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Lifestyle and NR3C1 exon 1F gene methylation is associated with changes in glucose levels and insulin resistance

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Abstract

Aims the present study aimed to investigate how glucose and insulin levels may be associated with changes in NR3C1 gene methylation levels in adults. Main methods 375 volunteers users of the Brazilian Public Unified Health System (SUS) were recruited to assess socioeconomic status, lifestyle, anthropometric data, blood glucose and serum cortisol levels, insulin resistance, and NR3C1 gene methylation assessment. Factors associated with glucose levels and insulin resistance were investigated using multivariate analysis GLzM at 5 % significance (p < 0.05). Key findings our results verified that glucose levels and insulin resistance were directly related to NR3C1 gene methylation and age, while not being overweight and obese and no tobacco consumption were indirectly related to glucose levels and insulin resistance. Significance habits and lifestyle may influence NR3C1 gene regulation, revealing the complexity of environmental impacts on NR3C1 methylation. Furthermore, associated risk factors must be taken into account in epigenetic studies as they directly interfere with blood glucose levels and insulin resistance.

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... The models were adjusted for various socioeconomic factors (gender, age, education, location, income), psychosocial factors (stress, anxiety, BFIS, BDI-II 18), nutritional status (TyG Index, HDL-c, LDL-c, BMI, cortisol), and lifestyle factors (physical activity, smoking, drinking). These confounding variables were selected based on examples from the literature and previous research conducted by the research group (29,30,38,58,59). A generalized linear model (GzLM) was utilized to analyze the data. ...
... 38,58, 64,73). The utilization of peripheral ...
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Background Dietary composition can modify gene expression, favoring the development of chronic diseases via epigenetic mechanisms. Objective Our study aimed to investigate the relationship between dietary patterns and NR3C1 gene methylation in users of the Brazilian Public Unified Health System (SUS). Methods We recruited 250 adult volunteers and evaluated their socioeconomic status, psychosocial characteristics, lifestyle, and anthropometrics. Peripheral blood was collected and evaluated for cortisol levels, glycemia, lipid profile, and insulin resistance; methylation of CpGs 40–47 of the 1F region of the NR3C1 gene was also measured. Factors associated with degree of methylation were evaluated using generalized linear models (p < 0.05). Lifestyle variables and health variables were included as confounding factors. Results The findings of our cross-sectional study indicated an association between NR3C1 DNA methylation and intake of processed foods. We also observed relevant associations of average NR3C1 DNA across the segment analyzed, methylation in component 1 (40–43), and methylation in component 2 (44–47) with a pattern of consumption of industrialized products in relation to BMI, serum cortisol levels, and lipid profile. These results may indicate a relationship between methylation and metabolic changes related to the stress response. Conclusion These findings suggest an association of methylation and metabolic alterations with stress response. In addition, the present study highlights the significant role of diet quality as a stress-inducing factor that influences NR3C1 methylation. This relationship is further linked to changes in psychosocial factors, lifestyle choices, and cardiometabolic variables, including glucose levels, insulin resistance, and hyperlipidemia.
... However, there were no methylation differences between the buffy coats of individuals with and without MetS in the CpGs evaluated for the 1F region, even though the expression of these genes is similar in blood and hypothalamus. Although no association studies of MetS with NR3C1 differential methylation were found in the literature, variations in its methylation patterns have been observed for related comorbidities, such as cardiovascular diseases [22], subclinical arteriosclerosis (hypermethylation of the 1F promoter, in a study with monozygotic twins) [66], overweight (hypomethylation of the 1F region, CpGs 40 to 47) [51], unfavorable prognosis for coronary acute syndrome in individuals with depression (hypermethylation of exon 1F) [67], blood pressure (hypermethylation of 1F and 1H promoters associated with lower blood pressure) [68], and a positive association between methylation and glucose levels as well as insulin resistance [69]. Considering the multiple alternative first exons and their variability in tissue-specific expression, and that each of these exons has its own active promoter, DNA methylation and other epigenetic mechanisms should be evaluated in other regions. ...
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Type 2 diabetes (T2DM) is a common complex metabolic disorder that has a strong genetic predisposition. During the past decade, progress in genetic association studies has enabled the identification of at least 75 independent genetic loci for T2DM, thus allowing a better understanding of the genetic architecture of T2DM. International collaborations and large-scale meta-analyses of genome-wide association studies have made these achievements possible. However, whether the identified common variants are causal is largely unknown. In addition, the detailed mechanism of how these genetic variants exert their effect on the pathogenesis of T2DM requires further investigation. Currently, there are ongoing large-scale sequencing studies to identify rare, functional variants for T2DM. Environmental factors also have a crucial role in the development of T2DM. These could modulate gene expression via epigenetic mechanisms, including DNA methylation, histone modification and microRNA regulation. There is evidence that epigenetic changes are important in the development of T2DM. Recent studies have identified several DNA methylation markers of T2DM from peripheral blood and pancreatic islets. In this review, we will briefly summarize the recent progress in the genetic and epigenetic research on T2DM and discuss how environmental factors, genetics and epigenetics can interact in the pathogenesis of T2DM.
