Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes

Bacos, Karl; Gillberg, Linn; Volkov, Petr; Olsson, Anna; Hansen, Torben; Pedersen, Oluf; Gjesing, Anette P.; Eiberg, Hans; Tuomi, Tiinamaija; Almgren, Peter; Groop, Leif; Eliasson, Lena; Vaag, Allan; Dayeh, Tasnim; Ling, Charlotte

doi:10.1038/ncomms11089

Cited by 212 publications

(182 citation statements)

References 70 publications

Supporting

Mentioning

164

Contrasting

Unclassified

Order By: Relevance

“…It should be noted that, although both groups included obese women, the insulin-resistant group had a significantly higher BMI and greater waist circumference compared with the more insulin-sensitive group. There has been an increasing interest in linking epigenetic signatures in human tissues to those in blood cells, to potentially identify blood-based epigenetic biomarkers that predict disease [7]. In the present study, the authors examined whether the epigenetic pattern in peripheral blood mononuclear cells (PBMCs) mirrors DNA methylation in adipose tissue and could potentially be used as a marker for insulin resistance.…”

Section: Dnmt Dna (Cytosine-5)-methyltransferase Pbmc Peripheral Bloomentioning

confidence: 99%

Epigenetic markers to further understand insulin resistance

Ling

Rönn

2016

Diabetologia

Self Cite

View full text Add to dashboard Cite

Epigenetic variation in human adipose tissue has been linked to type 2 diabetes and its related risk factors including age and obesity. Insulin resistance, a key risk factor for type 2 diabetes, may also be associated with altered DNA methylation in visceral and subcutaneous adipose tissue. Furthermore, linking epigenetic variation in target tissues to similar changes in blood cells may identify new blood-based biomarkers. In this issue of Diabetologia, Arner et al studied the transcriptome and methylome in subcutaneous and visceral adipose tissue of 80 obese women who were either insulin-sensitive or -resistant (DOI 10.1007/s00125-016-4074-5). While they found differences in gene expression between the two groups, no alterations in DNA methylation were found after correction for multiple testing. Nevertheless, based on nominal p values, their methylation data overlapped with methylation differences identified in adipose tissue of individuals with type 2 diabetes compared with healthy individuals. Differential methylation of these overlapping CpG sites may predispose to diabetes by occurring already in the insulin-resistant state. Furthermore, some methylation changes may contribute to an inflammatory process in adipose tissue since the identified CpG sites were annotated to genes encoding proteins involved in inflammation. Finally, the methylation pattern in circulating leucocytes did not mirror the adipose tissue methylome of these 80 women. Together, identifying novel molecular mechanisms contributing to insulin resistance and type 2 diabetes may help advance the search for new therapeutic alternatives. Insulin resistance is a condition where the cellular response to insulin is impaired, resulting in elevated insulin levels in the fasting state, although glucose levels are normal or elevated. It affects multiple tissues and is believed to be an underlying cause of type 2 diabetes. It is also a contributing factor for cardiovascular diseases, explained by the association with, for example, obesity, hypertension and dyslipidaemia [1]. Thereby, to prevent and treat many of our global metabolic diseases, we need to further understand insulin resistance on a molecular level.As insulin resistance is caused by multiple factors and affects multiple tissues, there is a need to investigate the interactions between, for example, genetic and non-genetic factors and between different tissues. Epigenetic mechanisms, including DNA methylation, are strong candidates for mediating the environmental effect on the genome and are linked to gene activity and function [2]. In differentiated human cells, DNA methylation mainly takes place on a cytosine residue followed by guanine, a so called CpG site. Key enzymes regulating DNA methylation include DNA (cytosine-5)-methyltransferase (DNMT)3A and -3B, which are involved in de novo methylation, as well as DNMT1, which copies the methylation patterns during replication. In addition, the ten-eleven translocation (TET) enzymes were found to be involved in active demethylation b...

show abstract

Section: Dnmt Dna (Cytosine-5)-methyltransferase Pbmc Peripheral Bloomentioning

confidence: 99%

Epigenetic markers to further understand insulin resistance

Ling

Rönn

2016

Diabetologia

Self Cite

View full text Add to dashboard Cite

show abstract

“…The remaining 39 loci are allocated to 26 genes (Table 1). Many of these loci have been previously described as being either expressed or methylated in an age‐related or disease‐related manner in other tissues12, 13 or as being affected in lung cancer 14. The 39 loci were significantly enriched for DNase I hypersensitive sites (DHS, OR = 5.541, RR = 5.540, p < 0.0001; chi‐square test) and known differentially methylated regions (DMR, OR = 8.873, RR = 8.869, P < 0.0001) according to array annotation, suggesting a possible role in gene regulation.…”

Section: Resultsmentioning

confidence: 99%

Fountain of youth for squamous cell carcinomas? On the epigenetic age of non‐small cell lung cancer and corresponding tumor‐free lung tissues

Marwitz

Heinbockel

Scheufele

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Aging affects the core processes of almost every organism, and the functional decline at the cellular and tissue levels influences disease development. Recently, it was shown that the methylation of certain CpG dinucleotides correlates with chronological age and that this epigenetic clock can be applied to study aging‐related effects. We investigated these molecular age loci in non‐small cell lung cancer (NSCLC) tissues from patients with adenocarcinomas (AC) and squamous cell carcinomas (SQC) as well as in matched tumor‐free lung tissue. In both NSCLC subtypes, the calculated epigenetic age did not correlate with the chronological age. In particular, SQC exhibited rejuvenation compared to the corresponding normal lung tissue as well as with the chronological age of the donor. Moreover, the younger epigenetic pattern was associated with a trend toward stem cell‐like gene expression patterns. These findings show deep phenotypic differences between the tumor entities AC and SQC, which might be useful for novel therapeutic and diagnostic approaches.

show abstract

“…Apart from biochemical factors, epigenetic variations in islets [22] or alteration of DNA methylation are required to be considered for risk prediction in type 2 diabetes mellitus. Recent genome-wide study in islets revealed that a number of type 2 diabetes mellitus (T2DM) associated genes increased the levels of DNA methylation during aging and some of these genes play a role in the insulin secretion and development of T2DM [23]. For instance, it has been found that ZNF518B gene locus is gaining of DNA methylation as individuals are getting older and the higher level of DNA methylation negative correlates with the expression of this gene.…”

Section: Discussionmentioning

confidence: 99%