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1.
Article in Chinese | WPRIM | ID: wpr-878987

ABSTRACT

To investigate the effect of Gegen Qinlian Decoction(GQD) on enzyme activity, gene expression and methylation level of fatty acid synthase(FASN) in adipose tissue from rats with insulin resistance induced by high-fat diet. The 60% fat-powered high-fat diet was continuously given to male SD rats to induce the insulin resistance model. Then, they were divided into five groups randomly and administrated by gavage every day for 16 weeks with following drugs respectively: 10 mL·kg~(-1)water for control group(C) and insulin resistance model control group(IR), 1.65 g·kg~(-1)GQD per day for low-dose group(GQDL), 4.95 g·kg~(-1)GQD per day for medium-dose group(GQDM), 14.85 g·kg~(-1)GQD per day for high-dose group(GQDH), and 5 mg·kg~(-1) rosiglitazone per day for rosiglitazone group(RGN). Epididymal adipose tissue was taken to determine enzyme activity of FASN by colorimetric method, mRNA expression level of Fasn by quantitative Real-time PCR(Q-PCR) and CpGs methylation level between +313 and +582 by bisulfite sequencing PCR(BSP). These results showed that Fasn expression was significantly lowered in IR model rats compared with the control rats(P<0.01). Enzymatic activity and CpGs methylation level of Fasn in IR group showed downward trends. Low and medium-dose GQD can increase enzyme activity of FASN(P<0.05). Moreover, low-dose GQD increased the total CpGs methylation level of Fasn fragment between +313 and +582 in insulin resistance rats(P<0.05). For GQDM group, the methylation frequency of CpGs at positions +506 and +508(P<0.01) as well as the methylation frequency of CpGs on the binding sites of transcription factorzinc finger protein 161(P<0.05) were significantly increased. The methylation frequency of CpG at +442 position was positively correlated with Fasn expression(P<0.01, r=0.735), and methylation frequencies of CpGs at +345 and +366 positions were positively associated to enzyme activity of FASN respectively(P<0.05, r=0.479; P<0.01, r=0.640). In conclusion, GQD can reverse enzyme activity of FASN and methylation level of Fasn in adipose tissue of insulin resistant rats, and CpG sites at positions +506 and +508 may be the targets of GQD. The methylation level of CpGs at + 345 and + 366 sites were possibly related to FASN activity, while methylation of CpG at + 442 site may be closely correlated with mRNA level of Fasn. In addition, GQD did not significantly change mRNA expression level of Fasn, but effectively reversed enzymatic activity, suggesting that GQD may regulate the post transcriptional expression of Fasn.


Subject(s)
Adipose Tissue , Animals , Drugs, Chinese Herbal , Fatty Acid Synthases/genetics , Gene Expression , Insulin Resistance/genetics , Male , Methylation , Rats , Rats, Sprague-Dawley
2.
Arch. endocrinol. metab. (Online) ; 62(1): 79-86, Jan.-Feb. 2018. tab
Article in English | LILACS | ID: biblio-887629

ABSTRACT

ABSTRACT Objective Monocyte chemoattractant protein 1 (MCP-1) has been suggested to be involved in the pathophysiology of insulin resistance (IR); therefore, variants in the MCP-1 gene may contribute to the development of this disease. The aim of this study was to analyze the relationship of the -2518 A>G MCP-1 (rs1024611) gene polymorphism with insulin resistance in Mexican children. Subjects and methods A cross-sectional study was performed in 174 children, including 117 children without insulin resistance and 57 children with IR, with an age range of 6-11 years. Levels for serum insulin and high-sensitivity C-reactive protein were determined. The -2518 A>G MCP-1 polymorphism was identified by the polymerase chain reaction-restriction fragment length polymorphism method. Insulin resistance was defined as a HOMA-IR in the upper 75th percentile, which was ≥ 2.4 for all children. Results Genotype frequencies of the rs1024611 polymorphism for the insulin-sensitive group were 17% AA, 48% AG and 35% GG, and the frequency of G allele was 59%, whereas frequencies for the insulin-resistant group were 12% AA, 37% AG and 51% GG, and the frequency of G allele was 69%. The genotype and allele frequencies between groups did not show significant differences. However, the GG genotype was the most frequent in children with IR. The GG genotype was associated with insulin resistance (OR = 2.2, P = 0.03) in a genetic model. Conclusion The -2518 A>G MCP-1 gene polymorphism may be related to the development of insulin resistance in Mexican children.


Subject(s)
Humans , Male , Female , Child , Insulin Resistance/genetics , Chemokine CCL2/genetics , Polymorphism, Single Nucleotide/genetics , Genetic Markers/genetics , Case-Control Studies , Cross-Sectional Studies , Genetic Predisposition to Disease , Gene Frequency , Genotype
3.
São Paulo; s.n; s.n; 2018. 127 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-982133

