Peripheral Immune Reprogramming Characterizes a Low C-Peptide Subgroup of Type 2 Diabetes: Transcriptomic Profiling...

Type 2 diabetes (T2DM) is clinically heterogeneous. A subgroup with markedly reduced C-peptide has poorer glycemic stability and different therapeutic needs, but the associated peripheral immune features and practical non-invasive markers are not well defined. We investigated whether T2DM with low C-peptide (T2DM-LowC) is associated with a distinct peripheral immune profile.

In this single-center, cross-sectional study, patients with T2DM were propensity score-matched 1:1 by disease duration into low C-peptide (T2DM-LowC, n=109) and preserved C-peptide (T2DM-PresC, n=109) groups. Clinical and metabolic variables were compared. In an exploratory sub-cohort (n=21; HC=7, PresC=7, LowC=7), transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) was analyzed using differential expression analysis, weighted gene co-expression network analysis, and CIBERSORTx deconvolution. Candidate genes were validated in an independent cohort (n=40) by RT-qPCR.

Compared with T2DM-PresC, the T2DM-LowC subgroup had lower BMI and triglycerides, higher alkaline phosphatase, and a higher systemic inflammation response index (SIRI; neutrophils × monocytes/lymphocytes). Higher SIRI remained associated with low C-peptide status after adjustment (OR = 2.38, p = 0.007). Exploratory PBMC transcriptomic analyses identified lower mast-cell-related signatures, higher resting NK-cell and resting CD4 memory T-cell signatures, and a shift toward memory B cells. CSF2RB, NIBAN1, and TLR1 were consistently downregulated in T2DM-LowC, and the three-gene panel discriminated the two T2DM subgroups in the validation cohort (AUC = 0.903; sensitivity 75.0%; specificity 90.0%).

In this cross-sectional dataset, low C-peptide T2DM was associated with a distinct clinical and peripheral immune profile. Integrating SIRI with a three-gene PBMC signature may provide a non-invasive adjunct for identifying this subgroup. These deconvolution-derived immune-cell findings require validation in larger and functionally characterized cohorts.