Metabolic Adaptation of CD8⁺ T Cells Limits the Efficacy of Fatty Acid Oxidation Inhibition in Type 1 Diabetes

TL;DR

This study shows that the drug trimetazidine temporarily improves outcomes in a mouse model of type 1 diabetes by inhibiting fatty acid oxidation in immune cells, but metabolic adaptation limits its long-term effectiveness.

Contribution

The study reveals a novel evasion mechanism involving CPT1A upregulation in CD8⁺ T cells in response to fatty acid oxidation inhibition.

Findings

Trimetazidine delayed T1D progression and reduced islet infiltration in NOD mice.

Prolonged TMZ treatment induced compensatory CPT1A upregulation in CD8⁺ T cells.

Single-cell RNA sequencing showed improved pancreatic health and reduced stress-responsive cells.

Abstract

Type 1 Diabetes Mellitus (T1D) is an organ-specific autoimmune disease characterized by persistent hyperglycemia due to immune-mediated destruction of pancreatic islet β-cells. Targeting immune cell metabolism has emerged as a promising therapeutic strategy. We investigated whether the fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ), one of only three approved drugs directly targeting cellular metabolism, can restrain autoreactive immunity and delay T1D in non-obese diabetic mice (NOD). TMZ enhanced mitochondrial membrane potential, suppressed FAO, and curtailed activation and proliferation of human CD8+ T cells. In dysglycemic NOD mice, a clinically approved dose of TMZ delayed progression to T1D, reduced mean glycemia, and decreased islet CD4⁺/CD8⁺ infiltration. Single-cell RNA sequencing revealed depletion of FAO-high, stress-responsive cells and mitochondrially active stromal cells, indicating improved pancreatic health. Prolonged exposure induced compensatory upregulation of carnitine-palmitoyl-transferase-1A (CPT1A) in CD8⁺ subsets, counterbalancing early benefits. In summary, TMZ transiently restrains CD8⁺ T cell activity, reduces islet infiltration, and improves pancreatic health. The adaptive upregulation of CPT1A demonstrates a novel evasion mechanism to FAO inhibition and underscores the central role of FAO in sustaining pathogenic T cells. Our work highlights metabolic adaptation as a key determinant of autoimmune progression, validating FAO as a therapeutic target in T1D.

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