ABSTRACT

INTRODUÇÃO: A obesidade é uma doença multifatorial associada com alto risco de desenvolver resistência à insulina (RI), diabetes melito tipo 2 (DT2), síndrome metabólica (SM) e doenças cardiovasculares (DCV). Os mecanismos moleculares da fisiopatologia das doenças metabólicas não são totalmente compreendidos, emergindo a necessidade de novas estratégias. As modificações epigenéticas, especialmente os miRNAs, podem representar uma importante ferramenta, uma vez que são relacionados com o desenvolvimento de diversas doenças complexas, como as metabólicas. OBJETIVO: Avaliar o perfil de expressão de miRNAs séricos de indivíduos com obesidade, síndrome metabólica e resistência à insulina e sua relação com os mecanismos moleculares envolvidos nas suas fisiopatologias. CASUÍSTICA E MÉTODOS: O estudo foi realizado no Instituto Dante Pazzanese de Cardiologia (IDPC) e no Hospital Universitário da Universidade de São Paulo (HU/USP). Um total de 233 indivíduos foram distribuídos em três grupos: peso normal (n=47), sobrepeso (84) e obesos (102), de acordo com seu índice de massa corpórea (IMC). Os mesmos pacientes também foram re-classificados em com SM (n=89) e sem SM (n=144) de acordo com recomendações da Federação internacional de Diabetes e em com RI (n=123) e sem RI (n=110). As informações biodemográficas e amostras de sangue foram coletadas para testes laboratoriais clínicos e análises de perfis de expressão de miRNA pela PCR array (372 alvos). Analises in silico com a ferramenta Ingenuity Pathway Analysis (IPA) foi realizada para integração do perfil de miRNAs e seus genes alvos com doenças metabólicas. RESULTADOS: Os pacientes obesos e com RI, apresentaram aumento similar das concentrações de marcadores dos perfis lipídico, glicídico e inflamatório quando comparado com indivíduos com peso normal e sem RI. O perfil de miRNAs dos grupos obesos e com RI mostrou que o miR-346 (p=0,010; p=0,019), 483-5p (p=0,034; p=0,020), 296-3p (p=0,010; p=0,008), 1224-3p (p=0,044; p=0,012) e 95-3p (p=0,003; p=0,019) foram expressos similarmente nestes pacientes quando comparados a seus respectivos controles. Estes miRNAs, por predição in silico, desempenham um importante papel na regulação de vias metabólicas associadas a doenças hepáticas gordurosas, inflamação, DCV e doenças metabólicas. Na SM, o grupo portador da doença apresentou altas concentrações de marcadores do perfil lipídico, glicídico e inflamatório. O perfil de expressão de miRNA indicou uma expressão reduzida do miR-183-5p (p=0,008) e miR-301a-3p (p=0,007) e aumentada do miR-542-5p (p=0,003), miR-424-3p (p=0,040), miR-326 (p=0,037), miR-421 (p=0,023) e miR-574-3p (p=0,001) no grupo SM comparado ao sem SM. A análise de regressão linear múltipla stepwise indicou que a expressão aumentada do miR-421 explica em 22,5% o aumento da associação de Hb1Ac, LDL-C, PAI-1, HOMA-IR, glicose e insulina (p <0,001, p=0,014, p=0,009, p <0,001, p=0,001 e p=0,007, respectivamente). Além disso o miR-421 foi predito in silico estar associado com a regulação de 11 mRNA alvos envolvidos em vias regulatórias de doenças como infarto do miocárdio, obesidade, diabetes melito, esteatose hepática, tolerância a glicose, distúrbio do metabolismo da glicose, hiperglicemia e resistência à insulina, bem como atua em vias regulatórias da resposta inflamatória, sendo associado com a variabilidade na quantidade de citocinas, massa do tecido adiposo e quantidade de leptina no sangue. Mediante a relação do miR-421 com a homeostase da glicose, sua expressão foi testada em pacientes com RI e interessantemente se manteve aumentada nesses pacientes em comparação com os sem RI (p=0.014). CONCLUSÕES: Os miR-346, miR-483-5p, miR-296-3p, miR-1224-3p e miR-95-3p podem ser considerados potenciais biomarcadores como preditores de DCV em pacientes obesos e resistência à insulina e o miR-421 um potencial biomarcador precoce de predição de risco de DCV em pacientes com síndrome metabólica


BACKGROUND: Obesity is a multifactorial disease associated with high risk of developing insulin resistance (IR), Diabetes mellitus type 2 (DT2), metabolic syndrome (MetS) and cardiovascular disease (CVD). Molecular mechanisms of metabolic diseases' pathophysiology are not fully understood, emerging the need for new strategies. Epigenetic modifications, especially miRNAs, may represent an important tool, since they are related to the development of several complex diseases, such as those metabolic. OBJECTIVE: Evaluate miRNA-derived serum expression profile in individuals with obesity, MetS and IR and their relationship with molecular mechanisms involved in the metabolic disease pathophysiology. MATERIAL AND METHODS: The study was conducted at the Dante Pazzanese Institute of Cardiology (IDPC) and at University Hospital of the University of São Paulo (HU/USP). Two hundred thirty-three subjects were distributed into three groups: normal weight (n = 47), overweight (n=84) and obese (n=102), according to their body mass index (BMI). The same patients were also re-classified as MetS (n=89) and Non-MetS (n=144) according to recommendations of the International Diabetes Federation and in IR (n=123) and Non-IR. Biodemographic data were registered and blood samples were collected for clinical laboratory tests and miRNA expression profiles by PCR array (372 targets). In silico analysis using Ingenuity Pathway Analysis (IPA) tool was performed to integrate the miRNA profile and their target genes with metabolic diseases. RESULTS: Obese and IR patients had similar increases in the concentrations of lipid, glucose and inflammatory markers when compared to individuals with normal weight and without IR, respectively. miRNA profile of obese and IR groups showed that miR-346 (p = 0.010, p = 0.019), 483-5p (p = 0.034, p = 0.020), 296-3p (p = 0.010, p = 0.008), 1224-3p (p = 0.044, p = 0.012) and 95-3p (p = 0.003, p = 0.019) were similarly expressed in these patients in comparison to their respective controls. These miRNAs, by in silico prediction, play an important role in the regulation of metabolic pathways associated with fatty liver diseases, inflammation, CVD and metabolic diseases. In MetS, patients diagnosed with the disease showed high concentrations of lipid, glycogen and inflammatory markers. The miRNA expression profile indicated a reduced expression of miR-183-5p (p=0.008) and miR-301a-3p (p=0.007) and increased miR-542-5p (p=0.003), miR- 3 (p=0.040), miR-326 (p=0.037), miR-421 (p=0.023) and miR-574-3p (p=0.001) in the MetS group compared to Non-MetS. Stepwise multiple linear regression analysis indicated that increased expression of miR-421 explain in 22.5% increased of Hb1Ac, LDL-C, PAI-1, HOMA-IR, glucose and insulin (p<0.001, p=0.014, p=0.009, p<0.001, p=0.001 and p=0.007, respectively). In addition the miR-421 was predicted in silico to associated with regulation of eleven mRNA of gene targets involved in regulatory pathways of diseases such as myocardial infarction, obesity, diabetes mellitus, hepatic steatosis, glucose tolerance, glucose metabolism disorder, hyperglycemia and insulin resistance, as well inflammatory response and is also associated with variability in the amount of cytokines, adipose tissue mass and amount of leptin in the blood. Due the relationship of miR-421 with glucose homeostasis, the miRNA expression was tested in patients with IR. Interestingly, miR-421 remained increased in these patients compared to those without IR (p = 0.014). CONCLUSIONS: The miR-346, miR-483-5p, miR-296-3p, miR-1224-3p and miR-95-3p may be potential biomarkers to predict CVD in obese and IR patients, while the miR-421 is a potential biomarker to predict CVD in MetS patients


Subject(s)
Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Insulin Resistance/genetics , Cardiovascular Diseases/diagnosis , MicroRNAs/analysis , Obesity/complications , Computer Simulation/statistics & numerical data , Biomarkers/analysis , Metabolic Syndrome , Glycemic Index
4.
Braz. j. med. biol. res ; 49(5): e5129, 2016. tab, graf
Article in English | LILACS | ID: biblio-951677

