The Shared IL ‐12/ IL ‐35 p35 Subunit Is Associated With Heightened Atherogenic Risk in African Patients With Type 2 Diabetes

Abstract

INTRODUCTION: Interleukin (IL)-12 and IL-35 are heterodimeric cytokines that share the p35 subunit and have opposing inflammatory roles. Dysregulated IL-12/IL-35 p35 may reflect an imbalance between pro- and anti-inflammatory pathways linking metabolic dysfunction to cardiovascular risk in type 2 diabetes (T2D). However, the clinical significance of circulating IL-12/IL-35 p35 levels remains unclear. This study investigated the association between IL-12/IL-35 p35 levels and metabolic and atherogenic risk markers in T2D. METHODS: This cross-sectional study stratified 80 patients with T2D into Low and High IL-12/IL-35 p35 groups (n = 40/group) using a median split of plasma IL-12/IL-35 p35 (18.48 pg/mL). Laboratory parameters were measured using standard methods, and IL-12/IL-35 p35 concentrations were quantified by Enzyme Linked Immunosorbent Assay. RESULTS: Patients with High IL-12/IL-35 p35 had significantly elevated fasting glucose (p = 0.0318), triglycerides (p < 0.0001), triglyceride/HDL ratio (p < 0.0001), Triglyceride-Glucose (TyG) (p < 0.0001), and atherogenic index of plasma (AIP) (p < 0.0001). Circulating IL-12/IL-35 p35 levels positively correlated with triglycerides, AIP, Trig/HDL ratio and TyG index (all p < 0.0001), and negatively correlated with HDL (p = 0.0466). In the multiple linear regression analysis, IL-12/IL-35 p35 levels and TyG index (all p < 0.05) independently predicted atherogenicity after adjusting for glycaemic control. Receiver operating characteristic analysis demonstrated that IL-12/IL-35 p35 discriminated participants with high-risk AIP (AUC = 0.79, 95% CI: 0.68-0.89, p < 0.0001) and elevated TyG index (AUC = 0.78, 95% CI: 0.63-0.93, p = 0.0147). CONCLUSION: Elevated circulating IL-12/IL-35 p35 in T2D is associated with suboptimal glucose control and pronounced atherogenicity, suggesting altered activity within this immunoregulatory axis. These findings highlight the shared p35 subunit as a marker of immune imbalance and support its potential utility in identifying heightened atherogenic risk in T2D beyond the traditional markers. Future studies should directly quantify intact IL-12 and IL-35 to elucidate their individual contributions to the alteration of this immunoregulatory axis.