Aims/hypothesis
Youth with type 2 diabetes (T2D) have high rates of obesity, hypertension and suboptimal glycemic control. We hypothesized that renin-angiotensin system (RAS) activation is present in youth with T2D and associated with poor glycemic control and renal outcomes.

Methods
Cross-sectional analysis of 183 youth with T2D and 100 controls from the Improving renal Complications in Adolescents with T2D through REsearch cohort. Diabetes youth stratified by urine albumin:creatinine ratio (ACR) < or ≥2 mg/mmol. RAS levels measured with enzyme-linked immunosorbent assay (ELISA) and enzyme activities by synthetic substrates. In T2D, levels log transformed and Tobit linear regressions evaluated for associations with hemoglobin A1c (HbA1c), mean arterial pressure (MAP), estimated glomerular filtration rate (eGFR), ACR.

Results
Youth were 14 to 15 years, with diabetes duration 1.7 to 1.8 years; 21.3% albuminuria. Serum: differences in plasma renin activity (<0.0001), and angiotensin converting enzyme (ACE) activity (P = .003) in T2D vs controls. Urine: higher ACE activity and ACE2 protein/activity (all P < .0001) in T2D, higher levels in T2D with albuminuria. Multivariable regressions: higher serum ACE activity (ß = 0.03, SE 0.01;P < .01), urine ACE activity (ß = 0.44, SE 0.18;P < .01), ACE2 (ß = 0.51, SE 0.19;P < .01) positively associated with HbA1c; urine angiotensinogen (AGT) negatively associated (ß = -0.28 [SE 0.06;P < .01]). Higher serum aldosterone (ß = 0.11 [SE 0.04;P < .01]) and urine AGT (ß = 0.32 [SE 0.07;P < .01]) significantly associated with ACR and urine ACE2 (ß = 0.21 [SE 0.13;P < .03]). No associations between RAS markers and eGFR/MAP.

Conclusions/interpretation
RAS activation present in youth with T2D and associated with higher HbA1c. Higher serum aldosterone and urine AGT associated with albuminuria. The prognostic significance of the combined effect of glycemia and RAS activation on renal outcomes requires additional investigation.

Dart AB, Wicklow B, Scholey J, Sellers EA, Dyck J, Mahmud F, Sochett E, Hamilton J, Blydt-Hansen T, Burns K

Pediatric Diabetes

Published 2019

Research Project: iCARE