This thesis evaluates the potential of fasting pancreatic polypeptide (PP) as a biomarker of microvascular and macrovascular complications of diabetes mellitus. The prevalence of type 2 diabetes (T2DM) has already reached epidemic levels in most developed nations. Early identification of these vascular complications is essential to inform both individualised treatment strategies and effective national healthcare planning.
PP is a peptide hormone, synthesised by cells within the pancreas. Uniquely, these cells release PP in response to stimulation by branches of the vagus nerve, and hence PP is a marker of vagal tone. Fasting PP is elevated in people with T2DM and has been linked to perturbations of body fat distribution thought to increase vascular risk.
My research demonstrates that fasting PP is significantly higher in individuals with T2DM than either prediabetes or NGT, suggesting an association with microvascular risk, and shows significant and independent associations between elevated fasting PP and both prevalent diabetes-associated eye and kidney disease and incident progression of diabetic eye disease. Fasting PP was significantly associated with prevalent macrovascular complications of diabetes. In a mouse model of obesity and diabetes, the serum level of PP produced by continuous infusion of human PP over four weeks was significantly correlated with the intra-ocular concentration of Vascular Endothelial Growth Factor (VEGF), an angiogenic protein involved in the pathogenesis of diabetic retinal vascular disease, and with the weight of adipose tissue deposits. These associations were not present in untreated mice, suggesting that, consistent with the human studies, persistent elevation of baseline PP may be responsible.
This thesis adds to the body of evidence suggesting that elevation of fasting PP is associated with both microvascular and macrovascular risk in T2DM. Population studies with a longer duration of follow up, and animal studies with a longer duration of PP infusion, are now indicated.