The threat to global health posed by diabetes is a matter of concern to the international community. Type 2 diabetes accounts for over 90% of diabetes mellitus. Introducing some dietary measures early along with other lifestyle changes is key to addressing the global threat of diabetes. The following paper reflects the current mindset in the management of type 2 diabetes mellitus (T2DM). Teodoro et al. Therapeutic options targeting oxidative stress, mitochondrial dysfunction, and inflammation to prevent the progression of vascular complications in diabetes. Front. Physiol., January 17, 2019 | https://doi.org/10.3389/fphys.2018.01857
Type 2 diabetes mellitus (T2DM) is one of the global health problems of the 21st. The global prevalence of diabetes is growing rapidly, so that a total of 629 million people will suffer from diabetes by 2045, according to the International Diabetes Federation (IDF).
The rise in diabetes prevalence is in large part being driven by the rise in obesity and the aging of the world population, as well as lifestyle changes related to unhealthy eating habits and sedentary lifestyle, with significant costs to health systems. Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with hyperglycaemia (high blood sugar) and caused by defects in insulin secretion and / or action.
Over time, hyperglycemia induces toxic effects in virtually all organs of the body that particularly affect the vasculature, resulting in multiple complications at either the microvascular level (retinopathy-visual disturbances, nephropathy-kidney dysfunction, and neuropathy-nerve dysfunction) or the macrovascular level (Stroke, coronary artery disease, acute myocardial infarction, and peripheral vascular disease). About 40% of people with diabetes have late-stage complications, which are due to the fact that their disease progresses quietly before the diagnosis is made or even completed. The relationship between T2DM and vascular complications is closely related to the toxic effects of hyperglycemia and hyperlipidemia – glucotoxicity and lipotoxicity.
Hyperglycemia induces oxidative stress through mitochondrial dysfunction and increased production of reactive oxygen species (ROS). Hyperlipidemia (high lipid / cholesterol level) contributes to the release of proinflammatory cytokines by adipose tissue. The resulting oxidative stress and mild inflammation were believed to be 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 the blood vessel walls, which is manifested by 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 of an organism. The disruption and impairment of mitochondrial function is a hallmark of innumerable pathological conditions and a central event in the progression of many diseases, including diabetes. Mitochondrial dysfunction is at the core of endothelial damage, typically from inflammation, oxidative stress, cell death, and loss of tissue function. Therapeutic strategies that target oxidative stress, mitochondrial dysfunction, and inflammation are important to prevent the progression of vascular complications in diabetes.
Diabetics often have several risk factors for developing vascular complications, including age, insulin resistance, dyslipidemia, hyperglycemia, and high blood pressure. T2DM is both a metabolic and vascular disease characterized by chronic hyperglycemia and changes in cellular homeostasis that lead to vascular complications. The relationship between insulin resistance / hyperglycemia and endothelial dysfunction plays an important role in the development and progression of atherosclerotic disease in T2DM. High blood sugar induced by oxidative stress promotes endothelial dysfunction through increased production of reactive oxygen species (ROS), which play an important role in the pathogenesis and progression of diabetic vascular complications.
The vasoprotective beneficial effects of nitric oxide (NO) include vasodilation, increasing blood flow, hypotension, inhibiting platelet aggregation and adhesion, as well as reducing smooth muscle proliferation, restoring 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. In diabetic conditions, endothelial dysfunction leads to impaired NO availability, an increase in vascular resistance and contributes to atherogenesis. The decrease in vascular NO bioavailability is related to its inactivation by ROS, so it has been used as a biomarker of oxidative stress.
In T2DM, the mitochondria are the main sources of oxidative stress. The increase in the formation of mitochondrial ROS has been implicated as a mediator between hyperglycemia and its pathological consequences in the vessels, kidneys, neurons and retina. High blood sugar can directly stimulate the overproduction of ROS, which leads to the activation of multiple enzymatic cascades, leading to mitochondrial dysfunction. Insulin resistance is also linked to endothelial dysfunction, which leads to a decrease in the biosynthesis and 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 the increased production and release of inflammatory mediators. C-reactive protein (CRP) is considered an inflammatory protein of the acute phase – a sensitive and reliable marker for an inflammatory state. Elevated serum levels of CRP are also present in chronic inflammatory conditions such as atherosclerosis. If there is a risk of peripheral vascular diseases, their values are approximately tripled. The high CRP concentrations in the blood increase the risk of cardiovascular events (peripheral vascular disease, myocardial infarction, stroke and death), even in adults who have no previous chronic illnesses.
Endothelial cells are extremely sensitive to high glucose levels, which leads to apoptosis and loss of tissue function and is associated with increased mitochondrial fragmentation, altered mitochondrial ultrastructure and increased ROS production.
Diabetes is typically associated with obesity, with the majority of patients having high levels of LDL cholesterol which, in its oxidized form, has been shown to contribute to mitochondrial dysfunction and apoptotic death of the EC. Oxidative stress, inflammation, and mitochondrial dysfunction are closely related to endothelial dysfunction, which is critical to the progression of micro- and macrovascular diabetic complications. Therapeutic strategies that target these biological mechanisms are believed to be critical to the management of diabetes and its serious complications.
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Vascular complications are the main cause of morbidity and mortality in T2DM patients and are responsible for the lower life expectancy of these patients. Given the complex mechanisms involved in the disease, it is unlikely that a single therapeutic intervention could effectively control all of 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 treatment of T2DM. Apart from the most recent study with the SGLT-2 inhibitor empagliflozin (EMPA-REG OUTCOME), the oral antidiabetic agents that are already available for the treatment of T2DM patients do not show a consistent reduction in cardiovascular mortality, despite the fact that they are used in monotherapy and / or combined therapy. that can provide good glycemic control.
Polyphenol-rich food sources such as cocoa with proven anti-diabetic, antihypertensive, antiatherogenic, platelet aggregation-inhibiting, cholesterol-lowering properties and improved mitochondrial function should be an integral part of strategies to contain the global threat of diabetes.
BY DR. EDWARD O. AMPORFUL