Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes?
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 musc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3591301?pdf=render |
| _version_ | 1818657906953814016 |
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| author | Linn Gillberg Stine C Jacobsen Rasmus Ribel-Madsen Anette Prior Gjesing Trine W Boesgaard Charlotte Ling Oluf Pedersen Torben Hansen Allan Vaag |
| author_facet | Linn Gillberg Stine C Jacobsen Rasmus Ribel-Madsen Anette Prior Gjesing Trine W Boesgaard Charlotte Ling Oluf Pedersen Torben Hansen Allan Vaag |
| author_sort | Linn Gillberg |
| collection | DOAJ |
| description | 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 (β = 0.12, P = 0.03), supported by a borderline significant inverse correlation with fasting insulin levels (β = -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. |
| first_indexed | 2024-12-17T03:48:56Z |
| format | Article |
| id | doaj.art-b3a9316ca8cd4f88a49cf6da2e21a066 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T03:48:56Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b3a9316ca8cd4f88a49cf6da2e21a0662022-12-21T22:04:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0183e5838410.1371/journal.pone.0058384Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes?Linn GillbergStine C JacobsenRasmus Ribel-MadsenAnette Prior GjesingTrine W BoesgaardCharlotte LingOluf PedersenTorben HansenAllan VaagEpigenetics 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 (β = 0.12, P = 0.03), supported by a borderline significant inverse correlation with fasting insulin levels (β = -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.http://europepmc.org/articles/PMC3591301?pdf=render |
| spellingShingle | Linn Gillberg Stine C Jacobsen Rasmus Ribel-Madsen Anette Prior Gjesing Trine W Boesgaard Charlotte Ling Oluf Pedersen Torben Hansen Allan Vaag Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes? PLoS ONE |
| title | Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes? |
| title_full | Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes? |
| title_fullStr | Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes? |
| title_full_unstemmed | Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes? |
| title_short | Does DNA methylation of PPARGC1A influence insulin action in first degree relatives of patients with type 2 diabetes? |
| title_sort | does dna methylation of ppargc1a influence insulin action in first degree relatives of patients with type 2 diabetes |
| url | http://europepmc.org/articles/PMC3591301?pdf=render |
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