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 and supporting its potential utility in identifying heightened atherogenic risk beyond traditional markers.
Key Findings
Results
Patients with high IL-12/IL-35 p35 levels had significantly elevated fasting glucose compared to those with low levels.
80 African patients with T2D were stratified into Low and High IL-12/IL-35 p35 groups (n=40/group) using a median split of plasma IL-12/IL-35 p35 at 18.48 pg/mL
Fasting glucose was significantly higher in the High IL-12/IL-35 p35 group (p=0.0318)
Cross-sectional study design; laboratory parameters were measured using standard methods and IL-12/IL-35 p35 was quantified by ELISA
Results
Patients with high IL-12/IL-35 p35 levels had significantly elevated triglycerides, triglyceride/HDL ratio, TyG index, and atherogenic index of plasma (AIP).
Triglycerides were significantly higher in the High IL-12/IL-35 p35 group (p<0.0001)
Triglyceride/HDL ratio was significantly elevated (p<0.0001)
Triglyceride-Glucose (TyG) index was significantly elevated (p<0.0001)
Atherogenic index of plasma (AIP) was significantly elevated (p<0.0001)
Results
Circulating IL-12/IL-35 p35 levels positively correlated with triglycerides, AIP, triglyceride/HDL ratio, and TyG index, and negatively correlated with HDL.
Positive correlations with triglycerides, AIP, Trig/HDL ratio, and TyG index were all statistically significant (p<0.0001 for each)
Negative correlation with HDL cholesterol was statistically significant (p=0.0466)
Results
In multiple linear regression, IL-12/IL-35 p35 levels and TyG index independently predicted atherogenicity after adjusting for glycemic control.
Both IL-12/IL-35 p35 and TyG index were independent predictors (all p<0.05)
The model adjusted for glycemic control as a covariate
This suggests the association between IL-12/IL-35 p35 and atherogenicity is not fully explained by glucose levels alone
Results
ROC analysis demonstrated that IL-12/IL-35 p35 discriminated participants with high-risk AIP and elevated TyG index with moderate-to-good diagnostic accuracy.
AUC for discriminating high-risk AIP: 0.79 (95% CI: 0.68–0.89, p<0.0001)
These AUC values suggest IL-12/IL-35 p35 has potential utility as a biomarker for atherogenic risk stratification in T2D
Background
IL-12 and IL-35 are heterodimeric cytokines sharing the p35 subunit with opposing inflammatory roles, and dysregulation of this shared subunit may reflect an imbalance between pro- and anti-inflammatory pathways linking metabolic dysfunction to cardiovascular risk in T2D.
IL-12 is pro-inflammatory; IL-35 is anti-inflammatory; both share the p35 subunit
The clinical significance of circulating IL-12/IL-35 p35 levels was previously unclear prior to this study
The authors suggest that measuring the shared p35 subunit may capture net imbalance within this immunoregulatory axis
What This Means
This research suggests that a protein subunit shared by two immune signaling molecules — one that promotes inflammation (IL-12) and one that suppresses it (IL-35) — may serve as a useful indicator of heart disease risk in people with type 2 diabetes. The study measured blood levels of this shared subunit, called the p35 subunit, in 80 African patients with type 2 diabetes and found that those with higher p35 levels also had worse blood sugar control and higher levels of fats and other markers associated with clogged arteries and cardiovascular risk.
The findings showed that higher p35 levels were consistently linked to higher triglycerides, a worse cholesterol profile (lower HDL, or 'good' cholesterol), and higher scores on established measures of artery-clogging risk such as the Atherogenic Index of Plasma and the Triglyceride-Glucose index. Importantly, the association between p35 levels and atherogenic risk held up even after accounting for blood sugar control, suggesting the immune system imbalance captured by p35 provides additional information beyond standard glucose measurements. Statistical modeling also showed that p35 could moderately distinguish patients at high cardiovascular risk from those at lower risk.
This research suggests that measuring IL-12/IL-35 p35 in the blood could help identify type 2 diabetes patients who face heightened risk of cardiovascular disease, potentially complementing existing risk markers. Because this is a cross-sectional study, it cannot prove cause and effect, and the authors call for future research directly measuring intact IL-12 and IL-35 separately to better understand how each contributes to disease risk. The study was conducted in an African patient population, and how well findings generalize to other populations remains to be determined.
Nyambuya T, Shingenge E, Ndevahoma F, Nkambule B. (2026). The Shared IL-12/IL-35 p35 Subunit Is Associated With Heightened Atherogenic Risk in African Patients With Type 2 Diabetes.. Endocrinology, diabetes & metabolism. https://doi.org/10.1002/edm2.70306