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Diabetes mellitus is a group of physiological dysfunctions characterized by hyperglycemia resulting directly from insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. Type 1 diabetes (T1D) is an autoimmune disorder leading to the destruction of pancreatic beta-cells. Type 2 diabetes (T2D), which is much more common, is primarily a problem of progressively impaired glucose regulation due to a combination of dysfunctional pancreatic beta cells and insulin resistance. The purpose of this article is to review the basic science of type 2 diabetes and its complications, and to discuss the most recent treatment guidelines.
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This paper provides a summary of literature on epigenetic effects and infant health outcomes of maternal psychosocial stress during pregnancy. A search of literature yielded a large body of publications between 2008 and 2018. Relevant articles were selected, and additional sources were located from ancestry searches of reference lists. Results implicate maternal prenatal stress as a source of epigenetic mechanisms that affect fetal brain development and program risk for emotional dysregulation and mental disorders over a lifetime and across generations. Implications for nursing practice are explored at multiple levels of policy advocacy, public education, primary prevention, screening and intervention.
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Nearly a quarter of older adults in the U. S. have type 2 diabetes, and this population is continuing to increase with the aging of the population. Older adults are at high risk for the development of type 2 diabetes due to the combined effects of genetic, lifestyle, and aging influences. The usual defects contributing to type 2 diabetes are further complicated by the natural physiological changes associated with aging as well as the comorbidities and functional impairments that are often present in older people. This paper reviews the pathophysiology of type 2 diabetes among older adults and the implications for hyperglycemia management in this population.
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Glucocorticoid receptor (GR) activity plays a significant role in the etiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia and subsequent increased fat deposition. Several polymorphisms in the GR gene have been described, and at least three of them seem to be associated with altered glucocorticoid sensitivity and changes in glucose homeostasis, and other metabolic parameters. The N363S polymorphism has been associated with increased sensitivity to glucocorticoides, increased insulin response to dexamethasone and increased plasma glucose level. BclI polymorphism is associated with increased abdominal obesity, hyperinsulinaemia and increased insulin resistance. Another polymorphism, ER22/23EK, in contrast to the others, is associated with relative resistance to glucocoricides actions and more beneficial metabolic profile-lower insulin resistance level, decreased lower cardiovascular risk and subseuent prolongation of life time. More research is still needed to understand the mechanisms behind these associations at the molecular level.
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Aim: Although recognising insulin resistance in children is particularly important, the gold standard test used to diagnose it, the euglyceamic glucose clamp, is costly, invasive and is not routinely available in our clinical settings in Mexico. This study evaluated whether the triglyceride-glucose (TyG) index would provide a useful alternative. Methods: A total of 2,779 school children aged 7-17 years, from Durango, Mexico, were enrolled during 2015-2016. The gold standard euglyceamic-hyperinsulinemic clamp test was performed in a randomly selected subsample of 125 children and diagnostic concordance between the TyG index and the homeostasis model assessment of IR was evaluated in all of the 2,779 enrolled children. Results: The best cut-off values for recognising IR using the TyG index were 4.65 for prepubertal girls and boys, 4.75 for pubertal girls and 4.70 for pubertal boys. Concordance between the TyG index and the homeostasis model assessment of IR was 0.910 and 0.902 for the prepubertal girls and boys, 0.932 for the pubertal girls and 0.925 for the pubertal boys. Conclusion: The TyG index was useful for recognising IR in both prepubertal and pubertal children and could provide a feasible alternative to the costly and invasive gold standard test for IR in resource-limited settings. This article is protected by copyright. All rights reserved.
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The glucocorticoid receptor (GR) is a constitutively expressed transcriptional regulatory factor (TRF) that controls many distinct gene networks, each uniquely determined by particular cellular and physiological contexts. The precision of GR-mediated responses seems to depend on combinatorial, context-specific assembly of GR-nucleated transcription regulatory complexes at genomic response elements. In turn, evidence suggests that context-driven plasticity is conferred by the integration of multiple signals, each serving as an allosteric effector of GR conformation, a key determinant of regulatory complex composition and activity. This structural and mechanistic perspective on GR regulatory specificity is likely to extend to other eukaryotic TRFs.
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DNA methylation is altered by environmental factors. We hypothesized 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 and type 2 diabetic men before and after a glucose tolerance test. Insulin altered DNA methylation in the 3'UTR 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 type 2 diabetic patients. Carbohydrate ingestion reduced DAPK3 DNA methylation in healthy and type 2 diabetic men, suggesting glucose may play a role. Supporting this, DAPK3 DNA methylation was inversely correlated with the 2 hr glucose concentration. While glucose incorporation to glycogen was unaltered by siRNA against DAPK3, palmitate oxidation was increased. In conclusion, insulin and glucose exposure acutely alter the DNA methylation profile of skeletal muscle, indicating DNA methylation constitutes a rapidly and 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.
