RESUMO
BACKGROUND: Human skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects. METHODS: We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model. RESULTS: We observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects. CONCLUSIONS: Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.
Assuntos
Músculo Esquelético/fisiologia , Obesidade/genética , Obesidade/patologia , Células-Tronco/fisiologia , Animais , Diferenciação Celular/genética , Metilação de DNA , Epigênese Genética , Humanos , Camundongos , Pessoa de Meia-Idade , Desenvolvimento Muscular , Músculo Esquelético/patologia , Células-Tronco/patologiaRESUMO
BACKGROUND AND AIMS: The oxidation of low-density lipoprotein (LDL) cholesterol particles is an early atherogeninic event. Obese pediatric populations have higher levels of oxidized LDL (oxLDL) than normal weight children. The aim of this study was to evaluate the effect of a weight loss program on the biochemical profile and oxLDL levels in Spanish obese children and adolescents. METHODS: Forty obese children (mean age 11 years, 51% boys) followed a 10-week weight loss program. They were dichotomized at the median of body mass index-standard deviation score (BMI-SDS) change, as high (HR) and low responders (LR) after the intervention. The intervention included a moderate energy-restricted diet, nutritional education, and family involvement. Anthropometric and biochemical measurements were performed at the beginning and during the follow up. A cardiometabolic risk score (CMS) was calculated considering metabolic risk factors. RESULTS: Higher baseline oxLDL levels were associated with a higher CMS in obese children (P < .001). After the intervention, oxLDL significantly decreased in the HR group. Moreover, a positive correlation between changes in oxLDL and BMI-SDS (r = 0.385, P = .015) was found after the weight loss program. Interestingly, multiple-adjusted regression models showed an association between changes in total cholesterol [B: 0.127, 95% confidence interval (CI): 0.06 to 0.20] and LDL-cholesterol (B: 0.173, 95% CI: 0.08 to 0.26) with changes in oxLDL. CONCLUSIONS: Higher baseline oxLDL levels were associated with a higher CMS in obese children. After the weight loss program, a decrease in oxLDL levels was found in HR subjects and the oxLDL levels were associated with BMI-SDS and cholesterol levels.
Assuntos
Fenômenos Fisiológicos da Nutrição do Adolescente , Doenças Cardiovasculares/prevenção & controle , Fenômenos Fisiológicos da Nutrição Infantil , Dieta Redutora , Lipoproteínas LDL/sangue , Síndrome Metabólica/prevenção & controle , Obesidade Infantil/dietoterapia , Adolescente , Comportamento do Adolescente , Índice de Massa Corporal , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Criança , Comportamento Infantil , Ingestão de Energia , Família , Humanos , Estudos Longitudinais , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Cooperação do Paciente , Pacientes Desistentes do Tratamento , Educação de Pacientes como Assunto , Obesidade Infantil/sangue , Obesidade Infantil/fisiopatologia , Fatores de Risco , Espanha/epidemiologia , Redução de PesoRESUMO
The present study analyses the gene expression profile of peripheral blood mononuclear cells (PBMC) from obese boys. The aims of the present study were to identify baseline differences between low responders (LR) and high responders (HR) after 10 weeks of a moderate energy-restricted dietary intervention, and to compare the gene expression profile between the baseline and the endpoint of the nutritional intervention. Spanish obese boys (age 10-14 years) were advised to follow a 10-week moderate energy-restricted diet. Participants were classified into two groups based on the association between the response to the nutritional intervention and the changes in BMI standard deviation score (BMI-SDS): HR group (n 6), who had a more decreased BMI-SDS; LR group (n 6), who either maintained or had an even increased BMI-SDS. The expression of 28,869 genes was analysed in PBMC from both groups at baseline and after the nutritional intervention, using the Affymetrix Human Gene 1.1 ST 24-Array plate microarray. At baseline, the HR group showed a lower expression of inflammation and immune response-related pathways, which suggests that the LR group could have a more developed pro-inflammatory phenotype. Concomitantly, LEPR and SIRPB1 genes were highly expressed in the LR group, indicating a tendency towards an impaired immune response and leptin resistance. Moreover, the moderate energy-restricted diet was able to down-regulate the inflammatory 'mitogen-activated protein kinase signalling pathway' in the HR group, as well as some inflammatory genes (AREG and TNFAIP3). The present study confirms that changes in the gene expression profile of PBMC in obese boys may help to understand the weight-loss response. However, further research is required to confirm these findings.
