Role of TRAIL (TNF-Related Apoptosis-Inducing Ligand) in the onset and progression of type 1 diabetes mellitus

Experimental evidence in animal models suggests that TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, might play an important role in type 1 diabetes (T1D). No studies had fully evaluated TRAIL levels in children affected by T1D. Study I – What happens to TRAIL levels in children with T1D? Retrospective study on 507 pediatric subjects consisting of patients diagnosed with T1D at onset (n = 167) or at later time points after diagnosis (n = 220), healthy individuals (n = 98, considered as controls), and healthy subjects positive to autoantibodies against β-cells (n = 22). Study II – What happens to TRAIL levels at T1D onset and/or during diabetic ketoacidosis (DKA)? And what thereafter? Prospective study on a cohort of 11 pediatric subjects admitted for T1D onset or secondary DKA at the Emergency Department. A total of 80 blood samples were collected at admission (serial samples until stabilization), before hospital discharge and every 6 months during the clinical follow-up up to 18 months. Study III – What happens to TRAIL levels in long-standing T1D? Are TRAIL levels correlated with markers of residual β-cell mass, inflammation or autoimmunity? Retrospective cohort study on 232 young people with long-standing T1D (median 5.5 years); 219 patients had 2 available stored non-fasting serum samples collected (median time interval between visits 1.2 years), with a total of 451 samples available. Conclusions 1. TRAIL in type 1 diabetes - TRAIL levels are significantly reduced in children with T1D compared to unaffected individuals - a significant seasonal pattern of TRAIL was observed (with the lower levels during summer and higher during spring) which may have some impact on the seasonal variation in the initial presentation of T1D 2. TRAIL and autoimmunity - there are no differences in TRAIL levels between healthy subjects positive to autoantibodies against β-cells and controls - there are no differences in TRAIL levels between T1D patients with and without islet-specific autoantibodies - there are no differences in TRAIL levels between T1D patients with or without other concomitant autoimmune diseases - TRAIL levels are associated with sCD25 (IL-2RA), a known biomarker for immune activation, in long-standing T1D, both as single values and as changes over time 3. TRAIL at the onset of type 1 diabetes - the lowest levels of TRAIL are observed in patients at the onset of disease - among T1D patients at onset, the lowest levels of TRAIL are observed in patients with DKA - a worst metabolic status (documented by HCO3, BE, pH and CO2) is associated with lower TRAIL levels - TRAIL levels increase rapidly after short-standing insulin treatment has been established during the first hours after T1D onset and/or DKA - there is no association between TRAIL and C-peptide or A1c or insulin daily requirement at T1D onset 4. TRAIL in long-lasting type 1 diabetes - reduction in TRAIL levels with respect to healthy controls persisted also in patients analyzed >1 year from diagnosis - TRAIL levels significantly increase from hospital discharge to the 6-month follow-up, and then maintain without significant modulations up to 18 months after onset - the levels of TRAIL negatively correlate with the insulin requirement up to 21 months of follow-up - TRAIL levels decrease with T1D duration in long-standing disease - there is no association between TRAIL and C-peptide or CRP in long-lasting T1D