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- Gillberg, Linn, et al.
(författare)
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Does DNA Methylation of PPARGC1A Influence Insulin Action in First Degree Relatives of Patients with Type 2 Diabetes?
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetics may play a role in the pathophysiology of type 2 diabetes (T2D), and increased DNA methylation of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) has been reported in muscle and pancreatic islets from T2D patients and in muscle from individuals at risk of T2D. This study aimed to investigate DNA promoter methylation and gene expression of PPARGC1A in skeletal muscle from first degree relatives (FDR) of T2D patients, and to determine the association with insulin action as well as the influence of family relation. We included 124 Danish FDR of T2D patients from 46 different families. Skeletal muscle biopsies were excised from vastus lateralis and insulin action was assessed by oral glucose tolerance tests. DNA methylation and mRNA expression levels were measured using bisulfite sequencing and quantitative real-time PCR, respectively. The average PPARGC1A methylation at four CpG sites situated 867-624 bp from the transcription start was associated with whole-body insulin sensitivity in a paradoxical positive manner (beta = 0.12, P = 0.03), supported by a borderline significant inverse correlation with fasting insulin levels (beta = -0.88, P = 0.06). Excluding individuals with prediabetes and overt diabetes did not affect the overall result. DNA promoter methylation was not associated with PPARGC1A gene expression. The familiality estimate of PPARGC1A gene expression was high (h(2) = 79 +/- 27% (h(2) +/- SE), P = 0.002), suggesting genetic regulation to play a role. No significant effect of familiality on DNA methylation was found. Taken together, increased DNA methylation of the PPARGC1A promoter is unlikely to play a major causal role for the development of insulin resistance in FDR of patients with T2D.
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| 2. |
- Jacobsen, Stine C., et al.
(författare)
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Young men with low birthweight exhibit decreased plasticity of genome-wide muscle DNA methylation by high-fat overfeeding
- 2014
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 57:6, s. 1154-1158
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The association between low birthweight (LBW) and risk of developing type 2 diabetes may involve epigenetic mechanisms, with skeletal muscle being a prime target tissue. Differential DNA methylation patterns have been observed in single genes in muscle tissue from type 2 diabetic and LBW individuals, and we recently showed multiple DNA methylation changes during short-term high-fat overfeeding in muscle of healthy people. In a randomised crossover study, we analysed genome-wide DNA promoter methylation in skeletal muscle of 17 young LBW men and 23 matched normal birthweight (NBW) men after a control and a 5 day high-fat overfeeding diet. Methods DNA methylation was measured using Illumina's Infinium BeadArray covering 27,578 CpG sites representing 14,475 different genes. Results After correction for multiple comparisons, DNA methylation levels were found to be similar in the LBW and NBW groups during the control diet. Whereas widespread DNA methylation changes were observed in the NBW group in response to high-fat overfeeding, only a few methylation changes were seen in the LBW group (chi(2), p < 0.001). Conclusions/interpretation Our results indicate lower DNA methylation plasticity in skeletal muscle from LBW vs NBW men, potentially contributing to understanding the link between LBW and increased risk of type 2 diabetes.
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| 3. |
- Vaag, Allan, et al.
(författare)
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Genetic, non-genetic and epigenetic risk determinants in developmental programming of type 2 diabetes.
- 2014
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Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 93:11, s. 1099-1108
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Forskningsöversikt (refereegranskat)abstract
- Low birthweight (LBW) individuals and offspring of women with gestational diabetes mellitus (GDM) exhibit increased risk of developing type 2 diabetes (T2D) and associated cardiometabolic traits in adulthood, which for both groups may be mediated by adverse events and developmental changes in fetal life. T2D is a multifactorial disease occurring as a result of complicated interplay between genetic and both pre- as well as postnatal non-genetic factors, and it remains unknown to which extent the increased risk of T2D associated with LBW or GDM in the mother may be due to, or confounded by, genetic factors. Indeed, it has been shown that genetic changes influencing risk of diabetes may also be associated with reduced fetal growth as a result of reduced insulin secretion and/or action. Similarly, increased risk of T2D among offspring could be explained by T2D susceptibility genes shared between the mother and her offspring. Epigenetic mechanisms may explain the link between factors operating in fetal life and later risk of developing T2D, but so far convincing evidence is lacking for epigenetic changes as a prime and direct cause of T2D. This review addresses recent literature on the early origins of adult disease hypothesis, with a special emphasis on the role of genetic compared to non-genetic and epigenetic risk determinants and disease mechanisms. This article is protected by copyright. All rights reserved.
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