Aim: Bariatric surgery is highly effective for the treatment of obesity in individuals without (OB) and in those with type 2 diabetes (T2D). However, whether bariatric surgery triggers similar or distinct molecular changes in OB and T2D remains unknown. Given that individuals with type 2 diabetes often exhibit more severe metabolic deterioration, we hypothesized that bariatric surgery induces distinct molecular adaptations in skeletal muscle, the major site of glucose uptake, of OB and T2D after surgery-induced weight loss.
View Article and Find Full Text PDFObesity (Silver Spring)
February 2024
Objective: The aim of this study was to discover novel markers underlying the improvement of skeletal muscle metabolism after bariatric surgery.
Methods: Skeletal muscle transcriptome data of lean people and people with obesity, before and 1 year after bariatric surgery, were subjected to weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression. Results of LASSO were confirmed in a replication cohort.
Context: Exercise training is known to improve glucose tolerance and reverse insulin resistance in people with obesity. However, some individuals fail to improve or even decline in their clinical traits following exercise intervention.
Objective: This study focused on gene expression and DNA methylation signatures in skeletal muscle of low (LRE) and high responders (RES) to 8 weeks of supervised endurance training.
MicroRNAs (miRNAs) recently emerged as means of communication between insulin-sensitive tissues to mediate diabetes development and progression, and as such they present a valuable proxy for epigenetic alterations associated with type 2 diabetes. In order to identify miRNA markers for the precursor of diabetes called prediabetes, we applied a translational approach encompassing analysis of human plasma samples, mouse tissues and an in vitro validation system. MiR-652-3p, miR-877-5p, miR-93-5p, miR-130a-3p, miR-152-3p and let-7i-5p were increased in plasma of women with impaired fasting glucose levels (IFG) compared to those with normal fasting glucose and normal glucose tolerance (NGT).
View Article and Find Full Text PDFObjectives: Better disease management can be achieved with earlier detection through robust, sensitive, and easily accessible biomarkers. The aim of the current study was to identify novel epigenetic biomarkers determining the risk of type 2 diabetes (T2D).
Methods: Livers of 10-week-old female New Zealand Obese (NZO) mice, slightly differing in their degree of hyperglycemia and liver fat content and thereby in their diabetes susceptibility were used for expression and methylation profiling.
Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators.
View Article and Find Full Text PDFJ Cachexia Sarcopenia Muscle
August 2021
Background: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans.
Methods: We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18-89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis.
Aim: MicroRNAs play an important role in the maintenance of cellular functions by fine-tuning gene expression levels. The aim of the current study was to identify genetically caused changes in microRNA expression which associate with islet dysfunction in diabetic mice.
Methods: To identify novel microRNAs involved in islet dysfunction, transcriptome and miRNome analyses were performed in islets of obese, diabetes-susceptible NZO and diabetes-resistant B6-ob/ob mice and results combined with quantitative trait loci (QTL) and functional in vitro analysis.
Objective: Altered gene expression contributes to the development of type 2 diabetes (T2D); thus, the analysis of differentially expressed genes between diabetes-susceptible and diabetes-resistant mouse models is an important tool for the determination of candidate genes that participate in the pathology. Based on RNA-seq and array data comparing pancreatic gene expression of diabetes-prone New Zealand Obese (NZO) mice and diabetes-resistant B6.V-ob/ob (B6-ob/ob) mice, the gap junction protein beta 4 (Gjb4) was identified as a putative novel T2D candidate gene.
View Article and Find Full Text PDFType 2 diabetes and obesity are well-studied metabolic diseases, which are based on genetic and epigenetic alterations in combination with an obesogenic lifestyle. The aim of this study was to test whether SNPs in miRNA-mRNA binding sites that potentially disrupt binding, elevate the expression of miRNA targets, which participate in the development of metabolic diseases. A computational approach was developed that integrates transcriptomics, linkage analysis, miRNA-target prediction data, and sequence information of a mouse model of obesity and diabetes.
View Article and Find Full Text PDFObesity is a worldwide epidemic and contributes to global morbidity and mortality mediated via the development of nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), cardiovascular (CVD) and other diseases. It is a consequence of an elevated caloric intake, a sedentary lifestyle and a genetic as well as an epigenetic predisposition. This review summarizes changes in DNA methylation and microRNAs identified in blood cells and different tissues in obese human and rodent models.
View Article and Find Full Text PDFContext/objective: Impaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of T2D.
Design/patients: Male patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n = 14 each), underwent hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose and indirect calorimetry.
The mechanisms underlying improved insulin sensitivity after surgically-induced weight loss are still unclear. We monitored skeletal muscle metabolism in obese individuals before and over 52 weeks after metabolic surgery. Initial weight loss occurs in parallel with a decrease in muscle oxidative capacity and respiratory control ratio.
View Article and Find Full Text PDFRecent studies suggest that insulin-like growth factor binding protein 2 (IGFBP-2) may protect against type 2 diabetes, but population-based human studies are scarce. We aimed to investigate the prospective association of circulating IGFBP-2 concentrations and of differential methylation in the gene with type 2 diabetes risk.
View Article and Find Full Text PDFDipeptidyl peptidase 4 (DPP4) is known to be elevated in metabolic disturbances such as obesity, type 2 diabetes and fatty liver disease. Lowering DPP4 concentration by pharmacological inhibition improves glucose homeostasis and exhibits beneficial effects to reduce hepatic fat content. As factors regulating the endogenous expression of Dpp4 are unknown, the aim of this study was to examine whether the Dpp4 expression is epigenetically regulated in response to dietary components.
View Article and Find Full Text PDFObjective: Obesity and type 2 diabetes (T2D) arise from the interplay between genetic, epigenetic, and environmental factors. The aim of this study was to combine bioinformatics and functional studies to identify miRNAs that contribute to obesity and T2D.
Methods: A computational framework (miR-QTL-Scan) was applied by combining QTL, miRNA prediction, and transcriptomics in order to enhance the power for the discovery of miRNAs as regulative elements.
Background: Idiopathic short stature (ISS) has a strong familial component, but genetics explains only part of it. Indeed, environmental factors act on human growth either directly or through epigenetic factors that remain to be determined. Given the importance of the GH/IGF1 axis for child growth, we suspected that such epigenetic factors could involve the CG methylation at the IGF1 gene P2 promoter, which was recently shown to be a transcriptional regulator for IGF1 gene and a major contributor to GH sensitivity.
View Article and Find Full Text PDFContext: Like all hormones, GH has variable physiological effects across people. Many of these effects initiated by the binding of GH to its receptor (GHR) in target tissues are mediated by the expression of the IGF1 gene. Genetic as well as epigenetic variation is known to contribute to the individual diversity of GH-dependent phenotypes through two mechanisms.
View Article and Find Full Text PDFBackground: Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance.
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