Diabetes reprograms brain and systemic immune landscapes to impair repair after injury.

Diabetes is a major risk factor for poor outcomes following brain injury, yet the underlying mechanisms remain incompletely understood. Using stereotaxic ATP injection into the striatum combined with 9.4T MRI, we found that diabetic mice exhibited larger initial lesions and delayed recovery compared to controls, even after matching for initial lesion size. Transcriptomic profiling of the intact diabetic brain revealed extensive gene expression changes before injury, with prominent downregulation of excitatory synaptic transmission and cytoskeletal organization pathways. RNA-seq of peripheral blood mononuclear cells (PBMCs) showed that diabetes altered systemic immune response, mitochondrial metabolism, and cell structure-related genes after injury. Infiltrating monocytes in diabetic brains exhibited dispersed distribution, and transcriptional remodeling characterized by upregulation of transporters and channels and downregulation of mitochondrial and prostaglandin biosynthesis genes. Furthermore, diabetes attenuated astrocyte activation, impairing monocyte distribution. These results reveal that diabetes induces pre-injury transcriptional reprogramming in both the brain and immune system, leading to heightened injury severity and impaired repair responses.