Evaluating immune activation and cellular determinants of thrombosis in pre-diabetes.
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Introduction Platelet dysregulation in pre-diabetes plays a major role in the progression of prothrombotic and pro-inflammatory conditions. Cardiovascular disease (CVD), which may occur at the pre-diabetic stage, are a common cause of morbidity in diabetic individuals. Despite treatment, people living with type 2 diabetes are at an increased risk of developing CVD, which is attributed to increased platelet activation and platelet mediated cellular cross-talks. The aim of the study was to investigate platelet activation and function in prediabetes and to further evaluate the effects of oral glucose lowering and anti-inflammatory therapy on platelet function a pre-diabetic state. Methodology Male mice were fed experimental diets, control low-fat diet (D12450J 10 kcal% fat) and a high-fat diet (HFD) (D12492, 60 kcal% fat) (Research Diets, NJ, USA). Platelet activation was determined by measuring the formation of spontaneous platelet-monocyte aggregate (PMA). The high-fat diet (HFD) fed mice were then randomized into 3 treatment groups; metformin (150mg/kg) and low-dose aspirin (3mg/kg) dual therapy; low-dose aspirin (3mg/kg); and clopidogrel (0.25mg/kg). The drugs were administered orally, once a day, every day for 3-weeks. We determined the pre-diabetic status of the mice by measuring their oral glucose tolerance and insulin levels. We further measured the haematological parameters. Platelet function and reactivity were determined by stimulating them with endogenous agonists, adenosine diphosphate (ADP), collagen and arachidonic acid, before and after treatment. Results Overall, there were no significant differences in the baseline characteristics such as body weights and insulin levels. However, after three weeks on the experimental diets, the high-fat diet (HFD) fed group exhibited delayed glucose clearance (p=0.0362). Baseline levels of platelet-monocyte aggregates were increased in the HFD group, p=0.0156. Post-stimulation with 4μM ADP and 20μM ADP, the HFD group expressed elevated levels of activated platelets, p<0.05. Metformin and low-dose aspirin-treatment inhibited reversible platelet aggregation, p=0.0220. While, residual platelet activation was observed at a concentration of 20μM ADP, p=0.0535. In the low-dose aspirin group, there were no significant variations in platelet reactivity following stimulation with ADP, p>0.05. Clopidogrel treatment inhibited the platelet response to 20μM ADP (p=0.0313). Conclusion Despite anti-platelet treatment in pre-diabetes, platelets exhibit a varied response to endogenous agonists. Therapeutic targeting of these pathways may reduce the risk of thrombotic complications in pre-diabetes. We further highlight the potential synergistic benefit of using dual oral glucose lowering and antiplatelet treatment to minimize the high on-treatment platelet responses observed in pre-diabetes and T2DM.