Type 2 Diabetes: An Atherothrombotic Syndrome

Abstract

Insulin resistance is found in around 80-90% of subjects with older onset (type 2) diabetes and in approximately 25% of the general population. Insulin resistance prior to the development of frank type 2 diabetes and type 2 diabetes itself is associated with a significant increase in the risk of atherothrombotic disease, which is due in part to a disruption in the balance of factors regulating coagulation and fibrinolysis. Both insulin resistance and type 2 diabetes are associated with the development of endothelial dysfunction, and enhanced platelet aggregation and activation. Whilst the plasma levels of many clotting factors including fibrinogen, FVII, FVIII, FXII, FXIII b-subunit are elevated, the fibrinolytic system is relatively inhibited as a consequence of an increase in plasminogen activator inhibitor type-1 (PAI-1) levels. These changes favour the development of a hypercoagulable pro-thrombotic state, which may in turn enhance cardiovascular risk by increasing the likelihood of developing an occlusive thrombus within a coronary/cerebral artery, and/or contributing to the development of atherosclerotic lesions. This article reviews the current published evidence of the pro-thrombotic changes that occur in association with type 2 diabetes and insulin resistance, and the putative underlying mechanisms which lead to these changes.

Hypoglycaemia, thrombosis and vascular events in diabetes

“…Mechanisms for increased thrombosis risk include increased platelet activation as well as quantitative and qualitative changes in coagulation proteins such as plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and plasminogen generating a denser fibrin clots that are resistant to fibrinolysis [22][23][24][25][26]. Similar adverse changes have been noted during experimental hypoglycemia, and thus, acute hypoglycemia may be an equivalent atherothrombotic risk factor to chronic hyperglycemia as discussed later.…”

Does the oxidation of methionine in thrombomodulin contribute to the hypercoaguable state of smokers and diabetics?

“…Diabetics are equally well known to have an elevated risk of thrombosis [3][4][5]133,134] and cardiovascular disease [135]. The molecular causes are by no means fully understood.…”

“…We present here a hypothesis for the molecular root of this hypercoagulability. Further, we believe that this hypothesis is equally plausible for explaining the molecular origin of a similar prothrombotic state [3][4][5] and increased cardiovascular risk in diabetics and may also explain, in part, why elevated levels of homocysteine are a risk factor for heart disease.…”

Diabetes Mellitus and Cardiovascular Complications: Focus on Hemostasis

“…В некоторых иссле-дованиях активность фибринолиза при СД описыва-ется повышенной или неизмененной. Большинство же работ свидетельствует о снижении фибринолитиче-ского потенциала при СД [24,29]. Угнетение фибрино-лиза является следствием гликозилирования плазмино-гена, снижающим его чувствительность к профибрино-литическим ферментам с формированием устойчивости к деградации.…”

“…Изменение показателей свертывания крови при СД выявляется на всех этапах коагуляционного каскада и характеризуется повышением концентрации ткане-вого фактора, протромбиновых фрагментов, фибрино-гена, фактора Виллебранда, VII, VIII, IX, XI, XII факто-ров свертывания, активацией калликреин-кининовой системы [19,24].…”