High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria.

ABSTRACT

OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) plays an important role in glucose metabolism and renal function. However, the relationship between ACE2 and hyperglycemia or microalbuminuria has not been established in humans. We investigated whether urinary ACE2 levels are associated with abnormal glucose homeostasis and urinary albumin excretion. METHODS: We developed an ELISA for quantifying ACE2 in urine. The ELISA was used to measure urinary ACE2 levels in 621 subjects with normal glucose tolerance (NGT; n=77); impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (n=132); and type 2 diabetes mellitus (T2DM, n=412). Insulin resistance was assessed by homeostasis model assessment for insulin resistance (HOMA-IR) index and urinary albumin excretion by urine albumin-to-creatinine ratio (ACR). Other biochemical and anthropometric parameters were measured. RESULTS: Urinary ACE2 levels were significantly higher in insulin-resistant subjects with IFG, IGT, and T2DM than in the NGT group (P<0.001). Urinary ACE2 concentrations appeared to correlate with HOMA-IR, fasting blood glucose, triglyceride, high-sensitivity C-reactive protein, serum creatinine, urinary ACR, and systolic blood pressure (all P<0.05). After adjustment for impaired renal function and other metabolic parameters, urinary ACE2 concentration was still associated with a higher risk for T2DM (OR 1.80, 95% CI 1.05-3.08, P=0.02). In addition, urinary ACE2 levels were highly predictive of microalbuminuria after adjusting for clinical risk factors (OR 2.68, 95% CI 1.55-4.64, P<0.001). CONCLUSION: Our data suggest that the urinary ACE2 level is closely associated with T2DM and is an independent risk factor for microalbuminuria.