Diabetes and Cardiovascular Complications: The Epidemics Continue

Abstract

Purpose of review: The cardiovascular complications of type 1 and 2 diabetes are major causes of morbidity and mortality. Extensive efforts have been made to maximize glycemic control; this strategy reduces certain manifestations of cardiovascular complications. There are drawbacks, however, as intensive glycemic control does not impart perennial protective benefits, and these efforts are not without potential adverse sequelae, such as hypoglycemic events.

Recent findings: Here, the authors have focused on updates into key areas under study for mechanisms driving these cardiovascular disorders in diabetes, including roles for epigenetics and gene expression, interferon networks, and mitochondrial dysfunction. Updates on the cardioprotective roles of the new classes of hyperglycemia-targeting therapies, the sodium glucose transport protein 2 inhibitors and the agonists of the glucagon-like peptide 1 receptor system, are reviewed. In summary, insights from ongoing research and the cardioprotective benefits of the newer type 2 diabetes therapies are providing novel areas for therapeutic opportunities in diabetes and CVD.

Keywords: Cardiovascular disease; Diabetes; Epigenetics; Interferon pathways; Mitochondrial dysfunction; Therapeutic agents.

Fig. 1

Updates in diabetes and CVD. This review focused on recent updates in mechanisms underlying accelerated CVD in diabetes. In the field of epigenetics, high levels of glucose exert a long-lasting metabolic memory on vascular and immune cells, leading to molecular signatures linked to diabetes and CVD. High levels of glucose and their consequent increased formation of AGEs, leading to activation of RAGE, upregulate multiple elements of the interferon pathways, such as IRFs, IFNs, and ISGs, and downstream pathways that lead to CVD. Finally, evidence continues to accrue linking high levels of glucose and pathways such as aldose reductase (AR) and AGE-RAGE to oxidative stress and mitochondrial dysfunction; such dysfunction affects a broad range of cell types that contribute to CVD. This review considered the evidence for cardioprotective roles for inhibitors of SGLT2 and for agonists of the GLP1 Rs in clinical studies. Additionally, recent evidence links downstream consequences of high levels of glucose, such as increased flux through the AR pathway and AGE generation/RAGE activation with CVD-provoking mechanisms. Collectively, these considerations highlight that research has led to new therapies and new targets for therapeutic intervention in diabetes to prevent/mitigate CVD. Abbreviations: AGE, advanced glycation end product; AR, aldose reductase; CVD, cardiovascular disease; DNA-me, DNA methylation; IFN, interferon; IRF, interferon response factor; ISG, interferon stimulated genes; PTM, post-translational modification; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; T1D, type 1 diabetes; T2D, type 2 diabetes; Δ, differential; and DRP1, dynamin-related protein 1