Distinct immunometabolic signatures in peripheral blood mononuclear cells are linked to systemic inflammation in type 2 diabetes and diabetic kidney disease.

Diabetic kidney disease (DKD) is a frequent complication of type 2 diabetes and is closely linked to systemic inflammation. Peripheral blood mononuclear cells (PBMCs) are markers of systemic inflammatory and metabolic stress. It is unknown if metabolism-related transcriptomic alterations in these cells is associated with DKD. Using the nCounter® Human Metabolic Pathways Panel we profiled PBMC metabolic transcripts in individuals with type 2 diabetes or DKD and in controls (n = 12/group), and integrated transcriptomic data with clinical, inflammatory, and mitochondrial parameters. Patients with DKD showed increased inflammatory biomarkers and reduced PBMC mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Metabolism-related transcriptomic profiling identified 13 differentially expressed genes across groups. DKD subjects displayed downregulation of SLC7A11 versus controls and HLA-DQA1 versus type 2 diabetes, and upregulation of CPT1A and GBA1 versus controls. CPT1A upregulation was confirmed by RT-qPCR and supported by external GEO datasets, though ROC analyses indicated a limited discriminatory performance. Pathway analyses revealed enrichment of immune-related, fatty acid oxidation, and fructose-6-phosphate pathways and reduced cell proliferation pathways in DKD patients. Inflammatory markers correlated positively with energy-regulating pathways and negatively with anabolic processes. In conclusion, these findings suggest that PBMCs reflect immunometabolic remodeling in response to DKD, thus highlighting an association between systemic inflammation, mitochondrial dysfunction, and altered energy metabolism in circulating immune cells.