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Background and aims: Although the Glucose and Triglyceride levels (TyG) index is useful for identification of insulin resistance (IR) in different ethnic groups, it has not been evaluated in young adults. We undertook this study to evaluate the TyG index as a diagnostic test for IR in young adults. Methods: A total of 5,538 healthy young adults, 3,795 (68.5%) non-pregnant women and 1,743 (31.5%) men, with an average age of 19.2 ± 1.4 years, were enrolled in a population-based cross-sectional study. To estimate diagnostic characteristics of the TyG index, a randomized subsample of the target population (n = 75) was under euglycemic-hyperinsulinemic clamp test. Using the cutoff values obtained in the clamp study, the diagnostic concordance between TyG index and HOMA-IR was evaluated in the overall population. The TyG index was calculated as the Ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)]/2. Results: Normal weight, overweight, and obesity were identified in 3,632 (65.6%), 1,355 (24.5%), and 551 (9.9%) participants. A total of 346 (9.1%) men and 278 (15.9%) women exhibited IR. The best cutoff value of TyG index for diagnosis of IR was 4.55 (sensitivity 0.687, negative predictive value (NPV) 0.844, and negative likelihood ratio (NLR) 0.47) for women and 4.68 (sensitivity 0.673, NPV 0.900, and NLR 0.45) for men. In normal-weight individuals the diagnostic concordance between TyG index and HOMA-IR was 0.934 and 0.915, in the overweight subjects was 0.908 and 0.895 and, in the obese participants 0.916 and 0.950, for men and women, respectively. Conclusions: TyG index may be useful for screening IR in young adults.
Article
Introduction: Altered DNA methylation (DNAm) levels of hypothalamic-pituitary-adrenal (HPA) axis genes has been associated with exposure to childhood maltreatment (CM) and depression; however, it is unknown whether CM and depression have joint and potentially interacting effects on the glucocorticoid receptor (NR3C1) DNAm. We investigated the impact of CM and lifetime major depressive disorder (MDD) on NR3C1 DNAm and gene expression (GE) in 147 adult participants from the Detroit Neighborhood Health Study. Methods: NR3C1 promoter region DNAm was assessed via pyrosequencing using whole blood-derived DNA. Quantitative RT-PCR assays measured GE from leukocyte-derived RNA. Linear regression models were used to examine the relationship among CM, MDD, and DNAm. Results: Both CM and MDD were significant predictors of NR3C1 DNAm: CM was associated with an increase in DNAm in an EGR1 transcription factor binding site (TFBS), whereas MDD was associated with a decrease in DNAm downstream of the TFBS. No significant CM-MDD interactions were observed. CM alone was associated with significantly lower NR3C1 GE. Limitations: Our report of CM is a retrospective self-report of abuse, which may introduce recall bias. DNAm was measured in whole blood and may not reflect brain-derived DNAm levels. Conclusions: CM and MDD are both associated with altered DNAm levels in the NR3C1 promoter region, however the location and direction of effects differ between the two exposures, and the functional effects, as measured by GE, appear to be limited to CM exposure alone. CM exposure may be biologically embedded in this key HPA axis gene.
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The ability of people to resist the consequences of psychological stress and cope effectively with the challenges of life might be associated with reduced risk of future type 2 diabetes mellitus, according to a very large study of young men followed-up into middle age.
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Context: The hypothalamic pituitary-adrenal axis is thought to play a role in type 2 diabetes (T2D). However, evidence for an association between cortisol and future glucose disturbance is sparse. Objective: The aim was to examine the association of diurnal cortisol secretion with future T2D and impaired glucose metabolism in a community-dwelling population. Design: This is a prospective cohort study of salivary cortisol measured at the 2002-2004 clinical examination of the Whitehall II study, United Kingdom. We measured cortisol (nmol/l) from six saliva samples obtained over the course of a day: at waking, +30 min, +2.5 h, +8 h, +12 h, and bedtime. Participants who were normoglycaemic in 2002-2004 (phase 7) were re-examined in 2012-2013 (phase 11). Setting: The occupational cohort was originally recruited in 1985-1988. Participants: 3270 men and women aged 60.85 years on average in 2002/2004. Outcome measures: Incident T2D and impaired fasting glucose (IFG) in 2012-2013. Results: Raised evening cortisol at phase 7 was predictive of new onset T2D at phase 11 (odds ratio 1.18; 95% confidence interval (CI) 1.01-1.37) with a trend for a flatter slope in participants with incident T2D (odds ratio 1.15; 95% CI 0.99-1.33). When expanding this analysis to a broader category of glucose disturbance we found that a flattened diurnal cortisol slope at phase 7 was predictive of future IFG or T2D at phase 11 (odds ratio 1.12; 95% CI 1.02-1.22) as was high bedtime cortisol (odds ratio 1.10; 95% CI 1.01-1.20). Conclusions: In this non-clinical population, alterations in diurnal cortisol patterns were predictive of future glucose disturbance.
Article
Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN
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The aetiology of type 2 diabetes mellitus (T2DM) involves interactions between genetic, developmental and lifestyle environmental risk factors, which are partly influenced by epigenetic processes. Multhaup and colleagues have combined genome-wide analysis with analyses of an animal model of insulin resistance and tissues from individuals with obesity obtained before and after gastric bypass surgery to identify novel potential pathways that contribute to T2DM pathogenesis.