transplante das Ilhotas Pancreáticas/legislação & jurisprudência , Laboratórios/organização & administraçãoRESUMO
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.
Assuntos
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
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.
Assuntos
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
BACKGROUND: The rs1990760 polymorphism of interferon induced with helicase C domain 1 (IFIH1) has been associated with type 1 diabetes mellitus (T1DM). Here, we investigated whether this polymorphism is associated with T1DM or its clinical characteristics in a Brazilian population, and if IFIH1 gene expression in mononuclear cells from T1DM patients differs according to the genotypes of this polymorphism. A meta-analysis was also conducted to evaluate if the rs1990760 polymorphism is associated with T1DM. METHODS: Frequencies of the rs1990760 polymorphism were analyzed in 527 T1DM patients and in 517 healthy subjects. IFIH1 gene expressions according to genotypes were measured in a sub-sample of 26 T1DM patients by quantitative real-time PCR. RESULTS: Our data show the association of the A allele with risk to T1DM under a dominant model of inheritance [odds ratio (OR) = 1.421, P = 0.037], adjusting for ethnicity. The meta-analysis revealed significant association between the rs199760A allele and risk for T1DM for all analyzed inheritance models. Surprisingly, T1DM patients carrying the A allele showed lower levels of systolic (P = 0.001) and diastolic (P = 1 × 10(-10)) blood pressures as compared to G/G carriers. Furthermore, the A/A genotype seems to be associated with protection to arterial hypertension (AH) after adjustment for covariates (OR = 0.339, P = 0.019). IFIH1 gene expression in mononuclear cells from 26 T1DM patients did not differ among genotypes (P = 0.274). Nevertheless, IFIH1 gene expression was increased in mononuclear cells from T1DM patients with AH as compared with T1DM patients without AH [6.7 (1.7-2.0) vs. 1.8 (1.3-7.1) arbitrary units; P = 0.036]. The association with blood pressures and AH was not observed in patients with type 2 diabetes mellitus. CONCLUSIONS: Our results indicate that the rs1990760 polymorphism is associated with T1DM. Interestingly, the rs1990760 A allele seems to be associated with protection for AH in T1DM patients. Further studies are needed to confirm the association with AH.
Assuntos
Alelos , RNA Helicases DEAD-box/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/genética , Expressão Gênica , Hipertensão/etiologia , Polimorfismo Genético , Adulto , Pressão Sanguínea , Brasil , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/prevenção & controle , Helicase IFIH1 Induzida por Interferon , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Razão de ChancesRESUMO
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.
Assuntos
Povo Asiático , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Polimorfismo Genético , População Branca , Idoso , Alelos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Feminino , Frequência do Gene , Genes Dominantes , Genes Recessivos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Proteína Desacopladora 1 , Proteína Desacopladora 2 , Proteína Desacopladora 3RESUMO
PURPOSE: The purpose of this study was to evaluate the effect of the -634G/C polymorphism on VEGFA gene expression in the human retina. METHODS: A cross-sectional study was performed to analyze the frequency of the -634G/C polymorphism (rs2010963) in 190 cadaveric cornea donors. Individuals with diabetes mellitus, eye/retinal disease, or both were not included in this study. RESULTS: A total of 53 retinal samples were analyzed (18 GG, 17 GC, and 18 CC). VEGFA gene expression was measured by reverse transcription-quantitative polymerase chain reaction. Donor age ranged from 13 to 79 years (mean, 55.8 ± 15.8 years), and 49.1% (n = 26) were male. Subjects carrying the C allele (CC or GC genotypes, 5.15 ± 4.47 arbitrary units [AU] or 3.72 ± 3.25 AU, respectively) presented higher VEGFA gene expression than subjects with the GG genotype (2.62 ± 2.56 AU; P = 0.045). CONCLUSIONS: This study indicates that the C allele of the -634G/C polymorphism is associated with higher VEGFA gene expression in the human retina.
Assuntos
Polimorfismo de Nucleotídeo Único/genética , Retina/fisiologia , Vasos Retinianos/fisiologia , Fator A de Crescimento do Endotélio Vascular/genética , Adolescente , Adulto , Idoso , Alelos , Cadáver , Estudos Transversais , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/genética , Feminino , Expressão Gênica/fisiologia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Doadores de Tecidos/estatística & dados numéricos , Adulto JovemRESUMO
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.
Assuntos
DNA Complementar/genética , Retinopatia Diabética/genética , Expressão Gênica , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Polimorfismo Genético , Retina/metabolismo , Superóxido Dismutase/genética , Adulto , Alelos , Retinopatia Diabética/metabolismo , Feminino , Seguimentos , Frequência do Gene , Haplótipos , Humanos , Imuno-Histoquímica , Canais Iônicos/metabolismo , Masculino , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Superóxido Dismutase/biossíntese , Proteína Desacopladora 1RESUMO
Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with “brittle T1DM”, who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre – Rio Grande do Sul, Brazil.