Low C-peptide Type 2 Diabetes Subgroup Shows Distinct Peripheral Immune Reprogramming and Inflammatory Profile
Background
Type 2 diabetes (T2DM) is a heterogeneous condition, with a subgroup characterized by markedly reduced C-peptide levels often experiencing poorer glycemic stability and unique therapeutic needs. The specific peripheral immune features and practical non-invasive markers for this T2DM-LowC subgroup remain poorly defined. Understanding these distinctions is crucial for personalized medicine, as current standard-of-care approaches often fail to adequately address the diverse underlying pathologies within the broader T2DM population, particularly concerning immune dysregulation and inflammation.
Study Design
In this single-center, cross-sectional study, 218 patients with Type 2 diabetes 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. An exploratory sub-cohort (n=21, including 7 HC, 7 PresC, 7 LowC) underwent transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) 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.
Results
Compared with T2DM-PresC, the T2DM-LowC subgroup exhibited lower BMI and triglycerides, higher alkaline phosphatase, and a significantly higher systemic inflammation response index (SIRI; neutrophils × monocytes/lymphocytes). This higher SIRI remained associated with low C-peptide status after adjustment (OR = 2.38, p = 0.007).
Why It Matters
The critical heterogeneity within Type 2 diabetes is highlighted by this research, identifying a distinct low C-peptide subgroup with unique immune and inflammatory characteristics. Recognizing this subgroup is crucial for personalized therapeutic strategies, as these patients may require different interventions than those with preserved C-peptide. The identified SIRI and three-gene PBMC signature (CSF2RB, NIBAN1, TLR1) offer promising non-invasive adjuncts for early identification, potentially guiding clinicians toward more tailored treatments to improve glycemic stability and long-term outcomes. This moves beyond a one-size-fits-all approach, suggesting a future where T2DM management is stratified by underlying immune profiles.