ABSTRACT

This study aimed to evaluate the effects of exercise training on triglyceride deposition and the expression of musclin and glucose transporter 4 (GLUT4) in a rat model of insulin resistance. Thirty male Sprague-Dawley rats (8 weeks old, weight 160±10 g) were fed a high-fat diet (40% calories from fat) and randomly divided into high-fat control group and swimming intervention group. Rats fed with standard food served as normal control. We found that 8-week swimming intervention significantly decreased body weight (from 516.23±46.27 to 455.43±32.55 g) and visceral fat content (from 39.36±2.50 to 33.02±2.24 g) but increased insulin sensitivity index of the rats fed with a high-fat diet. Moreover, swimming intervention improved serum levels of TG (from 1.40±0.83 to 0.58±0.26 mmol/L) and free fatty acids (from 837.80±164.25 to 556.38±144.77 μEq/L) as well as muscle triglycerides deposition (from 0.55±0.06 to 0.45±0.02 mmol/g) in rats fed a high-fat diet. Compared with rats fed a standard food, musclin expression was significantly elevated, while GLUT4 expression was decreased in the muscles of rats fed a high-fat diet. In sharp contrast, swimming intervention significantly reduced the expression of musclin and increased the expression of GLUT4 in the muscles of rats fed a high-fat diet. In conclusion, increased musclin expression may be associated with insulin resistance in skeletal muscle, and exercise training improves lipid metabolism and insulin sensitivity probably by upregulating GLUT4 and downregulating musclin.


Subject(s)
Animals , Male , Rats , Insulin Resistance/genetics , Dietary Fats/administration & dosage , Glucose Transporter Type 4/metabolism , Lipid Metabolism/genetics , Muscle Proteins/metabolism , Physical Conditioning, Animal , Time Factors , Transcription Factors , Insulin Resistance/physiology , Dietary Fats/metabolism , Random Allocation , Gene Expression Regulation , Rats, Sprague-Dawley , Glucose Transporter Type 4/genetics , Real-Time Polymerase Chain Reaction , Muscle Proteins/genetics
5.
Rev. bras. psiquiatr ; 37(2): 106-112, 12/05/2015. tab
Article in English | LILACS | ID: lil-748974

ABSTRACT

Objective: Evidence points to a high prevalence of metabolic dysfunction in bipolar disorder (BD), but few studies have evaluated the relatives of subjects with BD. We conducted a cross-sectional study in an extended family of patients with BD type I. Methods: The available relatives of the same family were interviewed (DSM-IV-R) and assessed in fasting conditions for body mass index, constituent variables of the metabolic syndrome (MS), leptin levels, insulin resistance index, and single nucleotide polymorphisms (SNPs) for the leptin receptor and promoter and PPAR-γ2 genes. The frequency of MS was compared with that recorded in the local general population. Results: Ninety-three relatives of three adults with BD were evaluated (30 aged < 18 years, 63 aged > 18 years). The frequency of MS was similar to that of the general population. Significantly higher frequencies of abnormal glucose, total and low density cholesterol (LDL-c) levels (all p < 0.05), waist circumference (p = 0.057), and leptin and insulin resistance values (in adults only) were observed in the family. Adults with the QQ genotype of the leptin receptor displayed higher LDL-c levels than carriers of the R allele. Conclusions: The associations among BD consanguinity, familial hypercholesterolemia, and leptin receptor SNPs reported herein should be replicated and extended in other pedigrees. .


Subject(s)
Adolescent , Adult , Female , Humans , Male , Middle Aged , Young Adult , Bipolar Disorder/genetics , Insulin Resistance/genetics , Leptin/genetics , Metabolic Syndrome/genetics , PPAR gamma/genetics , Polymorphism, Genetic/genetics , Body Mass Index , Bipolar Disorder/blood , Cross-Sectional Studies , Genotype , Leptin/blood , Metabolic Syndrome/blood , Metabolic Syndrome/psychology , Pedigree , Rural Population , Venezuela
6.
Dental press j. orthod. (Impr.) ; 20(2): 55-60, Mar-Apr/2015. tab, graf
Article in English | LILACS | ID: lil-745858

ABSTRACT

OBJECTIVE: To assess bone thickness for miniscrew placement in the mandible during mixed dentition by using digital volumetric tomograph (DVT). MATERIAL AND METHODS: A total of 15 healthy patients aged 8-10 years old, with early exfoliated mandibular second deciduous molar, were included. DVT images of one quadrant of the mandible were obtained using Kodak extraoral imaging systems and analyzed by Kodak dental imaging software. The error of the method (EM) was calculated using Dahlberg's formula. Mean and standard deviation were calculated at 6 and 8 mm from the cementoenamel junction (CEJ).Paired t-test was used to analyze the measurements. RESULTS: Buccal cortical bone thickness, mesiodistal width and buccolingual bone depth at 6 mm were found to be 1.73 + 0.41, 2.15 + 0.49 and 13.18 + 1.22 mm, respectively; while at 8 mm measurements were 2.42 + 0.34, 2.48 + 0.33 and 13.65 + 1.25 mm, respectively. EM for buccal cortical bone thickness, mesiodistal width and buccolingual bone depth was 0.58, 0.40 and 0.48, respectively. The difference in measurement at 6 and 8 mm for buccal cortical plate thickness (P < 0.05) and buccolingual bone thickness (P < 0.05) was found to be significant, whereas for mesiodistal width it was insignificant (P > 0.05). CONCLUSION: Bone thickness measurement has shown promising evidence for safe placement of miniscrews in the mandible during mixed dentition. The use of miniscrew is the best alternative, even in younger patients. .


OBJETIVO: avaliar, por meio de tomografia volumétrica digital (TVD), a espessura óssea necessária para a instalação de mini-implante na arcada inferior durante a fase de dentição mista. MÉTODOS: um total de 15 pacientes saudáveis, com idades entre 8 e 10 anos, com segundo molar inferior decíduo irrompido recentemente, foram incluídos no presente estudo. Imagens de TVD da hemiarcada inferior foram obtidas utilizando sistemas de imagens extrabucais Kodak. As imagens foram analisadas por meio do programa de imagens Kodak. O erro do método (EM) foi calculado utilizando a fórmula de Dahlberg. Médias e desvios-padrão foram calculados de 6 a 8mm aquém da junção amelocementária. O teste t foi utilizado para a análise das medidas. RESULTADOS: a espessura do osso cortical vestibular, largura mesiodistal e profundidade óssea vestibulolingual, a 6mm, foram de 1,73 + 0,41; 2,15 + 0,49; e 13,18 + 1,22 mm, respectivamente. Já a 8mm, os valores foram de 2,42 + 0,34; 2,48 + 0,33; e 13,65 + 1,25mm. O EM para a espessura do osso cortical vestibular, largura mesiodistal e profundidade óssea vestibulolingual foi de 0,58, 0,40 e 0,48mm, respectivamente. A diferença entre as medidas a 6 e 8mm para a espessura do osso cortical vestibular (p < 0,05) e a espessura óssea vestibulolingual (p < 0,05) foi significativa, embora não tenha sido significativa para a largura mesiodistal (p < 0,05). CONCLUSÃO: a mensuração da espessura óssea demonstra evidências promissoras para a segura instalação de mini-implantes na arcada inferior e na fase de dentição mista. O uso de mini-implantes tem se mostrado a melhor alternativa, mesmo nos casos de pacientes mais jovens. .


