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Impact of glycemic variability on chromatin remodeling, oxidative stress, and endothelial dysfunction in patients with type 2 diabetes and with target HbAlevels


Costantino, Sarah; Paneni, Francesco; Battista, Rodolfo; Castello, Lorenzo; Capretti, Giuliana; Chiandotto, Sergio; Tanese, Luigi; Russo, Giulio; Pitocco, Dario; Lanza, Gaetano A; Volpe, Massimo; Lüscher, Thomas F; Cosentino, Francesco (2017). Impact of glycemic variability on chromatin remodeling, oxidative stress, and endothelial dysfunction in patients with type 2 diabetes and with target HbAlevels. Diabetes, 66(9):2472-2482.

Abstract

Intensive glycemic control (IGC) targeting HbAfails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D); however, the underlying mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigated whether epigenetic regulation of the adaptor protein p66, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA>7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbAof ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F(8-isoPGF), and epigenetic regulation of p66were assessed at baseline and follow-up. Continuous glucose monitoring was performed to determine the mean amplitude of glycemic excursion (MAGE) and postprandial incremental area under the curve (AUCpp). At baseline, patients with T2D showed impaired FMD, increased urinary 8-isoPGF, and p66upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF, and p66expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66promoter of patients with T2D, and IGC did not change such adverse epigenetic remodeling. Persistent downregulation of methyltransferase DNMT3b and deacetylase SIRT1 may explain the observed p66-related epigenetic changes. MAGE and AUCpp but not HbAwere independently associated with the altered epigenetic profile on the p66promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbAlevels.

Abstract

Intensive glycemic control (IGC) targeting HbAfails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D); however, the underlying mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigated whether epigenetic regulation of the adaptor protein p66, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA>7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbAof ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F(8-isoPGF), and epigenetic regulation of p66were assessed at baseline and follow-up. Continuous glucose monitoring was performed to determine the mean amplitude of glycemic excursion (MAGE) and postprandial incremental area under the curve (AUCpp). At baseline, patients with T2D showed impaired FMD, increased urinary 8-isoPGF, and p66upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF, and p66expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66promoter of patients with T2D, and IGC did not change such adverse epigenetic remodeling. Persistent downregulation of methyltransferase DNMT3b and deacetylase SIRT1 may explain the observed p66-related epigenetic changes. MAGE and AUCpp but not HbAwere independently associated with the altered epigenetic profile on the p66promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbAlevels.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:September 2017
Deposited On:26 Feb 2018 22:27
Last Modified:14 Mar 2018 18:05
Publisher:American Diabetes Association
ISSN:0012-1797
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.2337/db17-0294
PubMed ID:28634176

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