Circulating osteoprotegerin (OPG) promotes bone formation in vivo and correlates with the presence of type 2 diabetes, severity of vascular calcification and coronary artery disease. Obesity is a risk factor for diabetes and cardiovascular disease but little is known about the impact of body weight on circulating OPG. The purpose of these experiments was to evaluate the impact of body mass index, vascular dysfunction and insulin sensitivity on circulating concentrations of OPG. This thesis investigated; (i) The effect of obesity and insulin sensitivity on circulating OPG levels; (ii) The effect of type 2 diabetes and vascular dysfunction on OPG levels; (iii) The influence of glycaemic status on circulating OPG concentrations. Briefly, our findings were as follows (i) obese subjects who have normal glucose tolerance and are free from cardiovascular disease have lower circulating levels of OPG than their lean age matched counterparts. (ii) Osteoprotegerin is inversely correlated with insulin sensitivity, adiponectin and indicators of total body and visceral adiposity and positively correlated with aerobic fitness. (iii) TNF receptor apoptosis inducing ligand (TRAIL) is positively correlated with both fat mass and waist circumference, independent of age, gender and BMI. (iv) OPG is significantly higher as is IL-6 and hsCRP and adiponectin significantly lower in type 2 diabetics than in age and gender matched normoglycemic controls, while there is no difference in TNF-α, TRAIL or sRANKL concentrations. (v) Osteoprotegerin is higher in type 2 diabetics after excluding patients with previously diagnosed vascular disease, a distinction which could not be made using traditional inflammatory markers such as IL-6, hsCRP or TNF-α. (vi). There is no difference in OPG concentrations between those with prediabetes and overt type 2 diabetes, however both conditions appear to have significantly higher levels than age and BMI matched obese normoglycemic controls. (Sipos et al., 2008) Lean subjects have OPG concentrations which are similar to that of both prediabetic and type 2 diabetic patients but significantly higher than their matched lean counterparts. Circulating OPG is lower in obese, but otherwise healthy subjects, and correlates with indices of insulin sensitivity. OPG (but not RANKL or TRAIL) was found to be elevated in type 2 diabetes. OPG may have a protective effect on vascular cells and the observed decrease in circulating concentrations with increasing BMI could be an early biomarker of vascular dysfunction. It remains to be determined whether an increase in insulin secretion, insulin resistance, adiposity or systemic inflammation is the main regulatory factor.