Subject(s)
Humans , Male , Middle Aged , /genetics , /metabolism , Islets of Langerhans/metabolism , Alleles , Fasting/metabolism , Genome-Wide Association Study/methods , Glucose/genetics , Glucose/metabolism , Insulin Resistance/genetics , Insulin/genetics , Insulin/metabolism , Polymorphism, Single Nucleotide/genetics , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Signal Transduction/genetics
7.
Rev. Soc. Cardiol. Estado de Säo Paulo ; 24(4): 36-43, out.-dez. 2014.
Article in Portuguese | LILACS | ID: lil-761239

ABSTRACT

A obesidade está associada a risco aumentado de doença cardiovascular, tanto pela associação a múltiplos fatores de risco que frequentemente a acompanham como pelos efeitos diretos do excesso de peso sobre a estrutura e a dinâmica cardíacas. A patogênese da disfunção miocárdica na obesidade é complexa e multifatorial. Alterações hemodinâmicas, neuro-humorais e no metabolismo dos substratos energéticos estão implicadas no desenvolvimento da miocardiopatia da obesidade. Acredita-se que as mudanças estruturais e funcionais no miócito cardíaco representem uma “má adaptação” às alterações metabólicas descritas na obesidade,levando à disfunção miocárdica progressiva e, finalmente, à insuficiência cardíaca. A perda de peso induz significativas mudanças tanto na estrutura miocárdica quanto na disfunção diastólica relacionada à obesidade. Abordagens farmacológicas que atuem sobre o remodelamento cardíaco, bloqueando a fibrogênese, tais como TGF-β1, espécies reativas de oxigênio ou endotelina-1, têm apresentado resultados promissores em estudos experimentais.


Obesity is associated with increased risk of cardiovascular disease, both by the presence of multiple well documente drisk factors that often accompany this condition, and the direct effects of excess of weight on cardiac structure and dynamics. The pathogenesis of myocardial dysfunction in obesity is complex and multifactorial. Neurohumoral, hemodynamic, and metabolism changes of energy substrates are implicated in the development of the cardiomyopathy of obesity. It is believed that the structural and functional changes in cardiac myocytes represent a “maladaptive”metabolic alteration described in obesity, leading to progressive heart failure and ultimately to myocardial dysfunction. Weight loss can induce significant changes inboth myocardial structure and diastolic dysfunction relatedto obesity. Pharmacological approaches that act on cardiac remodeling blocking fibrogenesis, such as TGF-β1, reactive oxygen species and endothelin-1, have shown promising results in experimental research.


Subject(s)
Humans , Male , Female , Cardiomyopathies/complications , Cardiomyopathies/congenital , Cardiomyopathies/physiopathology , Obesity/diet therapy , Obesity/genetics , Comorbidity , Cardiovascular Diseases/complications , Epidemiology, Experimental , Risk Factors , Insulin Resistance/genetics
8.
Article in English | IMSEAR | ID: sea-158373

ABSTRACT

Background & objectives: Type 2 diabetes (T2D) is characterized as hyperglycaemia caused by defects in insulin secretion, and it affects target tissues, such as skeletal muscle, liver and adipose tissue. Therefore, analyzing the changes of gene expression profiles in these tissues is important to elucidate the pathogenesis of T2D. We, therefore, measured the gene transcript alterations in liver and skeletal muscle of rat with induced T2D, to detect differentially expressed genes in liver and skeletal muscle and perform gene-annotation enrichment analysis. Methods: In the present study, skeletal muscle and liver tissue from 10 streptozotocin-induced diabetic rats and 10 control rats were analyzed using gene expression microarrays. KEGG pathways enriched by differentially expressed genes (DEGs) were identified by WebGestalt Expander and GATHER software. DEGs were validated by the method of real-time PCR and western blot. Results: From the 9,929 expressed genes across the genome, 1,305 and 997 differentially expressed genes (DEGs, P<0.01) were identified in comparisons of skeletal muscle and liver, respectively. large numbers of DEGs (200) were common in both comparisons, which was clearly more than the predicted number (131 genes, P<0.001). For further interpretation of the gene expression data, three over-representation analysis softwares (WebGestalt, Expander and GATHER) were used. All the tools detected one KEGG pathway (MAPK signaling) and two GO (gene ontology) biological processes (response to stress and cell death), with enrichment of DEGs in both tissues. In addition, PPI (protein-protein interaction) networks constructed using human homologues not only revealed the tendency of DEGs to form a highly connected module, but also suggested a “hub” role of p38-MAPK-related genes (such as MAPK14) in the pathogenesis of T2D. Interpretation & conclusions: Our results indicated the considerably aberrant MAPK signaling in both insulin-sensitive tissues of T2D rat, and that the p38 may play a role as a common “hub” in the gene module response to hyperglycaemia. Furthermore, our research pinpoints the role of several new T2D-associated genes (such as Srebf1 and Ppargc1) in the human population.


