%0 Journal Article
%T Exacerbation of Glycoprotein VI-Dependent Platelet Responses in a Rhesus Monkey Model of Type 1 Diabetes
%A J. F. Arthur
%A Y. Shen
%A Y. Chen
%A J. Qiao
%A R. Ni
%A Y. Lu
%A R. K. Andrews
%A E. E. Gardiner
%A J. Cheng
%J Journal of Diabetes Research
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/370212
%X Thrombosis is a life-threatening complication of diabetes. Platelet reactivity is crucial to thrombus formation, particularly in arterial vessels and in thrombotic complications causing myocardial infarction or ischaemic stroke, but diabetic patients often respond poorly to current antiplatelet medication. In this study, we used a nonhuman primate model of Type 1 diabetes to measure early downstream signalling events following engagement of the major platelet collagen receptor, glycoprotein (GP)VI. Diabetic monkeys were given enough insulin to maintain their blood glucose levels either at ~8£żmM (well-controlled diabetes) or ~15£żmM (poorly controlled diabetes). Flow cytometric analysis was used to measure platelet reactive oxygen species (ROS) generation, calcium mobilisation, receptor surface expression, and immature platelet fraction. We observed exacerbated intracellular ROS and calcium flux associated with engagement of GPVI in monkeys with poorly controlled diabetes. GPVI surface levels did not differ between healthy monkeys or the two diabetic groups. Treatment of platelets with the specific Syk inhibitor BAY61-3606 inhibited GPVI-dependent ROS and, importantly, reduced ROS generation in the poorly controlled diabetes group to that observed in healthy monkeys. These data indicate that glycaemic control is important in reducing GPVI-dependent platelet hyperreactivity and point to a potential antithrombotic therapeutic benefit of Syk inhibition in hyperglycaemic diabetes. 1. Introduction Type 2 diabetes occurs when individuals with an underlying genetic disposition develop resistance to the glucose uptake/metabolism-promoting signals of insulin. Type 1 diabetes, which accounts for 5%¨C10% of all diabetes cases, generally results from autoimmune destruction of insulin-secreting pancreatic islet cells [1]. One of the high risk complications of diabetes is thrombosis, and platelets are pivotal to thrombus formation, particularly in arterial vessels, and hence the resultant thrombotic complications of myocardial infarction or ischaemic stroke. Platelets from individuals with diabetes, particularly Type 2 diabetes, are more sensitive to aggregation by a variety of agonists [2, 3], and 80% of diabetic patients are likely to die from thrombotic complications [4]. Considerably less is known about platelet activation in Type 1 diabetes, although the relative risk of cardiovascular disease in Type 1 diabetic patients can be as much as 10-fold greater than that in nondiabetic individuals [1]. However, the reduction of thrombotic events in diabetic patients has
%U http://www.hindawi.com/journals/jdr/2013/370212/