University of Hull PhD Scholarship: Understanding the role of glucose variability

Increased cardiovascular disease is the main cause of death in patients with type 2 diabetes. Obesity and diabetes are associated with insulin resistance (IR) and a hypercoagulable state, both of which play a role in the pathogenesis of atherothrombosis. Blood platelets play a privotal role in the atherthrombotic process by promoting vascular inflammation and thrombotic occlusion of key blood vessels.

The mechanism linking IR to thrombosis are unclear, but is thought to involve progressive platelet hyperactivity. We hypothesise that dysglycaemia associated with poor glycaemic controils induces platelet hyperactivity. Insulin treatment of patients with diabetes is associated with dysglycaemia, and particularly with hyperglycaemia and hypoglycaemia variability.

While chronic states of hyper or hypoglycaemia per se have a moderate effect on platelet activation through a degree of adaptation, we believe that rapid glucose variability such as from hyper to hypoglycaemia and often found in poorly controlled diabetic subjects may have a more profound effects on platelets leading to accumulative effects.

In this this project we will examine the effect of glucose variability on platelet function and thrombosis. Using hyperinsulinaemic euglycaemic clamp established in our laboratory we will simulate rapid changes in blood glucose levels in both type 2 diabetes and control subjects. We will examine (i) how rapid changes in glycaemic index alter platelet sensitivity to activators and inhibitors in whole blood, (ii) whether the platelet hyperactivity is due to a primary platelet defect or a change in the plasma environment, and (iii) examine the role of specific ligands in mediating hyperactivity. These data will provide novel information on the potential role of glucose variability in the pathobiology of diabetes.

This studentship provides an excellent opportunity to receive training in both clinical simulation of dysglycaemia, basic cell and molecular biology techniques (immunoblotting/, flow cytometry, fluorescence/confocal microscopy, platelet functional assays).

Location

The academic work will be based in HYMS Centre for Cardiovascular and Metabolic Research at the University of Hull campus.

Research Culture

The student will join a research team that utilises multidisciplinary approaches to identify new mechanisms regulating platelet function and determine if these newly identified mechanisms can be targets for prevention and treatment of arterial thrombosis associated with metabolic and cardiovascular diseases.