Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

Abstract

Diabetes is considered a major burden on the healthcare system of Western and non-Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro- and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism-based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu.

Keywords: cardiovascular disease; chronic kidney disease; diabetes; inflammation; oxidative stress; retinopathy.

Figure 1

A schematic diagram demonstrating the mediators involved in hyperglycaemia‐induced oxidative stress leading to the progression of diabetic cardiomyopathy and cardiovascular disease (CVD). Oxidative stress leads to the upregulation of nuclear factor kappa B (NFκB), NADPH oxidase (NOX1), heat‐shock protein 90 (Hsp90), transforming growth factor beta (TGFβ), tumor necrosis factor alpha (TNF‐α), connective tissue growth factor (CTGF), monocyte chemotactic protein 1 (MCP‐1), intercellular adhesion molecule 1 (ICAM‐1), interleukin 6 (IL‐6) and interleukin 1β (IL‐1β). In red is the NOX oxidative enzyme inhibitor GKT137831, the Il‐1β inhibitor (Canakinumab) and annexin A1 peptides, whereas in green are the Nrf2 activators (sulphoraphane, hydrogen sulphide, resveratrol, MG123, bardoxolone methyl and dh404) that have shown protective effects in diabetic cardiac and vascular disease.

Figure 2

A schematic diagram demonstrating the mediators involved in hyperglycaemia‐induced oxidative stress leading to the progression of diabetic nephropathy. In the kidney, oxidative stress leads to the upregulation of NADPH oxidase (NOX4/NOX5), monocyte chemotactic protein 1 (MCP‐1), tumor necrosis factor alpha (TNF‐α). In red are the inhibitors (GKT137831), Spiegelmer emapticap pegol (NOX‐E36) and vitamin E, whereas in green are antioxidant activators (digitoflavone, minocycline, bardoxolone methyl, dh404, selenium and ebselen) that have shown protective effects in diabetic nephropathy.

Figure 3

A schematic diagram demonstrating the mediators involved in hyperglycaemia‐induced oxidative stress leading to the progression of diabetic retinopathy. In the microvascular endothelial cells of the retina, oxidative stress leads to decreased expression of hypoxia‐inducible factor alpha (HIF1α) which in turn upregulates vascular endothelial growth factor (VEGF) leading to angiogenesis and vascular leakage. Oxidative stress upregulates retinal inflammation by increasing expression of pro‐inflammatory proteins, for example nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐kB), monocyte chemotactic protein 1 (MCP‐1) and intercellular adhesion molecule 1 (ICAM‐1). In addition, the Müller cells contribute to oxidative stress induced inflammation by upregulating glial fibrillary protein (GFAP). In red are current oxidative enzyme inhibitors (GKT137831) and antioxidant activators (ebselen and dh404) that have shown protective effects in diabetic retinopathy. In green are the T regulatory cells (Treg) recently shown to inhibit retinal inflammation.