The threat of diabetes to global health is of concern to the International community. Type 2 diabetes accounts for over 90% of diabetes mellitus. The early adoption of some dietary measures together with other lifestyle modifications holds the key to confronting the global menace of diabetes. The ensuing paper reflects the current thinking in the management of Type 2 diabetes mellitus (T2DM). Teodoro et al.Therapeutic Options Targeting Oxidative Stress, Mitochondrial Dysfunction and Inflammation to Hinder the Progression of Vascular Complications of Diabetes. Front. Physiol., 17 January 2019 | https://doi.org/10.3389/fphys.2018.01857

Type 2 diabetes mellitus (T2DM) is one of the 21st century’s global public health problems, with estimates of the affected population reaching 425 million people. The global prevalence of diabetes is rapidly growing in such a way that, according to the International Diabetes Federation (IDF) estimates, by 2045 a total of 629 million people will have diabetes. 

The increase in diabetes prevalence is driven in large part by increasing rates of obesity and aging of the global population as well as changes in lifestyle related to unhealthy eating habits and sedentarism, with significant costs to healthcare systems. Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with hyperglycemia (high blood glucose), caused by defects in insulin secretion and/or action.  

Over time, hyperglycemia induces toxic effects in virtually all of the organs of the body, of which the vascular system is particularly affected, resulting in multiple complications either at the microvascular level (retinopathy-visual defects, nephropathy-kidney dysfunction, and neuropathy-nerve dysfunction) or the macrovascular level (stroke, coronary heart disease, acute myocardial infarction, and peripheral vascular disease). About 40% of people with diabetes have late complications resulting from their disease progressing silently before the diagnosis is performed or even completed.The link between T2DM and vascular complications is strongly related to the toxic effects derived of hyperglycemia and hyperlipidemia  – glucotoxicity and lipotoxicity. 

Hyperglycemia induces oxidative stress, namely via mitochondrial dysfunction and enhanced reactive oxygen species (ROS) generation. Hyperlipidemia (high lipid/cholesterol level) contributes to the release of pro-inflammatory cytokines by the adipocyte tissue. The consequent oxidative stress and low-grade inflammation have been considered major contributors to the progression of T2DM and its complications. In addition to hyperglycemia and hyperlipidemia-induced toxicity, insulin resistance and hypertension promote damage at the level of blood vessel walls, which are manifested through the development of endothelial dysfunction. Endothelial dysfunction precedes the early development of micro and macrovascular diseases and complications.

Mitochondria play a key role in metabolic processes in all cells within an organism. Interference and hampering of mitochondrial function is a hallmark of countless pathologic conditions and a central event of the progression of many diseases including diabetes. Mitochondrial dysfunction is at the core of endothelial injury, typically by inflammation, oxidative stress, cell death, and loss of tissue function. Therapeutic strategies targeting oxidative stress, mitochondrial dysfunction, and inflammation are important to hinder the progression of vascular complications of diabetes.

Diabetic patients frequently have several risk factors for the development of vascular complications, including age, insulin resistance, dyslipidaemia, hyperglycaemia, and hypertension. T2DM is both a metabolic disease and vascular disease, characterized by chronic hyperglycemia and alterations of cellular homeostasis leading to vascular complications. The link between insulin resistance/hyperglycaemia and endothelial dysfunction plays an important role in the development and progression of atherosclerotic disease in T2DM. High blood glucose induced by oxidative stress promotes endothelial dysfunction through increased production of reactive oxygen species (ROS), which plays a major role in the pathogenesis and progression of diabetic vascular complications.

The vasoprotective beneficial actions of nitric oxide (NO) include vasodilatation, increase in blood flow, hypotension, inhibition of platelet aggregation and adhesion, as well as reduction of smooth muscle proliferation, restoration of endothelial function. Endothelial dysfunction refers to an imbalance in the release of NO or other vasodilatory factors and vasoconstrictor substances and is related to the pathology of diabetes and related complications. Under diabetic conditions, endothelial dysfunction leads to impaired NO availability, increase in vascular resistance, contributing to atherogenesis. The reduction in vascular NO bioavailability is related to its inactivation by ROS, in such a way that has been used as a biomarker of oxidative stress.

In T2DM, the main sources of oxidative stress are the mitochondria. The increase in the generation of mitochondrial ROS has been implicated as a mediator between hyperglycemia and its pathological consequences in the vessels, kidneys, neurons, and retina. High blood glucose can directly stimulate the overproduction of ROS, which leads to the activation of several enzymatic cascades resulting in mitochondrial dysfunction. Insulin resistance is also associated with endothelial dysfunction, resulting in a reduction of biosynthesis and the biological activity of NO. 

Glucotoxicity and lipotoxicity induce inflammation and recruitment and activation of immune cells. Changes in NO, cytokines, acute-phase reactants, and cellular adhesion molecules induced by the overproduction of ROS precede atherosclerosis.

Increased inflammation promotes increased production and release of inflammatory mediators. C-reactive protein (CRP) is considered an acute phase inflammatory protein- a sensitive and reliable marker of an inflammatory state. Increased serum levels of CRP are also present in chronic inflammatory conditions such as atherosclerosis. Their levels are approximately tripled in the presence of risk of peripheral vascular diseases. The high blood concentrations of CRP increase the risk of cardiovascular events (peripheral vascular disease, myocardial infarction, stroke, and death), even among adults who did not present previous chronic processes.

Endothelial cells are extremely sensitive to high glucose levels, which leads to apoptosis and loss of tissue function and is associated with elevated mitochondrial fragmentation, altered mitochondrial ultrastructure, and increased ROS generation.

Diabetes is typically associated with obesity, where a majority of patients present high levels of LDL-cholesterol which, in its oxidized form, has been shown to contribute to mitochondrial dysfunction and EC apoptotic death. Oxidative stress, inflammation, and mitochondrial dysfunction are closely linked with endothelial dysfunction, which is critical in the progression of micro and macrovascular diabetic complications. Therapeutic strategies targeting these biological mechanisms are considered pivotal to managing diabetes and its serious complications. 

Vascular complications represent the major cause of morbidity and mortality in T2DM patients and are responsible for the lower life expectancy of these subjects. In view of the complex mechanisms involved in the disease, it is unlikely that a single therapeutic measure could efficiently control all the factors underlying the slow but consistent deregulation of micro and macrovascular beds. There is a need for a combination of non-pharmacological and pharmacological interventions in the management of T2DM. However, apart from the most recent trial with the SGLT-2 inhibitor empagliflozin (EMPA-REG OUTCOME), the oral antidiabetic drugs already available for treating T2DM patients do not show a consistent reduction in cardiovascular mortality, despite collectively, in mono and/or combined therapy, being able to provide good glycaemic control.

Polyphenol-rich food sources such as cocoa with proven anti-diabetic, antihypertensive, antiatherogenic, antiplatelet, cholesterol-lowering properties, and improved mitochondrial function should be part and parcel of the strategies to curb the global menace of diabetes.




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