Cited by 301Pancreatic function and diabetesEpigenetics and DNA MethylationDiabetes and associated disorders

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Increased DNA Methylation and Decreased Expression of PDX-1 in Pancreatic Islets from Patients with Type 2 Diabetes

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Yang, Beatrice T., Dayeh, Tasnim A., Volkov, Petr A., Kirkpatrick, Clare L., Malmgren, Siri, Jing, Xingjun, Renström, Erik, Wollheim, Claes B., Nitert, Marloes Dekker, Ling, Charlotte·2012·Molecular Endocrinology

DOI 10.1210/me.2012-1004PMC PMC5416998

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Abstract

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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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: Kirkpatrick, Clare L.
Malmgren, Siri
Renström, Erik
Wollheim, Claes B.
Nitert, Marloes Dekker
Ling, Charlotte
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
DOI: 10.1210/me.2012-1004
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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Increased DNA Methylation and Decreased Expression of PDX-1 in Pancreatic Islets from Patients with Type 2 Diabetes

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