Assuntos
Dieta Redutora , Ingestão de Energia , Regulação da Expressão Gênica no Desenvolvimento , Resistência à Insulina , Leucócitos Mononucleares/metabolismo , Cooperação do Paciente , Obesidade Infantil/dietoterapia , Adolescente , Índice de Massa Corporal , Criança , Perfilação da Expressão Gênica , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Pacientes Desistentes do Tratamento , Educação de Pacientes como Assunto , Obesidade Infantil/sangue , Obesidade Infantil/imunologia , Obesidade Infantil/metabolismo , Espanha , Aumento de Peso , Redução de PesoRESUMO
AIMS: Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newly-diagnosed individuals with type 2 diabetes. METHODS AND RESULTS: We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for â¼ 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin's effects on HbA1c. CONCLUSION: Metformin-associated alterations in DNA methylation partially mediates metformin's antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Metformina/farmacologia , Metformina/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Metilação de DNA , Hemoglobinas GlicadasRESUMO
BACKGROUND AND AIMS: Obesity is a public health problem. The usual treatment is a reduction in calorie intake and an increase in energy expenditure, but not all individuals respond equally to these treatments. Epigenetics could be a factor that contributes to this heterogeneity. The aim of this research was to determine the association between DNA methylation at baseline and the percentage of BMI loss (%BMIL) after two dietary interventions, in order to design a prediction model to evaluate %BMIL based on methylation data. METHODS AND RESULTS: Spanish participants with overweight or obesity (n = 306) were randomly assigned to two lifestyle interventions with hypocaloric diets: one moderately high in protein (MHP) and the other low in fat (LF) for 4 months (Obekit study; ClinicalTrials.gov ID: NCT02737267). Basal DNA methylation was analyzed in white blood cells using the Infinium MethylationEPIC array. After identifying those methylation sites associated with %BMIL (p < 0.05 and SD > 0.1), two weighted methylation sub-scores were constructed for each diet: 15 CpGs were used for the MHP diet and 11 CpGs for the LF diet. Afterwards, a total methylation score was made by subtracting the previous sub-scores. These data were used to design a prediction model for %BMIL through a linear mixed effect model with the interaction between diet and total score. CONCLUSION: Overall, DNA methylation predicts the %BMIL of two 4-month hypocaloric diets and was able to determine which type of diet is the most appropriate for each individual. The results of this pioneer study confirm that epigenetic biomarkers may be further used for precision nutrition and the design of personalized dietary strategies against obesity.
Assuntos
Metilação de DNA , Obesidade , Humanos , Projetos Piloto , Redução de Peso/genética , Dieta com Restrição de Gorduras , Dieta RedutoraRESUMO
BACKGROUND & AIMS: Short telomeres have been observed in chronic disease patients. Identifying environmental and lifestyle factors that could reduce telomere attrition is crucial for disease prevention. The aim of this work was to determine whether weight-loss induced by an energy-reduced Mediterranean diet (erMedDiet) and physical activity (PA) could modify telomere length (TL). METHODS: In 317 randomized non-smoker participants (mean age, 65.8 ± 4.98 years) with metabolic syndrome from two "Prevención con Dieta Mediterránea-Plus" (PREDIMED-Plus) trial centers, we evaluated MedDiet adherence, PA, anthropometric variables and TL at baseline and after a 3-year intervention using an intensive lifestyle program (IG) with an erMedDiet and PA or an unrestricted MedDiet without PA promotion (CG). RESULTS: Participants in the IG displayed greater 3-year weight reductions (-3.7 ± 4 kg, P < 0.001) compared to those in the CG. No differences in TL changes between groups were observed in the cohort as a whole. However, an interaction was observed between the intervention group and sex for TL changes (pinteraction = 0.039). Women in the IG showed an increase in TL after 3-y (+0.25 ± 0.9, relative units) compared to women in the CG (-0.07 ± 1.0) (pANCOVA = 0.036), whereas no differences between groups were observed in men. Women in the IG had a lower risk of telomere shortening after the intervention (OR = 0.17, 95%CI: 0.05-0.64, p = 0.008) compared to women in the CG. CONCLUSIONS: A 3-year lifestyle intervention based on an erMedDiet and PA slowed telomere shortening in women but not in men. TRIAL REGISTRATION: ISRCTN, ISRCTN89898870. Registered 24 July 2014- Retrospectively registered, https://www.isrctn.com/ISRCTN89898870.
