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. 2008 Apr;51(4):615-22.
doi: 10.1007/s00125-007-0916-5. Epub 2008 Feb 13.

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

C Ling  1 , S Del Guerra, R Lupi, T Rönn, C Granhall, H Luthman, P Masiello, P Marchetti, L Groop, S Del Prato
Affiliations

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

C Ling et al. Diabetologia. 2008 Apr.

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<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 <or= 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.

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Figures

Fig. 1
Fig. 1
PPARGC1A mRNA expression in human pancreatic islets is influenced by type 2 diabetes, a PPARGC1A Gly482Ser polymorphism and DNA methylation. The influence of a type 2 diabetes and b the PPARGC1A Gly482Ser polymorphism on PPARGC1A mRNA expression in human pancreatic islets. c The PPARGC1A promoter sequence investigated, showing the four DNA methylation target sites; −772, −903, −936 and −961 and a putative binding-site for HNF-1. d The influence of type 2 diabetes on DNA methylation of the PPARGC1A promoter. The influence of e type 2 diabetes (T2D) and f the PPARGC1A Gly482Ser polymorphism on absolute insulin release (pmol islet−1 min−1) in response to 16.7 mmol/l glucose. g Correlations between PPARGC1A mRNA expression and absolute insulin release (pmol islet−1 min−1) in response to 16.7 mmol/l glucose in human pancreatic islets (r = 0.38, p < 0.05). Results are expressed as mean ± SEM. *p < 0.05
Fig. 2
Fig. 2
Transfection of human pancreatic islets with PPARGC1A siRNA is associated with reduced mRNA levels of aPPARGC1A (n = 3) and b insulin (n = 5) and c concomitant reduction of the insulin stimulation index (ISI), i.e. incremental fold change above basal insulin release. d Conversely, inhibition of PPARGC1A expression in human pancreatic islets has no effect on glucagon mRNA expression (n = 5). Results are expressed as mean ± SEM. *p < 0.05
Fig. 3
Fig. 3
PPARGC1A mRNA expression in rodent pancreatic islets. a Male Wistar rats (2–3 months old) were treated with STZ–NA (n = 5) or vehicles (control; n = 5) [10, 11] and PPARGC1A mRNA expression together with the internal standard cyclophilin A was analysed in pancreatic islets isolated from STZ–NA-treated animals showing a stable hyperglycaemia (8.9–10.0 mmol glucose/l) and controls. bPPARGC1A mRNA expression together with the internal standard cyclophilin A was analysed in pancreatic islets prepared from rats at 8 weeks of age after a 6 h fast. GK rats (n = 6) were obtained from the Stockholm colony and bred as described [12]. Inbred, normoglycaemic F344 (n = 6) were purchased from Charles River Laboratories. Transfer of GK alleles onto the genome of F344 rats by repeated backcrossing (ten generations) established the homozygous congenic strains NIDDM1F and NIDDM1I. NIDDM1F rats (n = 6) carry 0.5% of the GK genotype, based on genetic distance, on a homozygous F344 genetic background (8 cM) and display hyperglycaemia accompanied by fasting hyperinsulinaemia, implicating insulin resistance. NIDDM1I (n = 6) carries 0.8% of the GK genotype (14 cM) and display insulin secretion defects [–15]. Results are expressed as mean ± SEM. *p < 0.05
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References

    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1016/j.cmet.2005.05.004', 'is_inner': False, 'url': 'https://doi.org/10.1016/j.cmet.2005.05.004'}, {'type': 'PubMed', 'value': '16054085', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/16054085/'}]}
    2. Lin J, Handschin C, Spiegelman BM (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1:361–370 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1038/ng1180', 'is_inner': False, 'url': 'https://doi.org/10.1038/ng1180'}, {'type': 'PubMed', 'value': '12808457', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/12808457/'}]}
    2. Mootha VK, Lindgren CM, Eriksson KF et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/s001250100032', 'is_inner': False, 'url': 'https://doi.org/10.1007/s001250100032'}, {'type': 'PubMed', 'value': '11793024', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/11793024/'}]}
    2. Ek J, Andersen G, Urhammer SA et al (2001) Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to type II diabetes mellitus. Diabetologia 44:2220–2226 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'DOI', 'value': '10.1007/s00125-005-0130-2', 'is_inner': False, 'url': 'https://doi.org/10.1007/s00125-005-0130-2'}, {'type': 'PubMed', 'value': '16435105', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/16435105/'}]}
    2. Barroso I, Luan J, Sandhu MS et al (2006) Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Diabetologia 49:501–505 - PubMed
    1. {'text': '', 'ref_index': 1, 'ids': [{'type': 'PMC', 'value': 'PMC525741', 'is_inner': False, 'url': 'https://pmc.ncbi.nlm.nih.gov/articles/PMC525741/'}, {'type': 'PubMed', 'value': '15546003', 'is_inner': True, 'url': 'https://pubmed.ncbi.nlm.nih.gov/15546003/'}]}
    2. Ling C, Poulsen P, Carlsson E et al (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins. J Clin Invest 114:1518–1526 - PMC - PubMed

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