Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications

Objective: Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that counterbalances the actions of angiotensin (AT)II and promotes vasodilatation. Circulating ACE2 activity is increased in diabetes in experimental models. The role of ACE2 in human pathophysiology is unknown. We examined whether ACE2 activity is altered in patients with type 1 diabetes (T1D), with and without diabetic nephropathy. Methods: Quantitative ACE2 activity in serum was measured by a fluorometric assay in 859 patients with T1D in the Finnish Diabetic Nephropathy (FinnDiane) study and in 204 healthy controls. Pulse-wave analysis with augmentation index (AIx) measurement was performed in 319 patients with T1D and 114 controls. Results: ACE2 activity was increased in men with T1D and microalbuminuria (30.2 (+/-) 1.5 ngE/ml) when compared to patients without albuminuria (27.0 +/- 0.5 ngE/ml, P < 0.05) or controls (25.6 +/- 0.8 ngE/ml, P < 0.05). ACE2 activity was increased in male and female patients who were on ACE inhibitor (ACEi) treatment, also independently of albuminuria. Male and female patients with coronary heart disease (CHD) had significantly increased ACE2 activity (35.5 +/- 2.5 vs. 27.0 +/- 0.5 ngE/ml, P < 0.001 among male T1D patients vs. male controls). ACE2 activity correlated positively with systolic blood pressure (r(s) = 0.175, P < 0.001), AIx (r(s) = 0.191, P = 0.010) and diabetes duration (r(s) = 0.198, P < 0.001), and negatively with estimated glomerular filtration rate (r(s) = -0.109, P = 0.016) among male T1D patients. Conclusions: ACE2 activity increases with increasing vascular tone and when the patient with T1D has microvascular or macrovascular disease, indicating that ACE2 may participate as a compensatory mechanism in the regulation of vascular and renal function in patients with T1D.