The Effect of Omega-3 Polyunsaturated Acids Supplementation on Endothelial Function, Oxidative Stress, Platelet Aggregation, Blood Coagulation and Inflammation in Patients With Type 2 Diabetes and Cardiovascular Disease

The study will provide insight into:

1. The influence of the baseline level of omega-3 PUFA in patients with type 2 diabetes mellitus (T2D) and CVD on endothelial function, platelet aggregation and thrombotic, inflammatory, oxidative stress biomarkers.
2. The potential to improve the endothelial function, reduce the oxidative stress and to decrease the atherothrombotic and inflammatory biomarkers with the supplementation with a moderate dose of omega-3 PUFA
3. The mechanisms of the clinically observed effects of omega-3 PUFA in T2D patients with CVD.

SCIENTIFIC BACKGROUND The incidence of diabetes is growing in the world and the number of patients already exceeded 360 million and by 2030 this will rise to 552 million. The major source of mortality and morbidity of diabetic patients is cardiovascular disease (CVD). On average, it is estimated that people with type 2 diabetes (T2D) will die 5-10 years before people without T2D, mostly due to CVD. The treatment of CVD accounts for a large part of the huge healthcare costs attributable to T2D (10-12% of European health care expenditure). Despite significant improvements in the treatment of CVD with antiplatelet agents, statin, angiotensin converting enzyme inhibitors (ACEI) and newer antidiabetic drugs the mortality of diabetic patients with CVD is continuously significantly higher than in people without T2D. This pattern of elevated cardiovascular risk in diabetes has been attributed to several possible mediating factors, including the development of more extensive, multi-vessel coronary artery disease, the presence of impaired myocardial systolic contractility, diffuse small vessel endothelial dysfunction and the presence of a hypercoagulable or pro-thrombotic state attributable to diabetes.

The increased cardiovascular risk in T2D patients is generated by the metabolic disturbances related to diabetes (both hyperglycaemia and hypoglycaemia) and that includes:

• irreversible glycation of intra- and extracellular proteins leading to changes in gene expression and induction of oxidative stress leading to endothelial dysfunction,
• activation of protein kinase C resulting in activation of blood coagulation,
• increase in the levels of various pro-atherothrombotic and inflammatory biomarkers e.g. markers of platelet activation, thrombin generation, endothelin, von Willebrand factor, adhesion molecules (eg.VCAM-1, vascular endothelial cell adhesion molecule), growth factors (VEGF), factor VII, CRP, IL-6 (interleukin-6). Moreover it was recently described that hyperglycemia in T2D leads to nonenzymatic glycation of fibrinogen. Glycated fibrinogen leads to denser fibrin clots that are stiffer and more resistant to fibrinolysis, thus leading to an increased thrombotic burden,
• altered secretion of adipokines by adipose tissue in obese subjects with T2D. It was demonstrated that greater adiposity e.g. down-regulates secretion of adiponectin, an adipokine with anti-inflammatory and insulin-sensitizing properties.