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Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion.

Ling, Charlotte LU ; Del Guerra, S; Lupi, R; Rönn, Tina LU ; Granhall, Charlotte LU ; Luthman, Holger LU ; Masiello, P; Marchetti, P; Groop, Leif LU and Del Prato, S (2008) In Diabetologia 51. p.615-622
Abstract
AIMS/HYPOTHESIS: Insulin secretion in pancreatic islets is dependent upon mitochondrial function and production of ATP. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 alpha (protein PGC-1alpha; gene PPARGC1A) is a master regulator of mitochondrial genes and its expression is decreased and related to impaired oxidative phosphorylation in muscle from patients with type 2 diabetes. Whether it plays a similar role in human pancreatic islets is not known. We therefore investigated if PPARGC1A expression is altered in islets from patients with type 2 diabetes and whether this expression is influenced by genetic (PPARGC1A Gly482Ser polymorphism) and epigenetic (DNA methylation) factors. We also... (More)
AIMS/HYPOTHESIS: Insulin secretion in pancreatic islets is dependent upon mitochondrial function and production of ATP. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 alpha (protein PGC-1alpha; gene PPARGC1A) is a master regulator of mitochondrial genes and its expression is decreased and related to impaired oxidative phosphorylation in muscle from patients with type 2 diabetes. Whether it plays a similar role in human pancreatic islets is not known. We therefore investigated if PPARGC1A expression is altered in islets from patients with type 2 diabetes and whether this expression is influenced by genetic (PPARGC1A Gly482Ser polymorphism) and epigenetic (DNA methylation) factors. We also tested if experimental downregulation of PPARGC1A expression in human islets influenced insulin secretion. METHODS: The PPARGC1A Gly482Ser polymorphism was genotyped in human pancreatic islets from 48 non-diabetic and 12 type 2 diabetic multi-organ donors and related to PPARGC1A mRNA expression. DNA methylation of the PPARGC1A promoter was analysed in pancreatic islets from ten type 2 diabetic and nine control donors. Isolated human islets were transfected with PPARGC1A silencing RNA (siRNA). RESULTS: PPARGC1A mRNA expression was reduced by 90% (p < 0.005) and correlated with the reduction in insulin secretion in islets from patients with type 2 diabetes. After downregulation of PPARGC1A expression in human islets by siRNA, insulin secretion was reduced by 41% (p </= 0. 01). We were able to ascribe reduced PPARGC1A expression in islets to both genetic and epigenetic factors, i.e. a common PPARGC1A Gly482Ser polymorphism was associated with reduced PPARGC1A mRNA expression (p < 0.00005) and reduced insulin secretion (p < 0.05). In support of an epigenetic influence, the PPARGC1A gene promoter showed a twofold increase in DNA methylation in diabetic islets compared with non-diabetic islets (p < 0.04). CONCLUSIONS/INTERPRETATION: We have shown for the first time that PPARGC1A might be important in human islet insulin secretion and that expression of PPARGC1A in human islets can be regulated by both genetic and epigenetic factors. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetologia
volume
51
pages
615 - 622
publisher
Springer Verlag
external identifiers
  • pmid:18270681
  • wos:000254235200013
  • scopus:41149172495
ISSN
1432-0428
DOI
10.1007/s00125-007-0916-5
language
English
LU publication?
yes
id
06d93f63-4c04-4d5e-9777-bc69d1a56348 (old id 1042001)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18270681?dopt=Abstract
date added to LUP
2008-03-03 14:24:56
date last changed
2017-09-17 08:18:26
@article{06d93f63-4c04-4d5e-9777-bc69d1a56348,
  abstract     = {AIMS/HYPOTHESIS: Insulin secretion in pancreatic islets is dependent upon mitochondrial function and production of ATP. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator-1 alpha (protein PGC-1alpha; gene PPARGC1A) is a master regulator of mitochondrial genes and its expression is decreased and related to impaired oxidative phosphorylation in muscle from patients with type 2 diabetes. Whether it plays a similar role in human pancreatic islets is not known. We therefore investigated if PPARGC1A expression is altered in islets from patients with type 2 diabetes and whether this expression is influenced by genetic (PPARGC1A Gly482Ser polymorphism) and epigenetic (DNA methylation) factors. We also tested if experimental downregulation of PPARGC1A expression in human islets influenced insulin secretion. METHODS: The PPARGC1A Gly482Ser polymorphism was genotyped in human pancreatic islets from 48 non-diabetic and 12 type 2 diabetic multi-organ donors and related to PPARGC1A mRNA expression. DNA methylation of the PPARGC1A promoter was analysed in pancreatic islets from ten type 2 diabetic and nine control donors. Isolated human islets were transfected with PPARGC1A silencing RNA (siRNA). RESULTS: PPARGC1A mRNA expression was reduced by 90% (p &lt; 0.005) and correlated with the reduction in insulin secretion in islets from patients with type 2 diabetes. After downregulation of PPARGC1A expression in human islets by siRNA, insulin secretion was reduced by 41% (p &lt;/= 0. 01). We were able to ascribe reduced PPARGC1A expression in islets to both genetic and epigenetic factors, i.e. a common PPARGC1A Gly482Ser polymorphism was associated with reduced PPARGC1A mRNA expression (p &lt; 0.00005) and reduced insulin secretion (p &lt; 0.05). In support of an epigenetic influence, the PPARGC1A gene promoter showed a twofold increase in DNA methylation in diabetic islets compared with non-diabetic islets (p &lt; 0.04). CONCLUSIONS/INTERPRETATION: We have shown for the first time that PPARGC1A might be important in human islet insulin secretion and that expression of PPARGC1A in human islets can be regulated by both genetic and epigenetic factors.},
  author       = {Ling, Charlotte and Del Guerra, S and Lupi, R and Rönn, Tina and Granhall, Charlotte and Luthman, Holger and Masiello, P and Marchetti, P and Groop, Leif and Del Prato, S},
  issn         = {1432-0428},
  language     = {eng},
  pages        = {615--622},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion.},
  url          = {http://dx.doi.org/10.1007/s00125-007-0916-5},
  volume       = {51},
  year         = {2008},
}