332-OR: Multiomic Profiling of Extended Honeymoon Unveils New Therapeutic Targets

Introduction & Objective: Approximately 50% of patients with new-onset Type 1 Diabetes (T1D) experience a temporary recovery in pancreatic β-cell function, termed the "honeymoon" (HM) phase, lasting approximately 7-9 months on average, and only rarely extending to years. This phase provides a crucial window for interventions to preserve insulin secretion, yet the factors contributing to its occurrence remain unclear. This study presents the first comprehensive multi-omic profiling of children with new-onset T1D in an extended honeymoon phase (ExMoon), revealing potential molecular targets for preserving β-cell mass and function. Methods: Patients in ExMoon were defined by insulin dose-adjusted HbA1c (IDAA1c) below 9 and C peptide >300 pmol/l, sustained for at least 9 months. We conducted analyses of PBMC immunophenotype, immunoreactivity to islet antigens, serum secretomics, proteomics/metabolomics/lipidomics, and PBMC transcriptomics using flow cytometry, ELISpot, immunomagnetic separation, mass spectrometry, and RNA sequencing, respectively. Profiles of ExMoon patients were compared to age- and gender-matched patients with T1D not in the HM phase (n=10 per group), with 10 matched nondiabetic patients included as additional controls. Results: Differential serum levels of immune factors (IP-10, IL-2, FGF2), proteins (TGM2, SIR4), metabolites (kynurenine), and lipids (myristic acid and monoarachidonic acid triglyceride 18:0_38:6) were observed in ExMoon compared to the T1D group. PBMCs obtained from patients of the two groups exhibited distinct expression patterns of ERAP2, TSKS mRNAs, and of miR-339-3p, miR-8087-3p miRNAs. No differences were found in the proportion of immune cell subpopulations and islet autoreactivity between the ExMoon and T1D patient cohorts. Conclusion: Our unbiased multiomic approach identified several immune and non-immune factors as potential molecular candidates for targeted therapies aimed at preserving β-cell mass and function. Disclosure C. Loretelli: None. A. Gouda Abdelrahman Abdelsalam: None. M. Ben Nasr: Research Support; Altheia Sciences. V. Usuelli: None. E. Assi: None. M. Zocchi: None. A. Petrazzuolo: None. A. Petitti: None. G. Cannalire: None. F. D'Addio: None. C. Mameli: None. P. Fiorina: None. Funding Fondazione "Romeo ed Enrica Invernizzi"