Assuntos
Doenças Cardiovasculares , Dieta Mediterrânea , Síndrome Metabólica , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Doenças Cardiovasculares/prevenção & controle , Estilo de Vida , TelômeroRESUMO
Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by ß-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in ß-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient ß-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Humanos , Ratos , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Secreção de Insulina , Insulina/metabolismo , Metilação de DNA , Ilhotas Pancreáticas/metabolismo , Células Secretoras de Insulina/metabolismo , Fatores de Transcrição/metabolismo , Epigênese Genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição Forkhead/metabolismoRESUMO
OBJECTIVE: Type 2 diabetes (T2D) was recently reclassified into severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications. RESEARCH DESIGN AND METHODS: Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications. RESULTS: We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6-6.1 per 1-SD increase, P < 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4-1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue. CONCLUSIONS: We identified differential epigenetic patterns between T2D subgroups that associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.
Assuntos
Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Resistência à Insulina , DNA , Metilação de DNA/genética , Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Epigenômica , Humanos , Insulina/genética , Resistência à Insulina/genéticaRESUMO
INTRODUCTION: A Swedish data-driven cluster study identified four distinct type 2 diabetes (T2D) clusters, based on age at diagnosis, body mass index (BMI), hemoglobin A1c (HbA1c) level, and homeostatic model assessment 2 (HOMA2) estimates of insulin resistance and beta-cell function. A Danish study proposed three T2D phenotypes (insulinopenic, hyperinsulinemic, and classical) based on HOMA2 measures only. We examined these two new T2D classifications using the Danish Centre for Strategic Research in Type 2 Diabetes cohort. RESEARCH DESIGN AND METHODS: In 3529 individuals, we first performed a k-means cluster analysis with a forced k-value of four to replicate the Swedish clusters: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild age-related (MARD), and mild obesity-related (MOD) diabetes. Next, we did an analysis open to alternative k-values (ie, data determined the optimal number of clusters). Finally, we compared the data-driven clusters with the three Danish phenotypes. RESULTS: Compared with the Swedish findings, the replicated Danish SIDD cluster included patients with lower mean HbA1c (86 mmol/mol vs 101 mmol/mol), and the Danish MOD cluster patients were less obese (mean BMI 32 kg/m2 vs 36 kg/m2). Our data-driven alternative k-value analysis suggested the optimal number of T2D clusters in our data to be three, rather than four. When comparing the four replicated Swedish clusters with the three proposed Danish phenotypes, 81%, 79%, and 69% of the SIDD, MOD, and MARD patients, respectively, fitted the classical T2D phenotype, whereas 70% of SIRD patients fitted the hyperinsulinemic phenotype. Among the three alternative data-driven clusters, 60% of patients in the most insulin-resistant cluster constituted 76% of patients with a hyperinsulinemic phenotype. CONCLUSION: Different HOMA2-based approaches did not classify patients with T2D in a consistent manner. The T2D classes characterized by high insulin resistance/hyperinsulinemia appeared most distinct.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Hemoglobinas Glicadas/análise , Humanos , Insulina , Insulina Regular HumanaRESUMO
Aim: Statins lower cholesterol and reduce the risk of cardiovascular disease. However, the exact mechanisms of statins remain unknown. We investigated whether statin therapy associates with epigenetics in Type 2 diabetes (T2D) patients. Materials & methods: DNA methylation was analyzed in blood from newly diagnosed T2D patients in All New Diabetics in Scania (ANDIS) and a replication cohort All New Diabetics in Uppsala County (ANDiU). Results: Seventy-nine sites were differentially methylated between cases on statins and controls (false discovery rate <5%) in ANDIS. These include previously statin-associated methylation sites annotated to DHCR24 (cg17901584), ABCG1 (cg27243685) and SC4MOL (cg05119988). Differential methylation of two sites related to cholesterol biosynthesis and immune response, cg17901584 (DHCR24) and cg23011663 (ARIH2), were replicated in ANDiU. Conclusion: Statin therapy associates with epigenetic modifications in T2D patients.
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Diabetes Mellitus Tipo 2/genética , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Biomarcadores , Metilação de DNA , Epigenômica , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , MasculinoRESUMO
Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the Treatment of Obese Pregnant women (TOP)-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus control subjects (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus control subjects (false discovery rate [FDR] <5%) when using the Houseman reference-free method to correct for cell composition, and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms, including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared with control subjects. Methylation at 17 sites, annotated to, for example, DISC1, GBX2, HERC2, and HUWE1, partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR <5%). Moreover, 22 methylation sites were associated with offspring BMI z scores during the first 3 years of life (P < 0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring's lean mass and early growth.
