Therapeutic Options Targeting Oxidative Stress, Mitochondrial Dysfunction and Inflammation to Hinder the Progression of Vascular Complications of Diabetes

Abstract

Type 2 diabetes mellitus is a leading cause of morbidity and mortality worldwide, given its serious associated complications. Despite constant efforts and intensive research, an effective, ubiquitous treatment still eludes the scientific community. As such, the identification of novel avenues of research is key to the potential discovery of this evasive “silver bullet.” We focus on this review on the matter of diabetic injury to endothelial tissue and some of the pivotal underlying mechanisms, including hyperglycemia and hyperlipidemia evoked oxidative stress and inflammation. In this sense, we revisited the most promising therapeutic interventions (both non-pharmacological and antidiabetic drugs) targeting oxidative stress and inflammation to hinder progression of vascular complications of diabetes. This review article gives particular attention to the relevance of mitochondrial function, an often ignored and understudied organelle in the vascular endothelium. We highlight the importance of mitochondrial function and number homeostasis in diabetic conditions and discuss the work conducted to address the aforementioned issue by the use of various therapeutic strategies. We explore here the functional, biochemical and bioenergetic alterations provoked by hyperglycemia in the endothelium, from elevated oxidative stress to inflammation and cell death, as well as loss of tissue function. Furthermore, we synthetize the literature regarding the current and promising approaches into dealing with these alterations. We discuss how known agents and therapeutic behaviors (as, for example, metformin, dietary restriction or antioxidants) can restore normality to mitochondrial and endothelial function, preserving the tissue’s function and averting the aforementioned complications.

Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

“…This way of thinking of diabetic retinopathy as influenced by the same pathophysiologic mechanisms driving β-cell damage as well as other complications opens up the potential of preventing, treating, or delaying retinopathy with agents used for glycemic control that also have pleotropic effects on extra-pancreatic tissues via targeting mechanisms contributing to complications (e.g., SGLT-2s on renal disease, GLP-1 agonists on cardiovascular disease) as well as agents aimed specifically at pathophysiologic mechanisms driving diabetes complications (e.g., inflammation, insulin resistance, etc.) (44,45).…”

“…There is growing consensus regarding the key role of inflammation in pathogenesis of diabetic retinopathy (9,(45)(46)(47). The retina is the most metabolically active tissue in the body making it very susceptible to oxidative stress both from light-induced electron injury and oxygen free radical production leading to increased inflammation (48).…”

“…This method of thinking allows for the potential of preventing, treating, or delaying diabetic retinopathy progression with agents used for glycemic control that have additional impact on mechanisms contributing to complications as well as agents aimed specifically at pathophysiologic mechanisms driving diabetes complications (e.g., inflammation, insulin resistance, etc.) (6,20,44,45). One example of the potential to use an agent indicated to reduce hyperglycemia in patients with diabetes, but also has other beneficial impact on complications is glucagon-like peptide-1 (GLP-1) receptor agonists.…”

“…This intriguing data along with our new understanding of the multiple pathophysiologic mechanisms contributing to diabetes and its complications suggests that GLP-1 agonists could be beneficial in slowing and or preventing diabetic retinopathy in patients. Other promising "diabetes" agents that impact hyperglycemia through multiple routes and which may be beneficial in the treatment of diabetic retinopathy include metformin, DPP-4, and SGLT-2 inhibitors to name a few but are still unproven (44,45).…”

“…The inflammatory process, as discussed above, plays an important role in the pathogenesis of diabetic retinopathy including increased retinal vascular permeability, occlusion, neovascularization, and retinal neurodegeneration (9,45,47,59). Thus, consideration of treatments directed at inflammation should be added to physician's tool kit to treat, manage, or prevent diabetic retinopathy.…”