Peripheral Immune Reprogramming Characterizes a Low C-Peptide Subgroup of Type 2 Diabetes: Transcriptomic Profiling of Peripheral Blood Mononuclear Cells and Systemic Inflammation.

Authors

Yajing Xu, Yiting Li, Xiying Zeng, Lijun Chen, Hongli Lin, Wenxin Xie, Zitong Wang, Zhengrong Jiang, Honghong Duan, Huibin Huang

Published in

Journal of inflammation research. Volume 19. Pages 594793. Epub Jul 08, 2026.

Abstract

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.

PMID:
42438590
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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