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Increased DNA Methylation and Decreased Expression of PDX-1 in Pancreatic Islets from Patients with Type 2 Diabetes
Open accessAbstract
Mutations in pancreatic duodenal homeobox 1 (PDX-1) can cause a monogenic form of diabetes (maturity onset diabetes of the young 4) in humans, and silencing Pdx-1 in pancreatic β-cells of mice causes diabetes. However, it is not established whether epigenetic alterations of PDX-1 influence type 2 diabetes (T2D) in humans. Here we analyzed mRNA expression and DNA methylation of PDX-1 in human pancreatic islets from 55 nondiabetic donors and nine patients with T2D. We further studied epigenetic regulation of PDX-1 in clonal β-cells. PDX-1 expression was decreased in pancreatic islets from patients with T2D compared with nondiabetic donors (P = 0.0002) and correlated positively with insulin expression (rho = 0.59, P = 0.000001) and glucose-stimulated insulin secretion (rho = 0.41, P = 0.005) in the human islets. Ten CpG sites in the distal PDX-1 promoter and enhancer regions exhibited significantly increased DNA methylation in islets from patients with T2D compared with nondiabetic donors. DNA methylation of PDX-1 correlated negatively with its gene expression in the human islets (rho = -0.64, P = 0.0000029). Moreover, methylation of the human PDX-1 promoter and enhancer regions suppressed reporter gene expression in clonal β-cells (P = 0.04). Our data further indicate that hyperglycemia decreases gene expression and increases DNA methylation of PDX-1 because glycosylated hemoglobin (HbA1c) correlates negatively with mRNA expression (rho = -0.50, P = 0.0004) and positively with DNA methylation (rho = 0.54, P = 0.00024) of PDX-1 in the human islets. Furthermore, while Pdx-1 expression decreased, Pdx-1 methylation and Dnmt1 expression increased in clonal β-cells exposed to high glucose. Overall, epigenetic modifications of PDX-1 may play a role in the development of T2D, given that pancreatic islets from patients with T2D and β-cells exposed to hyperglycemia exhibited increased DNA methylation and decreased expression of PDX-1. The expression levels of PDX-1 were further associated with insulin secretion in the human islets.
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“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 [22]
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Cites
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β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes
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“Epigenetic modifications may be passed on from one cell generation to the next (mitotic inheritance) and/or between generations of a species (meiotic inheritance) (44).”
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Pathophysiology of type 2 diabetes mellitus
Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176275 · Cited by 3,360
Epigenetics in Human Obesity and Type 2 Diabetes
Ling, C., & Rönn, T. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.03.009 · Cited by 1,006
Self-citationRönn, T., Volkov, P., Davegårdh, C., Dayeh, T., Hall, E., Olsson, A. H., Nilsson, E., Tornberg, Å. B., Nitert, M. D., Eriksson, K., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003572 · Cited by 637
Self-citationDayeh, T., Volkov, P., Salö, S., Hall, E., Nilsson, E., Olsson, A. H., Kirkpatrick, C. L., Wollheim, C. B., Eliasson, L., Rönn, T., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004160 · Cited by 523
Self-citationβ-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment
Halban, P. A., Polonsky, K. S., Bowden, D. W., Hawkins, M. A., Ling, C., Mather, K. J., Powers, A. C., Rhodes, C. J., Sussel, L., & Weir, G. C. (2014) · Diabetes Care · doi:10.2337/dc14-0396 · Cited by 460
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Metadata
- Authors
- Yang, B. T., Dayeh, T. A., Volkov, P. A., Kirkpatrick, C. L., Malmgren, S., Jing, X., Renström, E., Wollheim, C. B., Nitert, M. D., & Ling, C.
- Affiliations
- Lund University (SE)
- Department of Cell Physiology and Metabolism (C.L.K., C.B.W.), University Medical Center, 1211 Geneva 4, Switzerland
- Corresponding author
- Ling, Charlotte
- ORCID
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2012-07-01
- Volume
- 26
- Issue
- 7
- Pages
- 1203-1212
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC5416998
- OpenAlex
- W2116017402
- Cited by
- 301
- References
- 50
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 25 · 2023: 20 · 2022: 18 · 2021: 21 · 2020: 26 · 2019: 24 · 2018: 18 · 2017: 21 · 2016: 18 · 2015: 25 · 2014: 32 · 2013: 19 · 2012: 6
- FWCI
- 26.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Science Foundation
- Eli Lilly and Company
- European Foundation for the Study of Diabetes (B31 5631/2006)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Lunds Universitet
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Vetenskapsrådet
- Uppsala Universitet
- Università di Pisa
- Region Skåne
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- PDX1, DNA methylation, type 2 diabetes, pancreatic islets, pancreatic beta cells, epigenetic regulation, hyperglycemia, HbA1c, DNMT1, insulin secretion, gene silencing
- MeSH terms
- Diabetes Mellitus, Type 2, Female, Glucose, Humans, Hyperglycemia, Insulin, Male, Middle Aged, Pancreas, Promoter Regions, Genetic, RNA, Messenger, Trans-Activators, Homeodomain Proteins, DNA Methylation, Insulin-Secreting Cells
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