Study of OPG/RANKL/RANK axis in children and adolescents with type 1 diabetes mellitus

Type 1 diabetes (T1D) has been associated with a higher fracture risk due to alterations in bone structure and metabolism. On the other hand, the important role of the RANKL/OPG/RANK signaling axis in bone physiology is well established. The aim of this study was to evaluate the levels of receptor activator of nuclear factor kappa-B ligand (RANKL), receptor activator of nuclear factor kappa-B (RANK) and plasma osteoprotegerin (OPG) levels, in T1D youngsters and to investigate factors that could influence the OPG/RANK/RANKL signaling axis such as 25-hydroxy vitamin D [25(OH) D3], parathormone (PTH) and age. Serum RANKL, RANK, 25(OH) D3, PTH levels and plasma OPG levels, were measured in 71 youngsters with T1D and 50 healthy controls matched for age and gender. Plasma OPG levels were significantly lower (p=0.025) in T1D patients compared to controls. Serum RANKL levels were significantly higher (p=0.037), while no differences were observed in serum RANK levels (p=0.946) between the two groups. Serum 25(OH) D3 levels found significantly decreased (p<0.001) while serum PTH levels were significantly elevated (p<0.001) in T1D patients than in controls. Our results demonstrated that OPG and RANKL may be promising biomarkers for T1D patients. However, their circulating levels were associated with several factors including PTH, 25(OH) D3 and therefore, may represent an integrative biomarker for a variety of endocrine signaling disturbances observed in T1D.Ο σακχαρώδης διαβήτης τύπου 1 (T1D) έχει συσχετιστεί με υψηλότερο κίνδυνο κατάγματος εξαιτίας αλλοιώσεων στη δομή και στο μεταβολισμό των οστών. Από την άλλη πλευρά, ο σημαντικός ρόλος του άξονα σηματοδότησης RANKL / OPG / RANK στη φυσιολογία των οστών είναι καλά τεκμηριωμένος. Σκοπός αυτής της μελέτης ήταν η αξιολόγηση των επιπέδων του συνδέτη του υποδοχέα ενεργοποίησης του πυρηνικού παράγοντα kΒ (RANKL), του υποδοχέα ενεργοποίησης του πυρηνικού παράγοντα kΒ (RANK) και της οστεοπροτεγερίνης πλάσματος (OPG) σε νεαρούς ασθενείς με ΣΔ1 και η διερεύνηση παραγόντων που θα μπορούσαν να επηρεάσουν τον άξονα σηματοδότησης OPG / RANK / RANKL όπως, η 25-υδροξυ βιταμίνη D3 [25 (OH) D3], η παραθορμόνη (PTH) και η ηλικία. Τα επίπεδα RANKL, RANK, 25 (OH) D3, ΡΤΗ, στον ορό και τα επίπεδα OPG στο πλάσμα, μετρήθηκαν σε 71 νεαρούς ασθενείς με ΣΔ1 και 50 υγιείς ως ομάδα ελέγχου, της ίδιας ηλικίας και φύλου. Τα επίπεδα OPG του πλάσματος ήταν σημαντικά χαμηλότερα (p = 0,025) στους ασθενείς με ΣΔ1 σε σύγκριση με την ομάδα ελέγχου. Τα επίπεδα RANKL στον ορό ήταν σημαντικά υψηλότερα (p = 0,037), ενώ δεν παρατηρήθηκαν διαφορές στα επίπεδα RANK στον ορό (p = 0,946) μεταξύ των δύο ομάδων. Τα επίπεδα 25 (ΟΗ) D3 του ορού βρέθηκαν σημαντικά μειωμένα (p <0,001), ενώ τα επίπεδα της PTH στον ορό ήταν σημαντικά αυξημένα (p <0,001) στους ασθενείς με ΣΔ1 από ό,τι στην ομάδα ελέγχου. Τα αποτελέσματα μας έδειξαν ότι η OPG και ο RANKL μπορεί να είναι πολλά υποσχόμενοι βιοδείκτες για τους ασθενείς με ΣΔ1. Δεδομένου ότι τα επίπεδα κυκλοφορίας τους συσχετίστηκαν με διάφορους παράγοντες συμπεριλαμβανομένης της PTH και της 25 (OH) D3, πιθανό να αντιπροσωπεύουν ένα ολοκληρωμένο σύστημα βιοδεικτών, για ποικιλία ενδοκρινικών διαταραχών σηματοδότησης που παρατηρούνται στο ΣΔ1

Association of clinical, laboratory and imaging biomarkers with the occurrence of acute myocardial infarction in patients without standard modifiable risk factors – rationale and design of the “Beyond-SMuRFs Study”

Abstract Background Acute myocardial infarction (AMI) remains the leading cause of mortality worldwide. The majority of patients who suffer an AMI have a history of at least one of the standard modifiable risk factors (SMuRFs): smoking, hypertension, dyslipidemia, and diabetes mellitus. However, emerging scientific evidence recognizes a clinically significant and increasing proportion of patients presenting with AMI without any SMuRF (SMuRF-less patients). To date, there are no adequate data to define specific risk factors or biomarkers associated with the development of AMIs in these patients. Methods The ‘‘Beyond-SMuRFs Study’’ is a prospective, non-interventional cohort trial designed to enroll patients with AMI and no previous coronary intervention history, who undergo coronary angiography in two academic hospitals in Thessaloniki, Greece. The rationale of the study is to investigate potential relations between SMuRF-less AMIs and the clinical, laboratory and imaging profile of patients, by comparing parameters between patients with and without SMuRFs. Complete demographic and comprehensive clinical data will be recorded, Venous blood samples will be collected before coronary angiography and the following parameters will be measured: total blood count, standard biochemistry parameters, coagulation tests, hormone levels, glycosylated hemoglobin, N- terminal pro-B-type natriuretic peptide and high-sensitivity troponin T levels- as well as serum levels of novel atherosclerosis indicators and pro-inflammatory biomarkers. Furthermore, all participants will undergo a complete and comprehensive transthoracic echocardiographic assessment according to a pre-specified protocol within 24 h from admission. Among others, 2D-speckle-tracking echocardiographic analysis of cardiac chambers and non-invasive calculation of myocardial work indices for the left ventricle will be performed. Moreover, all patients will be assessed for angiographic parameters and the complexity of coronary artery disease using the SYNTAX score. Multivariable linear and logistic regression models will be used to phenotypically characterize SMuRF-less patients and investigate independent clinical, laboratory, echocardiographic and angiographic biomarkers-predictors of SMuRF-less status in AMI.The first patient was enrolled in March 2022 and completion of enrollment is expected until December 2023. Discussion The ‘‘Beyond-SmuRFs’’ study is an ongoing prospective trial aiming to investigate potential clinical, laboratory and imaging biomarkers associated with the occurrence of AMIs in SMuRF-less patients. The configuration of these patients’ profiles could lead to the development of personalized risk-stratification models predicting the occurrence of cardiovascular events in SΜuRF-less individuals. Trial Registration ClinicalTrials.gov Identifier: NCT05535582 / September 10, 2022