Pathophysiology of Platelet Resistance to Anti-Aggregating Agents in Insulin Resistance and Type 2 Diabetes: Implications for Anti-Aggregating Therapy

Abstract

The insulin resistance syndrome, which presents among its many facets obesity and type 2 diabetes mellitus, is a major risk factor for cardiovascular events. Thus, therapeutic guidelines recommend multifactorial treatment programs including, especially in the presence of type 2 diabetes, antiplatelet drugs. Few data, however, are available about the protective effect of antiplatelet therapy in both obese and type 2 diabetic patients. Furthermore, some reports showed a decreased sensitivity to the platelet antiaggregating effect of acetylsalicylic acid in diabetic patients. In the first part of this review, we focused our attention to alterations of platelets from insulin resistant subjects with or without type 2 diabetes, underlining that platelet hyperactivation is explained, at least in part, by: i) a reduced sensitivity to agents exerting an inhibitory modulation of platelet responses, ii) an altered intracellular milieu with elevated cytosolic Ca2+, iii) an enhanced thromboxane A2 synthesis, and iv) an increased number and/or function of GPIIb/IIIa complexes on platelet membranes. Furthermore, oxidative stress, which increases isoprostane production from arachidonic acid, may be involved in platelet hyperactivation, since isoprostanes activate platelets by interplaying with thromboxane receptors. These defects explain why antiplatelet therapy for both chronic atherosclerotic vascular disease and acute coronary syndromes should be specifically tailored in obese, insulin resistant subjects, especially in the presence of type 2 diabetes mellitus. Thus, in the second part of this review we carried out a critical overview of the clinical trials in subjects with metabolic syndrome and type 2 diabetes mellitus with or without macroangiopathy.

Atherothrombotic disease and the metabolic syndrome

“…In vitro and in vivo studies have demonstrated that in obese individuals and in obese type 2 diabetics the antiaggregating effect of insulin is blunted, consistent with the finding that human platelets, which have insulin receptors that modulate platelet function, are sites of insulin resistance [22].…”

“…Resistance to the metabolic and vascular actions of insulin [22] leads to a chronic proinflammatory state, an increased oxidative stress with augmented ROS generation, a procoagulant/anti-fibrinolytic state, coupled with platelet hyperaggregability. In this regard, we demonstrated a significant association between insulin resistance and markers of inflammation and thrombin generation.…”

Predictors of Biochemical Aspirin and Clopidogrel Resistance in Patients With Ischemic Stroke

“…This may be explained in part by an increased platelet turnover and thus a less effective inhibition of COX-1 in platelets by aspirin. Diabetes mellitus, [16][17][18] hyperlipidemia, 19 and heart failure were previously found to be associated with increased prevalene of aspirin resistance. The aspirin resistance was considered to be related to increased lipid peroxidation of arachidonic acid and overproduction of isoprostanes.…”

Clinical importance of aspirin and clopidogrel resistance

“…Antiplatelet resistance and up-regulation of the COX-2 enzyme coupled with increased levels of F2-isoprostanes may lead to uncontrolled thromboxane synthesis. Such COX-1-independent mechanisms are especially relevant to patients with diabetes mellitus, hyperlipidemia, smoking and heart failure; all of which are associated with augmented lipid peroxidation of arachidonic acid and consequent overproduction of isoprostanes [38,[42][43][44][45][46][47][48][49] (Figure 3). In our recent work, 599 patients with chronic cardioand cerebrovascular diseases (355 men, mean age 64 ± 11 years; 244 women, mean age 63 ± 10 years) who were taking aspirin 100-325 mg/d were examined [28] .…”