BA Bartolo Di

G Tornese

G Zauli

Gianluca Tornese

Giorgio Zauli

K Karavanaki

Liza Vecchi Brumatti

Lorenzo Monasta

P Secchiero

Paola Secchiero

Veronica Tisato

English

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SHORT COMMUNICATIONSerum TRAIL levels increase shortly after insulin therapyand metabolic stabilization in children with type 1 diabetesmellitusGianluca Tornese1 • Veronica Tisato2 • Lorenzo Monasta1 • Liza Vecchi Brumatti1 •Giorgio Zauli1 • Paola Secchiero2Received: 13 February 2015 / Accepted: 2 March 2015 / Published online: 12 April 2015 The Author(s) 2015. This article is published with open access at Springerlink.comKeywords TRAIL  Type 1 diabetes mellitus Ketoacidosis  Metabolic statusIntroductionTNF-related apoptosis-inducing ligand (TRAIL) is amember of the TNF superfamily, which plays an importantrole in regulating cell death and inflammation. Beyond itsanti-tumor activity, increasing evidence in animal studiessuggests that TRAIL plays a role in the control of au-toimmune diseases, and in particular in type 1 diabetesmellitus (T1DM) [1, 2]. In this context, in a previous studycarried out in a retrospective cohort of T1DM pediatricpatients, we found significant lower levels of circulatingTRAIL in T1DM patients with respect to healthy age-matched controls [3]. However, a limitation of our previousstudy was as follows: (1) the lack of serial serum samplesharvested from the same patients at different time postonset and (2) the lack of information about concurrentmetabolic status at time of blood sampling.On these bases, the aim of the present study was toanalyze the evolution of circulating TRAIL levels in a pilotgroup of pediatric patients admitted at EmergencyDepartment for T1DM, from the time of hospital admissionthroughout the re-establishment of a normal metabolicbalance and up to 18 months of clinical follow-up. More-over, the serum levels of TRAIL in T1DM patients wereanalyzed in relation to the metabolic status determined atthe same times.Materials and methodsPatients and sample collectionA total of 80 blood samples were obtained from 11 pe-diatric patients (Table 1) admitted for T1DM onset orsecondary diabetic ketoacidosis (DKA) at the EmergencyDepartment of the Institute for Maternal and Child Health‘‘Burlo Garofolo’’ of Trieste (Italy). For all patients, in-cluding patient 7, which was overweight ([85th centile)and had high non-fasting C-peptide levels, the presence ofdiabetes-associated autoantibodies together with the lackof signs of insulin resistance (i.e. acanthosis nigricans),reasonably excluded T2DM, as well as monogenic dia-betes. Blood samples were taken at admission and, in caseof DKA, serial blood samples were harvested as perprotocol until stabilization. Additional blood samples weretaken from each patient before hospital discharge andevery 3–6 months during the clinical follow-up. Parentsprovided informed consent to blood sample drawing forresearch purposes, in accordance with the Declaration ofHelsinki of 1975. The study was approved by theBioethics Committee of the IRCCS ‘‘Burlo Garofolo’’(Trieste, Italy; RC 18/13).Managed by Massimo Porta.& Giorgio Zauligiorgio.zauli@unife.itVeronica Tisatoveronica.tisato@unife.it1 Institute for Maternal and Child Health - IRCCS ‘‘BurloGarofolo’’, via dell’Istria, 65/1, 34137 Trieste, Italy2 Department of Morphology, Surgery and ExperimentalMedicine and LTTA Centre, University of Ferrara, Ferrara,Italy123Acta Diabetol (2015) 52:1003–1006DOI 10.1007/s00592-015-0731-2Laboratory analyses and TRAIL ELISA assaysBlood samples were collected into heparinized tubes. Allbiochemical laboratory tests were performed in Burloclinical laboratories by using standard commercial kits andfollowing manufacturers’ instructions. Patients demo-graphic characteristics, as well as laboratory/clinical dataand treatment, were retrieved from medical records. SerumTRAIL was measured on frozen serum aliquots by using acommercially available ELISA kit (R&D Systems, Min-neapolis, MN) following the manufacturer’s instructions,as previously described [3].Statistical analysisDifferences between values at two different time pointswere evaluated with a pairwise sign-rank Wilcoxon’s test.Correlation coefficients were calculated with the