Subject(s)
Adipose Tissue/metabolism , Adipose Tissue/pathology , Animals , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Gene Expression Profiling , Humans , Hyperglycemia/genetics , Hyperglycemia/pathology , Insulin/metabolism , Insulin Resistance/genetics , Liver/metabolism , Liver/pathology , Mitogen-Activated Protein Kinase Kinases/biosynthesis , Mitogen-Activated Protein Kinase Kinases/genetics , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Rats , Signal Transduction
9.
Clinics ; 69(3): 179-184, 3/2014. tab
Article in English | LILACS | ID: lil-703600

ABSTRACT

OBJECTIVES: We aimed to investigate whether glucocorticoid receptor gene polymorphisms are associated with clinical and metabolic profiles in patients with polycystic ovary syndrome. Polycystic ovary syndrome is a complex endocrine disease that affects 5-8% of women and may be associated with metabolic syndrome, which is a risk factor for cardiovascular disease. Cortisol action and dysregulation account for metabolic syndrome development in the general population. As glucocorticoid receptor gene (NR3C1) polymorphisms regulate cortisol sensitivity, we hypothesized that variants of this gene may be involved in the adverse metabolic profiles of patients with polycystic ovary syndrome. METHOD: Clinical, metabolic and hormonal profiles were evaluated in 97 patients with polycystic ovary syndrome who were diagnosed according to the Rotterdam criteria. The alleles of the glucocorticoid gene were genotyped. Association analyses were performed using the appropriate statistical tests. RESULTS: Obesity and metabolic syndrome were observed in 42.3% and 26.8% of patients, respectively. Body mass index was positively correlated with blood pressure, triglyceride, LDL-c, total cholesterol, glucose and insulin levels as well as HOMA-IR values and inversely correlated with HDL-c and SHBG levels. The BclI and A3669G variants were found in 24.7% and 13.4% of alleles, respectively. BclI carriers presented a lower frequency of insulin resistance compared with wild-type subjects. CONCLUSION: The BclI variant is associated with a lower frequency of insulin resistance in women with polycystic ovary syndrome. Glucocorticoid gene polymorphism screening during treatment of the syndrome may be useful for identifying subgroups of at-risk patients who would benefit the most from personalized treatment. .


Subject(s)
Adult , Female , Humans , Young Adult , Polycystic Ovary Syndrome/genetics , Polycystic Ovary Syndrome/metabolism , Polymorphism, Genetic/genetics , Receptors, Glucocorticoid/genetics , Alleles , Body Mass Index , Cholesterol , Fluoroimmunoassay , Gene Frequency , Genes, bcl-1/genetics , Hypertension/genetics , Hypertension/metabolism , Insulin Resistance/genetics , Metabolic Syndrome/genetics , Metabolic Syndrome/metabolism , Obesity/genetics , Obesity/metabolism , Polymerase Chain Reaction , Risk Factors , Statistics, Nonparametric , Time Factors
10.
Egyptian Journal of Chest Diseases and Tuberculosis [The]. 2014; 63 (1): 133-139
in English | IMEMR | ID: emr-154305

ABSTRACT

OSA is a common condition that is characterized by intermittent and recurrent pauses in respiration results in multiple cycles of hypoxia/reoxygenation with an increased production of reactive oxygen species [ROS]. Is to assess serum insulin level and insulin resistance in obese patients with and without OSA. Study was performed on 51 obese subjects who had been referred to the Chest Department of Kasr Alaini Hospital with clinical suspicion of OSA in order to perform polysomnography. They were classified into two groups; cases: consist of 33 obese patients who were diagnosed as obstructive sleep apnea [OSA] and controls: consist of 18 obese subjects, without OSA as a control group. The two groups were subjected to polysomnographic study, serum insulin by ELISA and assessment of insulin resistance by calculation of HOMA index. There was statistically highly significant increase in Epworth sleepiness scale [ESS] among cases compared to controls. As regards the polysomnographic data, there was statistically highly significant increase in AHI, desaturation index and duration of desaturation < 90% among cases compared to control subjects. Regarding minimal O2 sat% and average O[2] sat% were lower in cases than in the control subjects and this reduction was statistically significant. There was statistically highly significant increase in serum insulin, HOMA index among cases as compared to controls. Insulin resistance in OSA is related to sleep associated hypoxemia and hypoxic stress


Subject(s)
Humans , Male , Female , Insulin Resistance/genetics , Obesity , Hypoxia, Brain/blood , Hospitals, University
11.
Article in English | WPRIM | ID: wpr-23625

ABSTRACT

Ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been studied in relation to type 2 diabetes mellitus (T2DM) and insulin resistance (IR). We hypothesized that the difference in genotype may be one of the factors that affect the outcome of intervention. We genotyped 448 men with fasting glucose> or =5.6 mM/L, including 371 in subjects with K allele (KK) (69 control group [CG]; and 302 intervention group [IG]) and 77 in subjects with Q allele (KQ+QQ) (13 CG and 64 IG). The web-based intervention based on a lifestyle modification was delivered by e-mail once a month for 10 months. In the KK, IG demonstrated significantly decreased levels of fasting serum insulin (FSI) as compared to CG and homeostasis model of assessment of insulin resistance (HOMA-IR). In the KQ+QQ IG group, hemoglobin A1c (HbA1c), FSI and HOMA-IR were significantly decreased, and showed further reduction in the HOMA-IR than KQ+QQ CG. After analysis of covariance, K121Q did significantly influence the change of HbA1c in CG after appropriate adjustment. In a multivariate model, BMI change predicted HOMA-IR change (adjusted beta=0.801; P=0.022) in KK IG subjects with T2DM. ENPP1 K121Q did not influence the change in IR. However, individuals with T2DM carrying the K121 variant are very responsive to the effect of BMI reduction on HOMA-IR.


Subject(s)
Alleles , Asian Continental Ancestry Group/genetics , Blood Glucose/analysis , Body Mass Index , Diabetes Mellitus, Type 2/blood , Feeding Behavior , Glycated Hemoglobin A/analysis , Humans , Insulin Resistance/genetics , Internet , Life Style , Male , Middle Aged , Phosphoric Diester Hydrolases/genetics , Pyrophosphatases/genetics , Republic of Korea , Weight Loss/genetics
12.
Arq. bras. endocrinol. metab ; 57(8): 583-593, Nov. 2013. ilus, tab
Article in Portuguese | LILACS | ID: lil-696897

ABSTRACT

OBJETIVO: Avaliar características clínicas, bioquímicas, hormonais e genéticas de familiares de duas pacientes portadoras de lipodistrofia parcial familiar (FPLD) tipo 2. MATERIAIS E MÉTODOS: Foram avaliados 50 indivíduos de duas famílias brasileiras não relacionadas a partir de dois propósitos com fenótipo de FPLD. Foi confirmada a mutação no éxon 8 do gene LMNA em 18 destes e identificada a substituição em heterozigose no códon 482, resultando na mutação p.R482W. Com base na presença ou não da mutação, os indivíduos foram separados em afetados e não afetados, e comparados quanto a parâmetros clínicos, bioquímicos e hormonais. RESULTADOS: Indivíduos afetados tiveram 2,8 vezes mais chance de manifestar diabetes e síndrome dos ovários policísticos (SOP), maiores índices HOMA-IR, níveis de insulina e de triglicérides e menores níveis de leptina. Essas alterações precedem o início do diabetes, pois foram evidenciadas nos afetados diabéticos e não diabéticos. Foi constatada heterogeneidade fenotípica entre os portadores da mutação. CONCLUSÃO: A mutação no gene da LMNA é determinante de alterações clínicas, bioquímicas e hormonais que implicam deterioração metabólica nos portadores da mutação.


