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Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA(1c) levels in human pancreatic islets.

Yang, Beatrice LU orcid ; Dayeh, Tasnim LU ; Kirkpatrick, C L ; Taneera, Jalal LU ; Kumar, Rajesh LU ; Groop, Leif LU ; Wollheim, Claes LU ; Dekker Nitert, Marloes LU and Ling, Charlotte LU (2011) In Diabetologia Dec. p.360-367
Abstract
AIMS/HYPOTHESIS: Although recent studies propose that epigenetic factors influence insulin expression, the regulation of the insulin gene in type 2 diabetic islets is still not fully understood. Here, we examined DNA methylation of the insulin gene promoter in pancreatic islets from patients with type 2 diabetes and non-diabetic human donors and related it to insulin expression, HbA(1c) levels, BMI and age. METHODS: DNA methylation was analysed in 25 CpG sites of the insulin promoter and insulin mRNA expression was analysed using quantitative RT-PCR in pancreatic islets from nine donors with type 2 diabetes and 48 non-diabetic donors. RESULTS: Insulin mRNA expression (p = 0.002), insulin content (p = 0.004) and glucose-stimulated insulin... (More)
AIMS/HYPOTHESIS: Although recent studies propose that epigenetic factors influence insulin expression, the regulation of the insulin gene in type 2 diabetic islets is still not fully understood. Here, we examined DNA methylation of the insulin gene promoter in pancreatic islets from patients with type 2 diabetes and non-diabetic human donors and related it to insulin expression, HbA(1c) levels, BMI and age. METHODS: DNA methylation was analysed in 25 CpG sites of the insulin promoter and insulin mRNA expression was analysed using quantitative RT-PCR in pancreatic islets from nine donors with type 2 diabetes and 48 non-diabetic donors. RESULTS: Insulin mRNA expression (p = 0.002), insulin content (p = 0.004) and glucose-stimulated insulin secretion (p = 0.04) were reduced in pancreatic islets from patients with type 2 diabetes compared with non-diabetic donors. Moreover, four CpG sites located 234 bp, 180 and 102 bp upstream and 63 bp downstream of the transcription start site (CpG -234, -180, -102 and +63, respectively), showed increased DNA methylation in type 2 diabetic compared with non-diabetic islets (7.8%, p = 0.03; 7.1%, p = 0.02; 4.4%, p = 0.03 and 9.3%, p = 0.03, respectively). While insulin mRNA expression correlated negatively (p < 1 × 10(-6)), the level of HbA(1c) correlated positively (p ≤ 0.01) with the degree of DNA methylation for CpG -234, -180 and +63. Furthermore, DNA methylation for nine additional CpG sites correlated negatively with insulin mRNA expression (p ≤ 0.01). Also, exposure to hyperglycaemia for 72 h increased insulin promoter DNA methylation in clonal rat beta cells (p = 0.005). CONCLUSIONS/INTERPRETATIONS: This study demonstrates that DNA methylation of the insulin promoter is increased in patients with type 2 diabetes and correlates negatively with insulin gene expression in human pancreatic islets. (Less)
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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetologia
volume
Dec
pages
360 - 367
publisher
Springer
external identifiers
  • wos:000286001800022
  • pmid:21104225
  • scopus:78951472134
  • pmid:21104225
ISSN
1432-0428
DOI
10.1007/s00125-010-1967-6
language
English
LU publication?
yes
id
46d7740c-53a8-46fd-ad50-0dfdf963f7c3 (old id 1731605)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21104225?dopt=Abstract
date added to LUP
2016-04-04 07:40:29
date last changed
2021-10-06 03:20:16
@article{46d7740c-53a8-46fd-ad50-0dfdf963f7c3,
  abstract     = {AIMS/HYPOTHESIS: Although recent studies propose that epigenetic factors influence insulin expression, the regulation of the insulin gene in type 2 diabetic islets is still not fully understood. Here, we examined DNA methylation of the insulin gene promoter in pancreatic islets from patients with type 2 diabetes and non-diabetic human donors and related it to insulin expression, HbA(1c) levels, BMI and age. METHODS: DNA methylation was analysed in 25 CpG sites of the insulin promoter and insulin mRNA expression was analysed using quantitative RT-PCR in pancreatic islets from nine donors with type 2 diabetes and 48 non-diabetic donors. RESULTS: Insulin mRNA expression (p = 0.002), insulin content (p = 0.004) and glucose-stimulated insulin secretion (p = 0.04) were reduced in pancreatic islets from patients with type 2 diabetes compared with non-diabetic donors. Moreover, four CpG sites located 234 bp, 180 and 102 bp upstream and 63 bp downstream of the transcription start site (CpG -234, -180, -102 and +63, respectively), showed increased DNA methylation in type 2 diabetic compared with non-diabetic islets (7.8%, p = 0.03; 7.1%, p = 0.02; 4.4%, p = 0.03 and 9.3%, p = 0.03, respectively). While insulin mRNA expression correlated negatively (p &lt; 1 × 10(-6)), the level of HbA(1c) correlated positively (p ≤ 0.01) with the degree of DNA methylation for CpG -234, -180 and +63. Furthermore, DNA methylation for nine additional CpG sites correlated negatively with insulin mRNA expression (p ≤ 0.01). Also, exposure to hyperglycaemia for 72 h increased insulin promoter DNA methylation in clonal rat beta cells (p = 0.005). CONCLUSIONS/INTERPRETATIONS: This study demonstrates that DNA methylation of the insulin promoter is increased in patients with type 2 diabetes and correlates negatively with insulin gene expression in human pancreatic islets.},
  author       = {Yang, Beatrice and Dayeh, Tasnim and Kirkpatrick, C L and Taneera, Jalal and Kumar, Rajesh and Groop, Leif and Wollheim, Claes and Dekker Nitert, Marloes and Ling, Charlotte},
  issn         = {1432-0428},
  language     = {eng},
  pages        = {360--367},
  publisher    = {Springer},
  series       = {Diabetologia},
  title        = {Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA(1c) levels in human pancreatic islets.},
  url          = {http://dx.doi.org/10.1007/s00125-010-1967-6},
  doi          = {10.1007/s00125-010-1967-6},
  volume       = {Dec},
  year         = {2011},
}