Spear-man’s rank coefficient rho. A p value\0.05 was consid-ered statistically significant, after applying a Bonferronicorrection if multiple rank-correlations were calculatedsimultaneously.ResultsThe main demographical and clinical characteristics ofthe pediatric patients enrolled in the present study aresummarized in Table 1. Comparative analysis of thecirculating TRAIL levels, showed median TRAIL level atadmission of 52.8 pg/ml (mean ± SD 57.2 ± 27.1 pg/ml), with the lowest levels measured in the patients withDKA. Of interest, in all patients included in the study, wedocumented a significant increase of TRAIL levels(p\ 0.01, using the sign-rank pairwise Wilcoxon test) atthe time of discharge, with a median value of 100.3 pg/ml(mean ± SD 109.8 ± 33.9 pg/ml) (Fig. 1a). Of interest, afurther significant (p\ 0.05) increase was documentedafter 6 months, reaching median values of TRAIL of147.3 pg/ml (mean ± SD 146.1 ± 37.1 pg/ml) that weremaintained without significant modulations also in thesubsequent time points/assessments up to 18 months(Fig. 1a).As for clinical protocol, in the patients with DKA(n = 6) upon admission between 5 and 10, blood sam-ples were taken for each subject before reaching nor-malization of venous blood gas (VBG) and/or bloodglucose (BG). This allowed us to monitor TRAIL levelsalso at the time points corresponding to metabolic sta-bilization (median time between admission and stabi-lization of 15.5 h; IQR 10.1–20.9). Analysis of TRAILlevels in relationship with all the clinical/metabolic pa-rameters reported in Table 1 revealed a significant(p\ 0.05) correlation only between TRAIL levels and:HCO3 (Spearman’s rank correlation, q = 0.4944,p = 0.0014; Fig. 1b), BE (q = 0.4405, p = 0.0044;Fig. 1b), pH (q = 0.368, p = 0.0193), pCO2(q = 0.3962 p = 0.0114).Table 1 Characteristics of the subjects included in the studyPatient Sex Age PubertalstatusBMI BMISDSAdmission DKAa BG pH HCO3 HbA1c C-peptideInsulinrequirement1 F 14.3 Post-pubertal 26.03 ?1.42 Secondary DKA Severe 753 6.96 6 8–64 N/A 0.652 M 13.7 In establishedpuberty20.20 -0.17 Secondary DKA Mild 291 7.26 14 9.6–81 N/A 0.603 M 8.6 Pre-pubertal 14.38 -0.62 New onset Moderate 302 7.12 13 13.3–122 0.26 0.704 M 12.2 In establishedpuberty14.76 -2.06 New onset Moderate 567 7.2 10 11.8–105 0.25 0.855 F 7.0 Pre-pubertal 18.94 ?0.98 New onset Moderate 343 7.18 11 12.2–110 0.35 0.946 F 5.8 Pre-pubertal 13.91 -1.38 New onset Mild 570 7.34 11.5 10.7–93 N/A 0.977 M 12.6 In establishedpuberty26.05 ?1.48 New onset None 398 7.45 25 8.6–70 2.56 0.208 F 11.6 In establishedpuberty16.22 -1.25 New onset None 593 7.56 24 11.3–100 0.67 0.759 F 16.8 Post-pubertal 16.10 -2.63 New onset None 394 7.44 25 8.3–67 0.59 0.5210 M 9.8 Pre-pubertal 14.85 -1.49 New onset None 270 7.32 17 12.0–108 0.21 0.7511 M 9.8 Pre-pubertal 16.74 -0.45 New onset None 367 7.41 24 9.7–83 0.37 0.31BMI body mass index (kg/m2), BMI SDS body mass index standard deviation score, BG blood glucose (mg/dl), HbA1c glycated hemoglobin(%—mmol/mol)HCO3 (mEq/l), C-peptide (ng/ml), Insulin requirement (U/kg/day)a DKA was defined: ‘‘mild’’, if pH was 7.2–7.3 and HCO3 10–15 mEq/l; ‘‘moderate’’, if pH was 7.1–7.2 and HCO3 5–10 mEq/l; ‘‘severe’’, if pHwas\7.1 and HCO3\ 5 mEq/l1004 Acta Diabetol (2015) 52:1003–1006123DiscussionIn both newly diagnosed T1DM and in secondary DKApediatric patients, we documented a significant increase ofserum TRAIL levels after short-standing insulin treatmenthas been established. Moreover, the circulating levels ofTRAIL correlated with the metabolic parameters. To ourknowledge, this is the first report demonstrating a rapidmodulation of circulating TRAIL during the first hoursafter T1DM onset and/or DKA and its relationship with themetabolic status, further supporting a link between TRAILand T1DM. In particular, even if carried out in a smallcohort, our pilot study can strongly suggest the link be-tween TRAIL and the metabolic status, because (1) a worstmetabolic status (documented by HCO3, BE, pH and CO2assessments) is associated with lower TRAIL levels, and(2) improvement in TRAIL levels is seen shortly uponmetabolic stabilization. A potential molecular mechanismthat links metabolic state and circulating levels of TRAILmight be represented by C reactive protein (CRP). Indeed,it has been shown that CRP is elevated in children withnewly diagnosed T1DM and DKA crisis and that it likelyenhances inflammation process by modulating a variety ofcytokines [4]. In particular, it has been reported that CRP isable to up-regulate pro-inflammatory cytokines IL-6, IL-8and TNF-a, and also to decrease IL-10 secretion. Likewise,we have previously documented that TRAIL expressionand release is down-regulated by CRP [5]. Although theFig. 