OBJECTIVE: To evaluate clinical, biochemical, hormonal and genetic characteristics of relatives of two patients with familial partial lipodystrophy (FPLD) type 2. MATERIALS AND METHODS: Fifty subjects, members of two non-related Brazilian families from two different probands with FPLD phenotype, were evaluated. A mutation in exon 8 of LMNA gene was confirmed in 18 of them, and a heterozygous substitution at codon 482 was identified, predicting a p.R482W mutation. Based on the presence or absence of the mutation, subjects were classified in affected and unaffected, and compared in terms of clinical, biochemical and hormonal parameters. RESULTS: Affected subjects were 2.8 times more likely to manifest diabetes and PCOS, higher HOMA-IR, insulin and triglyceride levels, and lower levels of leptin. These changes preceded the onset of diabetes, because they were observed in diabetic and non-diabetic affected patients. A phenotypic heterogeneity was found among mutation carriers. CONCLUSION: A mutation in the LMNA gene is a determinant of clinical, biochemical and hormonal changes that imply in metabolic deterioration in mutation carriers.


Subject(s)
Adolescent , Adult , Female , Humans , Middle Aged , Young Adult , Diabetes Mellitus/diagnosis , Lamin Type A/genetics , Lipodystrophy, Familial Partial/genetics , Polycystic Ovary Syndrome/complications , Biomarkers , Blood Glucose , Insulin Resistance/genetics , Leptin/blood , Lipodystrophy, Familial Partial/complications , Mutation , Pedigree , Sequence Analysis, DNA
13.
J. pediatr. (Rio J.) ; 89(5): 492-498, set.-out. 2013. ilus, tab
Article in Portuguese | LILACS | ID: lil-690074

ABSTRACT

OBJETIVO: Elaboramos este estudo para avaliar se o polimorfismo -675 4G/5G no gene inibidor 1 do ativador do plasminogênio se associa à obesidade e à resistência insulínica em crianças mexicanas. MÉTODOS: Foi realizado um estudo transversal em 174 crianças, 89 delas com peso normal e 85 obesas, variando sua idade de 6 a 13 anos. Todas as crianças eram do estado de Guerrero e foram recrutadas de três escolas primárias na cidade de Chilpancingo, México. Os níveis de insulina foram determinados por prova imunoenzimática. Foi usado o modelo de avaliação da homeostase para determinar resistência insulínica. O polimorfismo -675 4G/5G no gene PAI-1 foi analisado pelo método reação de polimerase em cadeia-polimorfismo no comprimento dos fragmentos de restrição. RESULTADOS: A prevalência de resistência insulínica no grupo obeso foi mais alta (49,41%) do que no grupo com peso normal (16,85%). O polimorfismo 4G/5G do PAI-1 foi encontrado em equilíbrio de Hardy Weinberg. O genótipo 4G/5G contribuiu para um aumento significativo da relação cintura-quadril (β = 0,02, p = 0,006), da circunferência da cintura (β = 4,42, p = 0,009) e da espessura da prega subescapular (β = 1,79, p = 0,04), mas não se relacionou com a resistência insulínica. CONCLUSÃO: O genótipo -675 4G/5G do gene PAI-1 se associou a aumento da adiposidade corporal em crianças mexicanas.


OBJECTIVE: To assess whether the -675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is associated with obesity and insulin resistance in Mexican children. METHODS: A cross-sectional study was performed in 174 children, 89 with normal-weight and 85 with obesity, aged from 6 to 13 years. All children were from state of Guerrero, and recruited from three primary schools in the city of Chilpancingo, Mexico. Insulin levels were determined by immunoenzymatic assay. The homeostasis model assessment was used to determine insulin resistance. The -675 4G/5G polymorphism in PAI-1 gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The prevalence of insulin resistance in the obese group was higher (49.41%) than in the normal-weight group (16.85%). The 4G/5G PAI-1 polymorphism was found in Hardy Weinberg equilibrium. The 4G/5G genotype contributed to a significant increase in waist-hip ratio (β = 0.02, p = 0.006), waist circumference (β = 4.42, p = 0.009), and subscapular skinfold thickness (β = 1.79, p = 0.04); however, it was not related with insulin resistance. CONCLUSION: The -675 4G/5G genotype of PAI-1 gene was associated with increase of body adiposity in Mexican children.


Subject(s)
Adolescent , Child , Female , Humans , Male , Adiposity/genetics , Insulin Resistance/genetics , Plasminogen Activator Inhibitor 1/genetics , Polymorphism, Genetic/genetics , Blood Glucose , Body Weight , Case-Control Studies , Cross-Sectional Studies , Genetic Predisposition to Disease , Insulin/blood , Linear Models , Mexico , Obesity/genetics , Polymerase Chain Reaction/methods , Waist Circumference
14.
Braz. j. med. biol. res ; 46(7): 623-628, ago. 2013. tab, graf
Article in English | LILACS | ID: lil-682397

ABSTRACT

Recent animal studies have indicated that overexpression of the elongation of long-chain fatty acids family member 6 (Elovl6) gene can cause insulin resistance and β-cell dysfunction. These are the major factors involved in the development of type 2 diabetes mellitus (T2DM). To identify the relationship between single nucleotide polymorphisms (SNP) of ELOVL6 and T2DM pathogenesis, we conducted a case-control study of 610 Han Chinese individuals (328 newly diagnosed T2DM and 282 healthy subjects). Insulin resistance and islet first-phase secretion function were evaluated by assessment of insulin resistance in a homeostasis model (HOMA-IR) and an arginine stimulation test. Three SNPs of the ELOVL6 gene were genotyped with polymerase chain reaction-restriction fragment length polymorphism, with DNA sequencing used to confirm the results. Only genotypes TT and CT of the ELOVL6 SNP rs12504538 were detected in the samples. Genotype CC was not observed. The T2DM group had a higher frequency of the C allele and the CT genotype than the control group. Subjects with the CT genotype had higher HOMA-IR values than those with the TT genotype. In addition, no statistical significance was observed between the genotype and allele frequencies of the control and T2DM groups for SNPs rs17041272 and rs6824447. The study indicated that the ELOVL6 gene polymorphism rs12504538 is associated with an increased risk of T2DM, because it causes an increase in insulin resistance.