Assuntos
Metilação de DNA/fisiologia , Sangue Fetal/metabolismo , Obesidade/genética , Peso ao Nascer/fisiologia , Composição Corporal/genética , Composição Corporal/fisiologia , Índice de Massa Corporal , Metilação de DNA/genética , Exercício Físico/fisiologia , Feminino , Humanos , Estilo de Vida , Gravidez , GestantesRESUMO
Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Preparações Farmacêuticas , Glicemia , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Humanos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêuticoRESUMO
Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.
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Dieta Mediterrânea , Estudos Transversais , Humanos , Estudos Prospectivos , Telômero , Encurtamento do TelômeroRESUMO
BACKGROUND: Type 2 diabetes (T2D) is a multifactorial, polygenic disease caused by impaired insulin secretion and insulin resistance. Genome-wide association studies (GWAS) were expected to resolve a large part of the genetic component of diabetes; yet, the single nucleotide polymorphisms identified by GWAS explain less than 20% of the estimated heritability for T2D. There was subsequently a need to look elsewhere to find disease-causing factors. Mechanisms mediating the interaction between environmental factors and the genome, such as epigenetics, may be of particular importance in the pathogenesis of T2D. SCOPE OF REVIEW: This review summarizes knowledge of the impact of epigenetics on the pathogenesis of T2D in humans. In particular, the review will focus on alterations in DNA methylation in four human tissues of importance for the disease; pancreatic islets, skeletal muscle, adipose tissue, and the liver. Case-control studies and studies examining the impact of non-genetic and genetic risk factors on DNA methylation in humans will be considered. These studies identified epigenetic changes in tissues from subjects with T2D versus non-diabetic controls. They also demonstrate that non-genetic factors associated with T2D such as age, obesity, energy rich diets, physical activity and the intrauterine environment impact the epigenome in humans. Additionally, interactions between genetics and epigenetics seem to influence the pathogenesis of T2D. CONCLUSIONS: Overall, previous studies by our group and others support a key role for epigenetics in the growing incidence of T2D.
Assuntos
Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Humanos , Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismoRESUMO
Context: Epigenetics may contribute to sex-specific differences in human liver metabolism. Objective: To study the impact of sex on DNA methylation and gene expression in human liver. Design/Setting: Cross-sectional, Kuopio Obesity Surgery Study. Participants/Intervention: We analyzed DNA methylation with the Infinium HumanMethylation450 BeadChip in liver of an obese population (34 males, 61 females). Females had a higher high-density lipoprotein (HDL)-cholesterol levels compared with males. Gene expression was measured with the HumanHT-12 Expression BeadChip in a subset of 42 participants. Results: Females displayed higher average methylation in the X-chromosome, whereas males presented higher methylation in autosomes. We found 9455 CpG sites in the X-chromosome and 33,205 sites in autosomes with significant methylation differences in liver between sexes (q < 0.05). When comparing our findings with published studies, 95% of the sex-specific differences in liver methylation in the X-chromosome were also found in pancreatic islets and brain, and 26 autosomal sites showed sex-specific methylation differences in the liver as well as in other human tissues. Furthermore, this sex-specific methylation profile in liver was associated with hepatic gene expression changes between males and females. Notably, females showed higher HDL-cholesterol levels, which were associated with higher KDM6A expression and epigenetic differences in human liver. Accordingly, silencing of KDM6A in cultured liver cells reduced HDL-cholesterol levels and APOA1 expression, which is a major component of HDL particles. Conclusions: Human liver has a sex-specific methylation profile in both the X-chromosome and autosomes, which associates with hepatic gene expression changes and HDL-cholesterol. We identified KDM6A as a novel target that regulates HDL-cholesterol levels.
