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Does DNA Methylation of PPARGC1A Influence Insulin Action in First Degree Relatives of Patients with Type 2 Diabetes?

Gillberg, Linn ; Jacobsen, Stine ; Ribel-Madsen, Rasmus ; Gjesing, Anette Prior ; Boesgaard, Trine W. ; Ling, Charlotte LU orcid ; Pedersen, Oluf ; Hansen, Torben and Vaag, Allan (2013) In PLoS ONE 8(3).
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... (More)
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. (Less)
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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
8
issue
3
article number
e58384
publisher
Public Library of Science (PLoS)
external identifiers
  • wos:000318334500076
  • scopus:84874701361
  • pmid:23505498
ISSN
1932-6203
DOI
10.1371/journal.pone.0058384
language
English
LU publication?
yes
id
41835c1c-e419-407c-b923-31ba47fa0eab (old id 3851482)
date added to LUP
2016-04-01 14:24:20
date last changed
2022-09-20 05:27:21
@article{41835c1c-e419-407c-b923-31ba47fa0eab,
  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.}},
  author       = {{Gillberg, Linn and Jacobsen, Stine and Ribel-Madsen, Rasmus and Gjesing, Anette Prior and Boesgaard, Trine W. and Ling, Charlotte and Pedersen, Oluf and Hansen, Torben and Vaag, Allan}},
  issn         = {{1932-6203}},
  language     = {{eng}},
  number       = {{3}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{Does DNA Methylation of PPARGC1A Influence Insulin Action in First Degree Relatives of Patients with Type 2 Diabetes?}},
  url          = {{https://lup.lub.lu.se/search/files/3957500/4058017.pdf}},
  doi          = {{10.1371/journal.pone.0058384}},
  volume       = {{8}},
  year         = {{2013}},
}