Endocrine Abstracts

JOINT554

GoalLatent Autoimmune Diabetes in Adults (LADA) exhibits a hybrid autoimmune-metabolic phenotype, sharing features of both type 1 and type 2 diabetes. However, the molecular mechanisms underlying its slower β-cell decline remain poorly characterized. We aimed to clarify the role of two key immune signaling pathways, JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) and TRAIL (TNF-Related Apoptosis-Inducing Ligand), in shaping the autoimmune landscape of LADA compared to classic type 1 diabetes mellitus (T1DM).

Methods: Peripheral blood mononuclear cells (PBMCs) were collected from 15 individuals with LADA, 21 with T1DM, and 22 healthy controls. Single-cell RNA sequencing (10x Genomics platform) provided 5’single-cell transcriptomic profiling (scRNA-seq) of immune subsets (T-cells, B-cells, NK-cells, and monocytes). After quality control and batch-correction, pathway-centric analyses (PROGENy-based scoring) assessed relative JAK/STAT and TRAIL pathway activities across these groups, focusing on T- and NK-cell subpopulations.

Results: In T1DM, JAK/STAT showed robust hyperactivation across CD4+ and CD8+ T-cell subsets, often reaching 10- to 20-fold higher scores than in healthy controls. Concomitantly, TRAIL activity was markedly reduced 2- to 5-fold, suggesting a diminished apoptotic checkpoint against hyperreactive lymphocytes. This imbalance likely contributes to the rapid β-cell destruction typically observed in T1DM. LADA, however, demonstrated more moderate JAK/STAT activity 2- to 6-fold, consistently lower than T1DM but slightly above healthy levels. Notably, TRAIL signaling scores were significantly elevated in LADA 2- to 3-fold compared with T1DM. This pattern implies that, while JAK/STAT-driven inflammation persists, enhanced TRAIL-mediated apoptosis selectively eliminates the most aggressive immune clones. Hence, LADA appears to adopt an attenuated autoimmune response that slows β-cell decline. NK-cells (CD56dim) mirrored these findings, showing intense JAK/STAT upregulation in T1DM but a tempered response in LADA. TRAIL in LADA NK-cells was consistently higher than in T1DM, reinforcing the idea of apoptotic regulation limiting full-blown cytotoxicity. Collectively, these pathway-level distinctions align with LADA’s milder clinical progression relative to T1DM.

Conclusion: Our single-cell profiling indicates that LADA’s immunopathology is shaped by an interplay of moderately elevated JAK/STAT signaling and heightened TRAIL-mediated apoptosis. This contrasts sharply with T1DM, where excessive JAK/STAT activation and insufficient TRAIL-related cell death of autoregressive T-cells foster a more aggressive β-cell attack. These findings suggest that targeting JAK/STAT hyperactivation or enhancing TRAIL-mediated apoptosis may provide novel therapeutic strategies to modulate LADA’s autoimmune trajectory and preserve β-cell mass. Pharmacological modulation of these pathways warrants further exploration as a potential strategy for LADA management.