Assuntos
HDL-Colesterol/sangue , Epigênese Genética , Histona Desmetilases/metabolismo , Fígado/metabolismo , Proteínas Nucleares/metabolismo , Obesidade/genética , Adulto , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Biópsia , HDL-Colesterol/metabolismo , Cromossomos Humanos X/genética , Ilhas de CpG/genética , Estudos Transversais , Metilação de DNA , Feminino , Finlândia , Derivação Gástrica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Histona Desmetilases/genética , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Obesidade/sangue , Obesidade/patologia , Obesidade/cirurgia , Transcriptoma , Regulação para CimaRESUMO
BACKGROUND: Given that metformin is the most common pharmacological therapy for type 2 diabetes, understanding the function of this drug is of great importance. Hepatic metformin transporters are responsible for the pharmacologic action of metformin. However, epigenetics in genes encoding metformin transporters has not been fully elucidated. We examined the DNA methylation of these genes in the liver of subjects with type 2 diabetes and tested whether epigenetic alterations associate with diabetes medication, i.e., metformin or insulin plus metformin treatment. RESULTS: DNA methylation in OCT1 encoded by SLC22A1, OCT3 encoded by SLC22A3, and MATE1 encoded by SLC47A1 was assessed in the human liver. Lower average and promoter DNA methylation of SLC22A1, SLC22A3, and SLC47A1 was found in diabetic subjects receiving just metformin, compared to those who took insulin plus metformin or no diabetes medication. Moreover, diabetic subjects receiving just metformin had a similar DNA methylation pattern in these genes compared to non-diabetic subjects. Notably, DNA methylation was also associated with gene expression, glucose levels, and body mass index, i.e., higher SLC22A3 methylation was related to lower SLC22A3 expression and to insulin plus metformin treatment, higher fasting glucose levels and higher body mass index. Importantly, metformin treatment did also directly decrease DNA methylation of SLC22A1 in hepatocytes cultured in vitro. CONCLUSIONS: Our study supports that metformin decreases DNA methylation of metformin transporter genes in the human liver. Moreover, higher methylation levels in these genes associate with hyperglycaemia and obesity.
Assuntos
Metilação de DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/administração & dosagem , Fígado/enzimologia , Metformina/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Adulto , Células Cultivadas , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Insulina/farmacologia , Fígado/efeitos dos fármacos , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/enzimologia , Obesidade/complicações , Fator 1 de Transcrição de Octâmero/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Regiões Promotoras GenéticasRESUMO
DNA methylation is altered by environmental factors. We hypothesized that DNA methylation is altered in skeletal muscle in response to either insulin or glucose exposure. We performed a genome-wide DNA methylation analysis in muscle from healthy men before and after insulin exposure. DNA methylation of selected genes was determined in muscle from healthy men and men with type 2 diabetes before and after a glucose tolerance test. Insulin altered DNA methylation in the 3' untranslated region of the calcium pump ATP2A3 gene. Insulin increased DNA methylation in the gene body of DAPK3, a gene involved in cell proliferation, apoptosis, and autophagy. DAPK3 methylation was reduced in patients with type 2 diabetes. Carbohydrate ingestion reduced DAPK3 DNA methylation in healthy men and men with type 2 diabetes, suggesting glucose may play a role. Supporting this, DAPK3 DNA methylation was inversely correlated with the 2-h glucose concentration. Whereas glucose incorporation to glycogen was unaltered by small interfering RNA against DAPK3, palmitate oxidation was increased. In conclusion, insulin and glucose exposure acutely alter the DNA methylation profile of skeletal muscle, indicating that DNA methylation constitutes a rapidly adaptive epigenetic mark. Furthermore, insulin and glucose modulate DAPK3 DNA methylation in a reciprocal manner, suggesting a feedback loop in the control of the epigenome.
Assuntos
Metilação de DNA , Proteínas Quinases Associadas com Morte Celular/genética , Diabetes Mellitus Tipo 2/genética , Glucose/farmacologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Músculo Esquelético/metabolismo , RNA Mensageiro/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Biópsia , Glicemia/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Teste de Tolerância a Glucose , Glicogênio/metabolismo , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND & AIMS: A healthy lifestyle has been associated with longer telomeres, but whether Mediterranean Diet (MeDiet) affect telomere length (TL) has not been fully elucidated yet. Our aim was to assess the relationship between MeDiet and TL in high cardiovascular risk subjects in the context of a randomized nutritional intervention trial. METHODS: We assessed 520 participants (55-80 years, 55% women) from the PREDIMED-NAVARRA trial. Leukocyte TL was measured by qPCR at baseline and after 5 years of a dietary intervention program where subjects were randomly assigned to a low-fat control diet or to two MeDiets, one supplemented with extra virgin olive oil (MeDiet-EVOO) and the other with mixed nuts (MeDiet-nuts). A validated 14-item questionnaire was used to appraise baseline adherence of participants to the MeDiet. RESULTS: Better adherence to MeDiet (as appraised by the 14-item score) was associated with longer basal telomeres in women in the baseline cross-sectional analysis, whereas the opposite was observed in men (P interaction = 0.036). Female subjects who scored 10 points had longer basal telomeres (0.27, 95% CI: 0.03-0.52) than women scoring ≤6 points at the beginning of the study (-0.46, 95% CI: -0.85 to -0.7) (P = 0.003). However, allocation to the MeDiet-nuts group (-0.24, 95% CI: -0.38 to -0.01) was associated with a higher risk of telomere shortening after 5 years of intervention, whereas no differences were found for the MeDiet-EVOO group (0.14, 95% CI: 0.02-0.27), in comparison with the Control group (0.07, 95% CI: -0.08 to 0.23) (P = 0.003 and P = 0.537, respectively). CONCLUSION: A greater baseline adherence to a Mediterranean dietary pattern was associated with longer telomeres only in women. No beneficial effect of the intervention with the MeDiet for the prevention of telomere shortening in comparison with a low-fat diet was observed.
