Vascular adhesion protein-1 (VAP-1) is one of the molecules on the endothelial cell membrane, which may guide inflammatory cells into atherosclerotic lesions. This dual function molecule may also contribute to the pathogenesis of
atherosclerosis and other vasculopathies via its enzymatic activity that oxidizes primary
amines to produce their corresponding
aldehydes,
hydrogen peroxide, and
ammonium. Because VAP-1 also exists in a soluble form, we analyzed its potential usefulness as a
biomarker to monitor and predict the extent of ongoing atherosclerotic processes. Soluble VAP-1 (sVAP-1) levels were determined from the sera of 136 Finnish men with established
coronary heart disease and in 275 controls using sandwich
enzyme immunoassays and correlated to multiple risk factors for coronary events. Intriguingly, sVAP-1 showed a statistically significant correlation with diabetes in both cohorts. We then collected patients with
type 1 diabetes and observed that sVAP-1 levels were highly elevated when the patients were metabolically compromised. On normalization of their
blood glucose and
ketone body levels by exogenous
insulin, their sVAP-1 concentration rapidly decreased to control levels. Intravenous
glucose tolerance and hyperinsulinemic clamp tests further showed that elevation of
blood glucose per se did not increase sVAP-1 levels, but rather, sVAP-1 was inversely correlated with circulating
insulin concentrations. In conclusion
insulin appears to regulate shedding or clearance of VAP-1, and an increase in sVAP-1 because of absolute or relative
insulin deficiency may be directly involved in the pathogenesis of
diabetic angiopathy.