Impact of Glycemic Variability on Chromatin Remodeling, Oxidative Stress, and Endothelial Dysfunction in Patients With Type 2 Diabetes and With Target HbA1c Levels

Abstract

Intensive glycemic control (IGC) targeting HbA 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 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 HbA of ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F (8-isoPGF), and epigenetic regulation of p66 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-isoPGF, and p66 upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF, and p66 expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66 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 p66-related epigenetic changes. MAGE and AUCpp but not HbA were independently associated with the altered epigenetic profile on the p66 promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA levels.

Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes

“…Accordingly, some consider the ApoE −/− streptozotocin model to be the most appropriate mouse model to study accelerated diabetes-associated atherosclerosis 52 . The recent clinical observation showing epigenetically sustained p66 Shc expression in diabetic patients 21 and the increased p66 Shc expression in atherosclerotic lesions from diabetic as compared to non-diabetic patients in the current study supports the translational relevance of the model used.…”

“…In agreement with these clinical results we observed increased p66 Shc expression in plaque-associated macrophages of diabetic, but not of non-diabetic patients and mice. The concordant observation in human peripheral blood monocytes 21 , human plaque-associated macrophages (Fig. 3), and the murine data presented within this manuscript argue against sustained p66 Shc expression in ApoE −/− DM mice as a consequence of toxic streptozotocin effects 33 .…”

“…The translational relevance of the current finding is supported by a recent clinical study which demonstrated that p66 Shc expression is epigenetically increased in peripheral blood monocytes of type 2 diabetic patients 21 . In agreement with these clinical results we observed increased p66 Shc expression in plaque-associated macrophages of diabetic, but not of non-diabetic patients and mice.…”

“…Expression of p66 Shc is epigenetically controlled, suggesting that sustained p66 Shc expression may provide a mechanistic link between the hyperglycaemic memory, sustained vascular ROS generation and inflammation, and progressive atherosclerotic disease despite improved blood glucose control 16,19 . A recent study demonstrated sustained p66 Shc expression in peripheral blood monocytes of diabetic patients despite improved blood glucose control 21 . However, whether sustained p66 Shc expression likewise occurs in atherosclerotic plaque-associated macrophages remains unknown.…”

Endothelial dysfunction and platelet hyperactivity in type 2 diabetes mellitus: molecular insights and therapeutic strategies

“…However, anti-inflammatory capacity of HDL was shown to be markedly impaired in T2DM patients, which can be partially attributed to chronic hyperglycemia, persistent low grade inflammation and reduced serum paraoxonase/arylesterase 1 (PON-1) activity [52]. This decrease in anti-inflammatory protection capacity of HDL leads to increased atherosclerosis risk in T2DM patients [53]. Furthermore, glucose fluctuation were also reported to contribute to chromatin remodeling and may describe the persistent vascular dysfunction in uncontrolled T2DM (HbA1c > 7.5% [54].…”