Assuntos
Doenças Cardiovasculares/epidemiologia , Dieta Mediterrânea , Telômero/metabolismo , Telômero/ultraestrutura , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos Transversais , Dieta com Restrição de Gorduras , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nozes , Azeite de Oliva , Fatores de Risco , Encurtamento do TelômeroRESUMO
BACKGROUND & AIMS: Oxidative stress and inflammation seem to be potential underlying mechanisms for telomere attrition. A lack of specific antioxidants is believed to increase free radical damage and a greater risk for telomere shortening. Our aim was to evaluate the relationship between diet and leukocyte telomere length in a cross-sectional study of children and adolescents. We hypothesized that dietary total antioxidant capacity would be positively associated with telomere length. METHODS: Telomere length was measured by quantitative real-time polymerase chain reaction in 287 participants (55% males, 6-18 years), who were randomly selected from the GENOI study. RESULTS: A positive correlation between dietary total antioxidant capacity and telomere length (r = 0.157, p = 0.007) was found after adjustment for age and energy intake. However, higher white bread consumption was associated with shorter telomeres (ß = -0.204, p = 0.002) in fully-adjusted models. Interestingly, those individuals who had simultaneously higher dietary total antioxidant capacity and lower white bread consumption significantly presented the longest telomeres. Moreover, the multivariable-adjusted odds ratio for very short telomeres was 0.30 for dietary total antioxidant capacity (p = 0.023) and 1.37 for white bread (p = 0.025). CONCLUSION: It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in Spanish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length.
Assuntos
Antioxidantes/administração & dosagem , Comportamento Alimentar , Leucócitos/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Adolescente , Pão , Criança , Estudos Transversais , Dieta , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Grão Comestível , Ingestão de Energia , Feminino , Genômica , Humanos , Leucócitos/química , Masculino , Avaliação Nutricional , Espanha , Inquéritos e Questionários , Telômero/efeitos dos fármacos , Telômero/metabolismo , Encurtamento do TelômeroRESUMO
BACKGROUND: The gene variant Pro/Ala (rs1801282) in the PPARγ2 has been associated with lower cardiovascular risk and greater benefit from lifestyle interventions. This polymorphism also seems to be associated with longer lifespan, but no information on telomere length (TL) is available. Our aim was to study the association between the Ala allele and changes in TL in high cardiovascular risk subjects and the potential interaction with a Mediterranean dietary pattern. METHODS AND RESULTS: A total of 521 subjects (55-80 years) participating in the Prevención con Dieta Mediterránea randomized trial were genotyped. Changes in TL, measured by quantitative real-time polymerase chain reaction (PCR), were assessed over 5 years of a nutritional intervention, which promoted adherence to the Mediterranean diet (MeDiet). Interestingly, Ala carriers showed lower telomere shortening after 5 years compared with the Pro/Pro genotype (P=0.031). This association was modulated by MeDiet because those Ala carriers who reported better conformity to the MeDiet exhibited increased TL (P<0.001). Moreover, a reduction in carbohydrate intake (≤9.5 g/d) resulted in increased TL among Ala carriers. Notably, an apparent gene-diet interaction was found through the observed changes in the MUFA+PUFA/carbohydrates ratio: as this ratio increased, TL lengthening was detected to a greater extent in the Ala carriers compared with the Pro/Pro subjects (P for interaction <0.001). CONCLUSIONS: The Pro12Ala polymorphism is associated with TL homeostasis after 5 years follow-up in subjects at high cardiovascular risk. In addition, a higher adherence to the MeDiet pattern strengthens the prevention of telomere shortening among Ala carriers. CLINICAL TRIAL REGISTRATION: www.controlled-trials.com; Unique Identifier: ISRCTN35739639.