Subject(s)
Adult , Female , Humans , Male , Middle Aged , Acetyltransferases/genetics , /genetics , Polymorphism, Single Nucleotide/genetics , China/ethnology , /ethnology , Genotype , Insulin Resistance/genetics , Insulin-Secreting Cells/pathology , Polymorphism, Restriction Fragment Length
15.
Clinics ; 68(6): 785-791, jun. 2013. tab
Article in English | LILACS | ID: lil-676928

ABSTRACT

OBJECTIVE: To investigate the influence of (CA)n repeats in the insulin-like growth factor 1 gene and a variable number of tandem repeats of the insulin gene on birth size in children who are small or adequate-sized for gestational age and to correlate these polymorphisms with serum insulin-like growth factor 1 levels and insulin sensitivity in children who are small for gestational age, with and without catch-up growth. PATIENTS AND METHODS: We evaluated 439 infants: 297 that were adequate-sized for gestational age and 142 that were small for gestational age (66 with and 76 without catch-up). The number of (CA)n repeat in the insulin-like growth factor 1 gene and a variable number of tandem repeats in the insulin gene were analyzed using GENESCAN software and polymerase chain reaction followed by enzymatic digestion, respectively. Clinical and laboratory data were obtained from all patients. RESULTS: The height, body mass index, paternal height, target height and insulin-like growth factor 1 serum levels were higher in children who were small for gestational age with catch-up. There was no difference in the allelic and genotypic distributions of both polymorphisms between the adequate-sized and small infants or among small infants with and without catch-up. Similarly, the polymorphisms were not associated with clinical or laboratory variables. CONCLUSION: Polymorphisms of the (CA)n repeats of the insulin-like growth factor 1 gene and a variable number of tandem repeats of the insulin gene, separately or in combination, did not influence pre- or postnatal growth, insulin-like growth factor 1 serum levels or insulin resistance. .


Subject(s)
Female , Humans , Infant, Newborn , Male , Infant, Small for Gestational Age , Insulin-Like Growth Factor I/genetics , Insulin/genetics , Polymorphism, Genetic , Tandem Repeat Sequences/genetics , Adenosine , Brazil , Birth Weight/genetics , Blood Glucose/genetics , Body Height/genetics , Body Weight/genetics , Cytosine , Insulin Resistance/genetics , Insulin-Like Growth Factor I/analysis , Risk Factors
16.
Braz. j. med. biol. res ; 46(1): 1-13, 11/jan. 2013. graf
Article in English | LILACS | ID: lil-665794

ABSTRACT

An important disease among human metabolic disorders is type 2 diabetes mellitus. This disorder involves multiple physiological defects that result from high blood glucose content and eventually lead to the onset of insulin resistance. The combination of insulin resistance, increased glucose production, and decreased insulin secretion creates a diabetic metabolic environment that leads to a lifetime of management. Appropriate models are critical for the success of research. As such, a unique model providing insight into the mechanisms of reversible insulin resistance is mammalian hibernation. Hibernators, such as ground squirrels and bats, are excellent examples of animals exhibiting reversible insulin resistance, for which a rapid increase in body weight is required prior to entry into dormancy. Hibernator studies have shown differential regulation of specific molecular pathways involved in reversible resistance to insulin. The present review focuses on this growing area of research and the molecular mechanisms that regulate glucose homeostasis, and explores the roles of the Akt signaling pathway during hibernation. Here, we propose a link between hibernation, a well-documented response to periods of environmental stress, and reversible insulin resistance, potentially facilitated by key alterations in the Akt signaling network, PPAR-γ/PGC-1α regulation, and non-coding RNA expression. Coincidentally, many of the same pathways are frequently found to be dysregulated during insulin resistance in human type 2 diabetes. Hence, the molecular networks that may regulate reversible insulin resistance in hibernating mammals represent a novel approach by providing insight into medical treatment of insulin resistance in humans.


Subject(s)
Animals , Diabetes Mellitus, Experimental/physiopathology , Hibernation/physiology , Insulin Resistance/physiology , Sciuridae/metabolism , Diabetes Mellitus, Experimental/metabolism , /metabolism , /physiopathology , Glucose/metabolism , Hibernation/genetics , Insulin Resistance/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Obesity/genetics , Obesity/metabolism , Obesity/physiopathology , Protein Biosynthesis/genetics , Sciuridae/physiology , Signal Transduction/genetics
17.
Caracas; s.n; oct. 2012. ^c30 cmilus, tab, tab.
Thesis in Spanish | LILACS, LIVECS | ID: biblio-1150987

ABSTRACT

La regulación ejercida por la insulina central en individuos diabéticos ha sido muy poco estudiada. La angiotensina II promueve el estrés oxidativo y la resistencia a la insulina. Dada la co-localización del receptor AT1 de la angiotensina II y el RI a nivel hipotalámico, en este trabajo, decidimos evaluar el efecto de la angiotensina II sobre las acciones centrales de la insulina en condiciones diabéticas, a través de un modelo animal de DM2 en ratas Sprague-Dawley, así como el posible efecto protector del tratamiento crónico con Valsartán. El modelo fue caracterizado y validado a través de la medición de diversos parámetros metabólicos, usando técnicas enzimáticas e inmunoenzimáticas. Los efectos de la angiotensina II sobre la señalización y acciones biológicas de la insulina a nivel hipotalámico fueron evaluadas in vivo e in vitro, mediante western blot, así como los cambios en los niveles de glicemia en las ratas tratadas ICV con ANG II y/o insulina. Fue evaluado además, el estado oxidativo a nivel hipotalámico, mediante la determinación de enzimas antioxidantes, así como el estado inflamatorio sistémico, mediante la determinación fluorométrica de citoquinas plasmáticas. El modelo experimental desarrollado mimetizó las características fenotípicas de la DM2. El valsartán previno parcialmente la resistencia a la insulina. En condiciones normales, se demostró que la angiotensina es capaz de inhibir la señalización de la insulina a nivel hipotalámico por un mecanismo dependiente de ERO. En condiciones diabéticas, hay una disminución basal de la activación de las proteínas de señalización de la insulina, la cual fue prevenida por el tratamiento con valsartán. El efecto hipoglicemiante inducido por la insulina central fue significativamente reducido en condiciones diabéticas. El tratamiento ICV con angiotensina II antagonizó los efectos hipoglicemiantes de la insulina central y este efecto fue potenciado en condiciones diabéticas. El valsartán bloquea la acción inducida por la ANG II ICV en todos los grupos. Los resultados demuestran que existe un estado de resistencia a la insulina en nuestro modelo de DM2, evidente tanto a nivel molecular como fisiológico, el cual es potenciado por la angiotensina y prevenido parcialmente por el tratamiento crónico con valsartán.


