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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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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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