Characterisation of platelet function and pro-inflammatory phenotype in type 1 diabetes mellitus and double diabetes

Patients with diabetes mellitus (DM) have an increased and premature risk of cardiovascular disease. Platelet-driven pathology has been implicated in the multifactorial and complex vascular abnormalities, yet this appears to be only partly studied, particularly in patients with type 1 diabetes mellitus (T1D). T1D has long been considered a more homogenous cohort than T2D but with an ever-growing obesity epidemic, there is an emerging group of T1D individuals displaying insulin resistance, often described as having double diabetes. Early evidence supports even greater risk of poor cardiovascular outcomes in this subgroup. This thesis has thoroughly investigated the functional and bioenergetic phenotype of platelets in young adults with T1D. Crucially, this little studied cohort was chosen to eliminate confounders such as pre-existing co-morbidities and perhaps more crucially interfering concomitant medications. In addition to the role of glycaemia, the effects of insulin resistance on platelet function was assessed to explore how patients with double diabetes may be impacted. Results indicate that even in young adults with T1D there is evidence of hyperreactive platelets with diminished sensitivity to inhibition by prostacyclin (PGI2). Moreover, this appears exacerbated by sub-optimal short- and medium-term glycaemic control with insulin resistance further adding to the adverse platelet profile. Contributing mechanisms were also explored through the assessment of platelet bioenergetic and metabolic profiles. My data strongly suggest a metabolic rewiring process in platelets from patients with T1D, characterised by reduced glycolysis and increased mitochondrial respiration which may be driven, at least in part, by a shift from glucose usage towards fatty acids. Together these data suggest that the disease environment leads to metabolic reprogramming of platelets that could be a causal factor in platelet hyperreactivity in individuals with diabetes. Further studies are required to determine the precise molecular mechanisms and whether targeting of platelet energy metabolism could be a novel therapy that mitigates thrombotic risk in these patients.