Subject(s)
Animals , Rats , Insulin Resistance/genetics , Angiotensin II/analogs & derivatives , Reactive Oxygen Species/pharmacology , Diabetes Mellitus, Type 2/chemically induced , In Vitro Techniques , Epidemiology, Experimental , Rats, Sprague-Dawley , Streptozocin/administration & dosage , Streptozocin/adverse effects , Oxidative Stress/drug effects , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Valsartan/therapeutic use , Hypoglycemic Agents/adverse effects , Insulin/adverse effects , Antioxidants/pharmacokinetics
18.
Article in English | IMSEAR | ID: sea-137382

ABSTRACT

Background & objectives: TNF-α is an adipocytokine that has been implicated in the development of insulin resistance. Dysregulation of TNF-α production has been implicated in a variety of human diseases including type 2 diabetes mellitus. We aimed to find out the association of TNF-α levels with insulin resistance, body mass index and waist hip ratio; and to elicit its role with respect to duration of the disease, if any. Methods: 50 type-2 diabetic patients attending Narayana Medical Hospital, Nellore, were studied. Body mass index and Waist hip ratio were calculated. Homeostasis model assessment method was used to calculate insulin resistance (HOMA IR) and per cent β cell function (HOMA B) . Insulin was estimated by chemiluminescence method and TNF-α by ELISA method. The subjects were arbitrarily categorized into three groups based on duration of diabetes. Group 1 included subjects with diabetes of less than 5 yr duration, group 2 included diabetics of 6-10 yr duration and group 3 greater than 10 yr duration. Results: Our study revealed a significant correlation between TNF-α levels and BMI (P=0.006), the correlation being stronger in males when compared to females. A significant correlation was found between per cent β cell function and TNF-α (P=0.008). TNF-α correlated significantly with HOMA IR, HOMA B and insulin, in group 2 diabetes. Interpretation & conclusions: Our results suggest the possible role of TNF-α in the pathogenesis of type-2 diabetes mellitus and the importance of reducing obesity to prevent elevated levels of the cytokine and related complications.


Subject(s)
Adult , Blood Glucose/metabolism , Body Mass Index , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Female , Humans , India , Insulin Resistance/genetics , Insulin-Secreting Cells/pathology , Male , Middle Aged , Statistics as Topic , Tumor Necrosis Factor-alpha/blood , Waist-Hip Ratio
19.
Article in English | WPRIM | ID: wpr-211930

ABSTRACT

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered the key determinants of insulin resistance. Impaired mitochondrial function in obese animals was shown to induce the ER stress response, resulting in reduced adiponectin synthesis in adipocytes. The expression of inducible nitric oxide synthase (iNOS) is increased in adipose tissues in genetic and dietary models of obesity. In this study, we examined whether activation of iNOS is responsible for palmitate-induced mitochondrial dysfunction, ER stress, and decreased adiponectin synthesis in 3T3L1 adipocytes. As expected, palmitate increased the expression levels of iNOS and ER stress response markers, and decreased mitochondrial contents. Treatment with iNOS inhibitor increased adiponectin synthesis and reversed the palmitate-induced ER stress response. However, the iNOS inhibitor did not affect the palmitate-induced decrease in mitochondrial contents. Chemicals that inhibit mitochondrial function increased iNOS expression and the ER stress response, whereas measures that increase mitochondrial biogenesis (rosiglitazone and adenoviral overexpression of nuclear respiratory factor-1) reversed them. Inhibition of mitochondrial biogenesis prevented the rosiglitazone-induced decrease in iNOS expression and increase in adiponectin synthesis. These results suggest that palmitate-induced mitochondrial dysfunction is the primary event that leads to iNOS induction, ER stress, and decreased adiponectin synthesis in cultured adipocytes.


Subject(s)
3T3-L1 Cells , Adipocytes/drug effects , Adiponectin/biosynthesis , Adipose Tissue/metabolism , Animals , Endoplasmic Reticulum Stress/drug effects , Insulin Resistance/genetics , Mice , Mitochondria/drug effects , Mitochondrial Turnover/drug effects , Nitric Oxide Synthase Type II/genetics , Nuclear Respiratory Factor 1 , Obesity/genetics , Palmitic Acid/pharmacology , Thiazolidinediones/pharmacology
20.
Arq. bras. endocrinol. metab ; 55(9): 677-685, dez. 2011. ilus, tab
Article in English | LILACS | ID: lil-610474

ABSTRACT

The increased prevalence of diabetes mellitus has caused a rise in the occurrence of its chronic complications, such as diabetic nephropathy (DN), which is associated with elevated morbidity and mortality. Familial aggregation studies have demonstrated that besides the known environmental risk factors, DN has a major genetic component. Therefore, it is necessary to identify genes associated with risk for or protection against DN. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is expressed in several tissues, including the kidneys. Increased levels of ENPP1 expression inhibit tyrosine-kinase activity of the insulin receptor in several cell types, leading to insulin resistance. K121Q polymorphism of the ENPP1 gene seems to be associated with insulin resistance and DN development. The elucidation of genetic factors and their associations will provide better understanding of the pathogenesis of DN and, may consequently, lead to a more effective approach to prevention and treatment.


A crescente prevalência do diabetes melito tem causado aumento na ocorrência das suas complicações crônicas, como a nefropatia diabética (ND), a qual está associada com elevada morbidade e mortalidade. Estudos de agregação familiar demonstram que a ND tem um importante componente genético, além dos conhecidos fatores de risco ambientais. Portanto, existe a necessidade de se identificarem genes associados ao risco ou proteção à ND. A ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1) é expressa em vários tecidos, incluindo nos rins. Foi encontrado que níveis aumentados de expressão da ENPP1 inibem a atividade tirosino-quinase do receptor da insulina em vários tipos celulares, causando resistência à insulina. O polimorfismo K121Q do gene ENNP1parece estar associado com resistência à insulina e com o desenvolvimento da ND. A elucidação dos fatores genéticos e de suas associações permitirá um melhor entendimento da patogênese da ND e, consequentemente, poderemos ter uma abordagem mais efetiva em sua prevenção e tratamento.


Subject(s)
Humans , /enzymology , Diabetic Nephropathies/enzymology , Insulin Resistance/genetics , Phosphoric Diester Hydrolases/genetics , Polymorphism, Genetic/genetics , Pyrophosphatases/genetics , /genetics , Diabetic Nephropathies/genetics , Genetic Markers , Genetic Predisposition to Disease
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