1 Evolution of the circulating TRAIL levels in relation to theclinical/metabolic status of T1DM patients. a Circulating TRAILlevels were monitored in serum samples collected at the indicatedtime points of the clinical history of the T1DM pediatric patientsenrolled in the study (n = 11). Horizontal bars are median, upper andlower edges of box are 75th and 25th percentiles, lines extending frombox are 10th and 90th percentiles. *p\ 0.01 compared to admission;**p\ 0.05 compared to discharge. b Correlation analyses betweenTRAIL circulating levels and clinical parameters related to themetabolic status of patients. Positive correlation between TRAIL andbase excess (BE) as well as between TRAIL and bicarbonate (HCO3)are shown. Correlation coefficients, calculated by Spearman’sanalysis, are reported for each correlation in the textActa Diabetol (2015) 52:1003–1006 1005123mechanism underlining the down-regulation of TRAIL inT1DM should be further investigated, these findings sug-gest how the metabolic endangerment, rather than au-toimmunity, is clearly linked to the decrease in thecirculating levels of TRAIL.Acknowledgments This study was supported by a grant from Ital-ian Ministry of Health (Bando 2010 Giovani Ricercatori, code GR-2010-2310832).Conflict of interest The authors declare that they have no conflictof interest.Ethical standard All procedures were in accordance with theethical standards of the institutional and national research committeeand with the 1975 Helsinki declaration and its later amendments.Human and animal rights All procedures followed were in ac-cordance with the ethical standards of the responsible committee onhuman experimentation (institutional and national) and with theHelsinki Declaration of 1975, as revised in 2008.Informed consent Informed consent was obtained from all indi-vidual participants included in the study.Open Access This article is distributed under the terms of theCreative Commons Attribution License which permits any use,distribution, and reproduction in any medium, provided the originalauthor(s) and the source are credited.References1. Di Bartolo BA, Chan J, Bennett MR, Cartland S, Bao S, Tuch BE,Kavurma MM (2011) TNF-related apoptosis-inducing ligand(TRAIL) protects against diabetes and atherosclerosis in Apoe-/-mice. Diabetologia 54(12):3157–31672. Zauli G, Toffoli B, di Iasio MG, Celeghini C, Fabris B, SecchieroP (2010) Treatment with recombinant tumor necrosis factor-relatedapoptosis-inducing ligand alleviates the severity of streptozotocin-induced diabetes. Diabetes 59(5):1261–12653. Tornese G, Iafusco D, Monasta L, Agnoletto C, Tisato V, VenturaA, Zauli G, Secchiero P (2014) The levels of circulating TRAIL atthe onset of type 1 diabetes are markedly decreased in patientswith ketoacidosis and with the highest insulin requirement. ActaDiabetol 51(2):239–2464. Karavanaki K, Kakleas K, Georga S, Bartzeliotou A, MavropoulosG, Tsouvalas M, Vogiatzi A, Papassotiriou I, Karayianni C (2012)Plasma high sensitivity C-reactive protein and its relationship withcytokine levels in children with newly diagnosed type 1 diabetesand ketoacidosis. Clin Biochem 45(16–17):1383–13885. Secchiero P, Rimondi E, di Iasio MG, Agnoletto C, Melloni E,Volpi I, Zauli G (2013) C-reactive protein downregulates TRAILexpression in human peripheral monocytes via an Egr-1-dependentpathway. Clin Cancer Res 19(8):1949–19591006 Acta Diabetol (2015) 52:1003–1006123

Acta Diabetologica

Serum TRAIL levels increase shortly after insulin therapy and metabolic stabilization in children with type 1 diabetes mellitus

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Serum TRAIL levels increase shortly after insulin therapy and metabolic stabilization in children with type 1 diabetes mellitus

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