Key result
Plasma from young children (<7 years) with recent-onset Type 1 diabetes induced mitochondrial metabolic gene signatures in immune cells.
Why the study?
Despite clinical heterogeneity in type 1 diabetes progression by age, the immunological and metabolic mechanisms underlying divergent progression patterns remain unclear.
Age-specific plasma factors in Type 1 diabetes drive distinct signaling and metabolic programs in immune cells, with younger patients showing enhanced mitochondrial bioenergetics via PI3K signaling.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for age-specific immune metabolic shifts in early T1D; leaves open progression role or targets.
Introduction and Objective: Type 1 diabetes (T1D) exhibits age-dependent heterogeneity in disease progression, with younger children (<7 years) typically experiencing more aggressive β-cell destruction than adolescents (>15 years). Despite this clinical heterogeneity, the immunological and metabolic mechanisms underlying divergent progression patterns remain unclear. We hypothesized that circulating plasma factors drive age-dependent signaling pathway activation in immune cells. Methods: Healthy individual PBMCs were stimulated with plasma from young recent-onset T1D (RO7, n=13; age <7 years), older recent-onset T1D (RO15, n=9; age >15 years), and age/HLA-matched healthy controls (HR7, n=10; HR15, n=10), followed by microarray analysis to identify differentially expressed genes. Gene signatures were integrated with TEDDY (The Environmental Determinants of Diabetes in the Young) metabolomics data (n=113-294; age <7) and validated using Seahorse XF assays. Results: RO7 and RO15 plasma induced 1,719 differentially expressed genes (FDR <0.1). Integration with TEDDY metabolomics revealed elevated TCA cycle metabolites (fumaric and malic acid; FDR <0.2) in the RO7 group. Consistently, RO7 plasma induced mitochondrial metabolic gene signatures (4.6-fold TCA cycle, 2-fold OXPHOS; p<0.05). LASSO, a machine learning algorithm, identified RTK-PI3K signaling as a key discriminator between RO7 and RO15 (misclassification score = 0). Seahorse assays showed that RO15 plasma suppressed mitochondrial potential in healthy PBMCs, limiting energy availability for immune activation. Conclusion: Age-specific plasma factors drive distinct signaling and metabolic programs in immune cells. In RO7, PI3K signaling enhances mitochondrial bioenergetics, while suppressive factors in RO15 plasma restrict metabolic capacity. These findings provide a mechanistic link between age-dependent signaling, immune metabolism, and heterogeneous disease progression in T1D. Disclosure K. Girdhar: Stock/Shareholder; Current; Hummsa Biotech, Sana Biotechnology Inc.
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Girdhar et al. (2026) studied Type 1 Diabetes (n=42). Plasma from young (<7 years) recent-onset T1D patients vs. Plasma from older (>15 years) recent-onset T1D patients and healthy controls was evaluated on Induction of mitochondrial metabolic gene signatures (TCA cycle and OXPHOS) (p=<0.05). Plasma from young children (<7 years) with recent-onset Type 1 diabetes induced mitochondrial metabolic gene signatures in immune cells.
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