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Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy.

ABSTRACT: AIM:To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus (Pre-DM) subjects who transitioned to type 2 diabetes mellitus (T2DM). METHODS:We performed DNA methylation study in bisulphite converted DNA from Pre-DM (n = 11) at baseline and at their transition to T2DM using Illumina Infinium HumanMethylation27 BeadChip, that enables the query of 27578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14495 genes. RESULTS:There were 694 CpG sites hypomethylated and 174 CpG sites hypermethylated in progression from Pre-DM to T2DM, representing putative genes involved in glucose and fructose metabolism, inflammation, oxidative and mitochondrial stress, and fatty acid metabolism. These results suggest that this high throughput platform is able to identify hundreds of prospective CpG sites associated with diverse genes that may reflect differences in Pre-DM compared with T2DM. In addition, there were CpG hypomethylation changes associated with a number of genes that may be associated with development of complications of diabetes, such as nephropathy. These hypomethylation changes were observed in all of the subjects. CONCLUSION:These data suggest that some epigenomic changes that may be involved in the progression of diabetes and/or the development of complications may be apparent at the Pre-DM state or during the transition to diabetes. Hypomethylation of a number of genes related to kidney function may be an early marker for developing diabetic nephropathy.

SUBMITTER: VanderJagt TA

PROVIDER: S-EPMC4530325 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy.

VanderJagt Thomas A TA Neugebauer Monica H MH Morgan Marilee M Bowden Donald W DW Shah Vallabh O VO

World journal of diabetes 20150801 9

<h4>Aim</h4>To examine DNA methylation profiles in a longitudinal comparison of pre-diabetes mellitus (Pre-DM) subjects who transitioned to type 2 diabetes mellitus (T2DM).<h4>Methods</h4>We performed DNA methylation study in bisulphite converted DNA from Pre-DM (n = 11) at baseline and at their transition to T2DM using Illumina Infinium HumanMethylation27 BeadChip, that enables the query of 27578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions o ...[more]

PMID: 26265998

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Project description:Background:The transition of young adults with type 1 diabetes (T1D) from pediatric to adult care is challenging and frequently accompanied by worsening of diabetes-related health. To date, there are no reports which prospectively assess the effects of theory-based psycho-behavioral interventions during the transition period neither on glycemic control nor on psychosocial factors that contribute to poor glycemic control. Therefore, the overall aim of this study was to develop and pilot test an integrative group intervention based on the underlying principles of self-determination theory (SDT), in young adults with T1D. Methods:Fifty-one young adults with T1D participated in an education and case management-based transition program, of which 9 took part in the Diabetes Empowerment Council (DEC), a 12-week holistic, multimodality facilitated group intervention consisting of "council" process based on indigenous community practices, stress-reduction guided imagery, narrative medicine modalities, simple ritual, and other integrative modalities. Feasibility, acceptability, potential mechanism of effects, and bio-behavioral outcomes were determined using mixed qualitative and quantitative methods. Results:The intervention was highly acceptable to participants, though presented significant feasibility challenges. Participants in DEC showed significant reductions in perceived stress and depression, and increases in general well-being relative to other control participants. Reduction in perceived stress, independent of intervention group, was associated with reductions in hemoglobin A1C. A theoretical model explaining the effects of the intervention included the promotion of relatedness and autonomy support, 2 important aspects of SDT. Conclusions:The DEC is a promising group intervention for young adults with T1D going through transition to adult care. Future investigations will be necessary to resolve feasibility issues, optimize the multimodality intervention, determine full intervention effects, and fully test the role of the underlying theoretical model of action.ClinicalTrials.gov Registration Number NCT02807155; Registration date: June 15, 2016 (retrospectively registered).

Project description:BackgroundPatients with Type 1 Diabetes (T1D) are particularly vulnerable to development of Diabetic nephropathy (DN) leading to End Stage Renal Disease. Hence a better understanding of the factors affecting kidney disease progression in T1D is urgently needed. In recent years microRNAs have emerged as important post-transcriptional regulators of gene expression in many different health conditions. We hypothesized that urinary microRNA profile of patients will differ in the different stages of diabetic renal disease.Methods and findingsWe studied urine microRNA profiles with qPCR in 40 T1D with >20 year follow up 10 who never developed renal disease (N) matched against 10 patients who went on to develop overt nephropathy (DN), 10 patients with intermittent microalbuminuria (IMA) matched against 10 patients with persistent (PMA) microalbuminuria. A Bayesian procedure was used to normalize and convert raw signals to expression ratios. We applied formal statistical techniques to translate fold changes to profiles of microRNA targets which were then used to make inferences about biological pathways in the Gene Ontology and REACTOME structured vocabularies. A total of 27 microRNAs were found to be present at significantly different levels in different stages of untreated nephropathy. These microRNAs mapped to overlapping pathways pertaining to growth factor signaling and renal fibrosis known to be targeted in diabetic kidney disease.ConclusionsUrinary microRNA profiles differ across the different stages of diabetic nephropathy. Previous work using experimental, clinical chemistry or biopsy samples has demonstrated differential expression of many of these microRNAs in a variety of chronic renal conditions and diabetes. Combining expression ratios of microRNAs with formal inferences about their predicted mRNA targets and associated biological pathways may yield useful markers for early diagnosis and risk stratification of DN in T1D by inferring the alteration of renal molecular processes.

Project description:Type I diabetes (T1D) is an autoimmune disease characterized by destruction of insulin-producing β-cells in the pancreas. Although several islet cell autoantigens are known, the breadth and spectrum of autoantibody targets has not been fully explored. Here the luciferase immunoprecipitation systems (LIPS) antibody profiling technology was used to study islet and other organ-specific autoantibody responses in parallel. Examination of an initial cohort of 93 controls and 50 T1D subjects revealed that 16% of the diabetic subjects showed anti-gastric ATPase autoantibodies which did not correlate with autoantibodies against GAD65, IA2, or IA2-β. A more detailed study of a second cohort with 18 potential autoantibody targets revealed marked heterogeneity in autoantibody responses against islet cell autoantigens including two polymorphic variants of ZnT8. A subset of T1D subjects exhibited autoantibodies against several organ-specific targets including gastric ATPase (11%), thyroid peroxidase (14%), and anti-IgA autoantibodies against tissue transglutaminase (12%). Although a few T1D subjects showed autoantibodies against a lung-associated protein KCNRG (6%) and S100-β (8%), no statistically significant autoantibodies were detected against several cytokines. Analysis of the overall autoantibody profiles using a heatmap revealed two major subgroups of approximately similar numbers, consisting of T1D subjects with and without organ-specific autoantibodies. Within the organ-specific subgroup, there was minimal overlap among anti-gastric ATPase, anti-thyroid peroxidase, and anti-transglutaminase seropositivity, and these autoantibodies did not correlate with islet cell autoantibodies. Examination of a third cohort, comprising prospectively collected longitudinal samples from high-risk individuals, revealed that anti-gastric ATPase autoantibodies were present in several individuals prior to detection of islet autoantibodies and before clinical onset of T1D. Taken together, these results suggest that autoantibody portraits derived from islet and organ-specific targets will likely be useful for enhancing the clinical management of T1D.

Dataset Information

Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy.

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Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy.

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