Overall Quality of Care Predicts the Variability of Key Risk Factors for Complications in Type 2 Diabetes: An Observational, Longitudinal Retrospective Study

Intensive glycemic control (IGC) targeting HbA1cfails 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 HbA1cof ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F2α(8-isoPGF2α), and epigenetic regulation of p66Shcwere 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-isoPGF2α, and p66Shcupregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF2α, and p66Shcexpression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66Shcpromoter 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 HbA1cwere independently associated with the altered epigenetic profile on the p66Shcpromoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA1clevels.

Variability in HbA1c and blood pressure is associated with the risk of diabetic kidney disease (DKD). No evidence exists on the role of variability in lipids or serum uric acid (UA), or the interplay between the variability of different parameters, in renal outcomes.