Urine -Glutathione S-Transferase, Systemic Inflammation and Arterial Function in Juvenile Type1 Diabetes Running head: Proximal tubular function and arterial function in juvenile diabetes Authors and affiliation:

Background: Despite marked improvement in therapy and monitoring of patients with insulindependent (type1) diabetes, diabetic nephropathy remains a serious complication, with subsequent endstage renal disease in about 20% of cases. Objective: To investigate in young patients with type1 diabetes whether urine -Glutathione Stransferase to creatinine ratio (-GST:crea) relates to markers of systemic inflammation and subclinical vasculopathy. Design: Children and adolescents (median age and diabetes duration 14 and 6 years, respectively) with type 1 diabetes screened in a previous study for proximal tubular (urine -GST:crea ratio) and renal (plasma creatinine, cystatin C glomerular filtration rate (GFR), timed urine albumin excretion rate (AER)) function were, within the same timeframe, also investigated for vascular (blood pressure, carotid artery intima-media thickness (IMT) and compliance (CAC), brachial flow-mediated dilatation (FMD) and plasma cyclic guanosine monophosphate (cGMP) and inflammatory (C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-)) profiles. Exposure to environmental tobacco smoke (ETS) was assessed through questionnaire (n=67 respondents). Results: None of the patients (n=69) had overt renal insufficiency. AER correlated with age (p=0.01, r=0.3), diabetes duration (p=0.02, r=0.3), FMD (p=0.04, r=-0.3, n=52), CAC (p=0.03, r=-0.3, n=62) and cGMP (p=0.01, r=-0.3, n=59). -GST:crea was lower (p=0.03) in patients than in controls. GST:crea appeared to be particularly lower in older patients (p=0.004, r=-0.34 vs age), in those with worse diabetic control (p=0.03, r=-0.26 vs HbA1c), and in those with lower carotid artery elasticity (p=0.017, r=0.3 vs CAC). Although ETS had no direct significant impact on -GST:crea, -GST:crea correlated with FMD only in patients with ETS (r=0.5, p=0.009, n=13). Instead, -GST:crea showed positive association with TNF- (p=0.01, r=0.3).