Type 2 diabetes is far more than a disorder of blood sugar. Persistent hyperglycaemia, insulin resistance and low-grade inflammation conspire to damage the endothelium, the delicate inner lining of blood vessels, setting the stage for atherosclerosis—the buildup of lipid-rich plaques that can rupture and trigger heart attacks and strokes. Oxidative stress and dyslipidaemia compound this damage. Even with modern glucose-lowering therapies, cardiovascular disease remains the leading cause of illness and death among people with type 2 diabetes, which is precisely why researchers are searching for biomarkers that capture the inflammatory dimension of risk beyond conventional lipid panels and glucose measurements.

The focus of the new study is a molecular oddity within the interleukin-12 family of cytokines. Interleukin-12, composed of the p35 and p40 subunits, is a potent driver of inflammatory immunity: it pushes naïve T cells toward the Th1 lineage and stimulates production of interferon-gamma, fuelling vascular inflammation and accelerating plaque formation. Interleukin-35, built from p35 paired with a different partner called Ebi3, does the opposite. Produced mainly by regulatory T cells and regulatory B cells, it suppresses effector immune responses and appears to protect blood vessels from injury. Because both cytokines incorporate the same p35 chain, measuring p35 in the bloodstream provides an integrated snapshot of the net balance between these opposing signals.

To test whether that balance relates to atherogenic risk, the team enrolled 80 adults with type 2 diabetes attending the Katutura Community Health Centre, diagnosing cases according to American Diabetes Association criteria. Participants were excluded if they had malignant disease, autoimmune disorders, pregnancy or recent infection, all of which could distort inflammatory readouts. Blood samples were analysed for full blood counts, erythrocyte sedimentation rate, glycated haemoglobin, fasting glucose, lipid profiles, C-reactive protein and globulins, while plasma p35 concentrations were quantified with a commercial enzyme-linked immunosorbent assay read at 450 nanometres. Patients were then split at the median p35 value of 18.48 picograms per millilitre into low and high groups of 40 each.

The two groups were remarkably well matched on the surface. Age, sex distribution, body mass index, blood pressure and disease duration were all comparable, with roughly 90 percent of the cohort being female. Yet beneath that apparent equivalence, striking metabolic differences emerged. Patients in the high-p35 group had significantly higher fasting glucose, averaging 10.71 versus 8.97 millimoles per litre, and a greater share of them—62.5 percent versus 42.5 percent—fell into the poor glycaemic control category defined by glycated haemoglobin above 8 percent. Most participants were on metformin, which the authors note may have dampened systemic inflammatory markers in both groups.

Indeed, standard inflammation measures told no story at all: C-reactive protein, erythrocyte sedimentation rate, the systemic immune-inflammation index, globulins and the neutrophil-to-lymphocyte ratio were statistically indistinguishable between groups. The lipid machinery, however, told a different tale. Triglycerides were markedly higher in the high-p35 group at 1.93 versus 1.24 millimoles per litre, high-density lipoprotein cholesterol was significantly lower at 0.97 versus 1.09 millimoles per litre, and the triglyceride-to-HDL ratio was substantially elevated. This pattern—more triglyceride-rich particles, less protective HDL—is precisely the profile that promotes lipid retention in arterial walls, foam cell formation and plaque growth.

Composite risk indices sharpened the picture further. The triglyceride-glucose index, a logarithmic measure of insulin resistance that integrates fasting triglycerides and glucose, averaged 9.63 in the high-p35 group versus 8.99 in the low group, with a striking 85 percent of high-p35 patients classified in the high-risk category above 9. The atherogenic index of plasma, calculated from triglycerides and HDL cholesterol, was more than six times higher in the high-p35 group, at 0.25 versus 0.04. Spearman correlation analysis confirmed that p35 levels rose in parallel with triglycerides, the atherogenic index, the triglyceride-to-HDL ratio and the triglyceride-glucose index, while showing a modest inverse relationship with HDL cholesterol. Notably, p35 showed no significant association with fasting glucose alone, suggesting the link runs through triglyceride-rich lipoprotein metabolism rather than glycaemia per se.

The relationship held up under statistical scrutiny. In a multiple linear regression model with the atherogenic index of plasma as the outcome, p35 remained an independent predictor alongside the triglyceride-glucose index, and the association persisted after adjusting for age, sex, body mass index, blood pressure, disease duration and medication use. Receiver operating characteristic analysis then tested whether p35 could actually discriminate high-risk patients: for identifying an elevated atherogenic index it achieved an area under the curve of 0.79, with an optimal threshold above 20.50 picograms per millilitre delivering 65 percent sensitivity and nearly 85 percent specificity, and a positive likelihood ratio of 4.30. Performance for detecting a high triglyceride-glucose index was similar, at an area under the curve of 0.78.

Mechanistically, the findings fit a coherent biological narrative. Excessive interleukin-12 signalling, transmitted through the JAK2-STAT4 pathway, promotes Th1 polarisation and interferon-gamma production, driving macrophage activation, adipose tissue inflammation and impaired insulin signalling—all of which feed insulin resistance and accelerate the transformation of macrophages into lipid-laden foam cells within plaques. Meanwhile, weakened interleukin-35 signalling from regulatory lymphocytes removes a brake on endothelial activation and leukocyte recruitment, allowing vascular inflammation to smoulder. Elevated triglycerides add their own insult through remnant lipoproteins that lodge in the arterial wall and through remodelling reactions that generate more atherogenic apolipoprotein B-containing particles while degrading the anti-inflammatory and cholesterol-efflux functions of HDL.

The authors are careful about the study’s central limitation: because p35 is shared, the assay cannot distinguish whether the signal reflects excess interleukin-12, deficient interleukin-35, or both. Prior studies have consistently reported elevated interleukin-12 in type 2 diabetes, whereas evidence on interleukin-35 remains inconclusive, so separate quantification of each cytokine is the logical next step. Unmeasured medications such as lipid-lowering agents and antihypertensives could also have influenced outcomes, and it remains unknown whether the association is specific to diabetes or reflects a general immune-metabolic response. Even so, the study’s strengths are considerable: a well-matched cohort, pre-powered sample size calculations, multivariable adjustment, and the use of composite indices that capture risk invisible to traditional lipid panels. If validated in larger and more diverse cohorts, a simple blood measurement of this shared cytokine subunit could become a practical immunometabolic tool for spotting cardiovascular danger in diabetic patients long before standard tests raise the alarm.

Subject of Research: The association between circulating IL-12/IL-35 p35 subunit levels and atherogenic risk in African patients with type 2 diabetes

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

Article References: Nyambuya, T. M., Shingenge, E., Ndevahoma, F., & Nkambule, B. 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, 9(5), Article e70306. https://doi.org/10.1002/edm2.70306

Image Credits: AI Generated

DOI: 10.1002/edm2.70306

Keywords: type 2 diabetes, interleukin-12, interleukin-35, p35 subunit, atherogenicity, cardiovascular risk, dyslipidaemia, insulin resistance, triglyceride-glucose index, atherogenic index of plasma, inflammation, Namibia