Impact of glycemic variability on chromatin remodeling, oxidative stress, and endothelial dysfunction in patients with type 2 diabetes and with target HbA1c levels

Dario Pitocco, Gaetano Antonio Lanza, Giulio Russo, Massimo Volpe, Francesco Cosentino, Sarah Costantino, Francesco Paneni, Rodolfo Battista, Lorenzo Castello, Giuliana Capretti, Sergio Chiandotto, Thomas F. Lüscher

Risultato della ricerca: Contributo in rivistaArticolo in rivista

72 Citazioni (Scopus)

Abstract

Intensive glycemic control (IGC) targeting HbA1c fails 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 p66Shc, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA1c >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 HbA1c of £7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F2a (8-isoPGF2a), and epigenetic regulation of p66Shc were 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-isoPGF2a, and p66Shc upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF2a, and p66Shc expression were not affected by IGC. DNA hypomethylation and histone 3 acetylationwere found on the p66Shc promoter 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 p66Shc-related epigenetic changes. MAGE and AUCpp but not HbA1c were independently associated with the altered epigenetic profile on the p66Shc promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA1c levels.
Lingua originaleEnglish
pagine (da-a)2472-2482
Numero di pagine11
RivistaDiabetes
Volume66
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Adult
  • Blood Glucose
  • Case-Control Studies
  • Chromatin Assembly and Disassembly
  • Diabetes Mellitus, Type 2
  • Endocrinology, Diabetes and Metabolism
  • Endothelium, Vascular
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation
  • Glycated Hemoglobin A
  • Humans
  • Internal Medicine
  • Male
  • Middle Aged
  • Oxidative Stress
  • Promoter Regions, Genetic
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Up-Regulation

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