Association between diabetes and elevated circulating advanced oxidation protein products: a comprehensive systematic...

Oxidative stress is a central feature of the metabolic disturbances observed in diabetes, often leading to cellular and molecular damage. Advanced oxidation protein products (AOPPs), formed during oxidative modification of plasma proteins, have been proposed as biomarkers of systemic oxidative stress. Despite increasing interest, the relationship between these markers and diabetes remains inconclusive. This study aimed to systematically evaluate and quantify differences in circulating AOPPs levels in diabetes.

A systematic review and meta-analysis was performed in accordance with PRISMA guidelines. Searches were conducted across PubMed, Scopus, Embase and Web of Science databases up to March 2025 to identify relevant observational studies involving adults aged 18 years or older. Studies were included if they reported circulating levels of AOPPs in individuals with type 1 diabetes (T1DM), type 2 diabetes (T2DM), or impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), compared to non-diabetic controls. Data extraction and quality assessment were conducted independently by two reviewers, and a random-effects model was used for meta-analysis.

Sixteen eligible articles with twenty individual studies were identified, encompassing diverse populations and diabetes subtypes. The meta-analysis demonstrated significantly elevated circulating AOPPs in both T₁DM (WMD ≈ 17.5 µmol/L) and T₂DM (WMD ≈ 24.68 µmol/L) compared with controls, though heterogeneity was high. Subgroup analyses confirmed the consistent direction of effect, with stronger associations in younger populations, studies with higher baseline AOPPs, and certain designs or regions. Meta-regression showed that examined moderators (continent, study design, baseline AOPPs, age, sample size, gender, study quality, presence of overweight/ obesity, hypertension, smoking and abnormal serum lipids) explained little to none of the variability. Sensitivity analyses indicated that results were robust. Publication bias assessment revealed funnel plot asymmetry for type 2 diabetes, but trim-and-fill analysis did not materially alter the pooled estimates, supporting the stability of the findings.

Elevated levels of AOPPs appear to be associated with diabetes, supporting the role of oxidative stress in its pathophysiology. Although pooled analyses demonstrated significantly higher circulating AOPP concentrations in patients with diabetes mellitus, substantial between-study heterogeneity and wide prediction intervals suggest that the magnitude and consistency of this association may vary across different populations and study settings. Also, the observational design of included studies limits the strength and generalizability of the pooled estimates. Therefore, causal inferences cannot be drawn, and further well-designed prospective research is warranted to clarify whether these biomarkers can reliably predict the onset or progression of diabetes.

CRD420251275798.