Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion
Open accessAbstract
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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Hyperglycemia alters DNA methylation of PDX1 and INS.
“further suggest that hyperglycemia alters DNA methylation of PDX1 and INS ( 22 – 25 ).”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [24]
The Methods and Results (page not available) examine DNA methylation of PPARGC1A and report higher methylation in diabetic than non-diabetic islets. Searches for PDX1, INS, and hyperglycemia-related methylation found no passage addressing whether hyperglycemia alters methylation of PDX1 or INS. (LLM, conf=0.74)
Experimental — accuracy not yet measuredSilencing PGC1α in healthy human islets reduces insulin secretion.
“In addition, PGC1α silencing in healthy human islets resulted in reduced insulin secretion145, a phenomenon also found in patients with a common mtDNA variant in mitochondrial transcription factor B1 (TFB1M)146.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [145]
PGC1α expression is reduced by 90% in islets from people with type 2 diabetes.
“In agreement with reduced insulin secretion, PGC1α expression was found to be reduced by 90% in islets from patients with T2DM.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [145]
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References 20 · Cited by 495
- Authors
- Ling, C., Del Guerra, S., Lupi, R., Rönn, T., Granhall, C., Luthman, H., Masiello, P., Marchetti, P., Groop, L., & Del Prato, S.
- Affiliations
- Lund University (SE)
- University of Pisa (IT)
- Corresponding author
- Ling, C.
- Venue
- Diabetologia
- Published
- 2008-02-13
- Volume
- 51
- Issue
- 4
- Pages
- 615-622
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC2270364
- OpenAlex
- W2153684035
- Cited by
- 495
- References
- 20
- Citations by year
- 2026: 23 · 2025: 11 · 2024: 30 · 2023: 25 · 2022: 22 · 2021: 27 · 2020: 29 · 2019: 30 · 2018: 20 · 2017: 40 · 2016: 32 · 2015: 33 · 2014: 41 · 2013: 31 · 2012: 35
- FWCI
- 22.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Diabetologia (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Lunds Universitet
- Novo Nordisk
- Vetenskapsrådet
- Malmö Högskola
- Region Skåne
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- PGC-1α, type 2 diabetes, pancreatic islets, insulin secretion, DNA methylation, epigenetic regulation, mitochondrial function, siRNA knockdown, gene expression, oxidative phosphorylation, transcriptional coactivator, promoter methylation
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Insulin Secretion, Animals, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genotype, Heat-Shock Proteins, Humans, Insulin, Islets of Langerhans, Male, Mitochondria, Reference Values, RNA, Messenger, Tissue Donors, Transcription Factors, Polymerase Chain Reaction, Rats, Wistar, DNA Methylation, RNA, Small Interfering, Rats
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