Peripheral blood HIF-1α levels in type 2 diabetes mellitus and their association with diabetic complications: a systematic review and meta-analysis.

BACKGROUND

Hyperglycemia is known to exacerbate cellular hypoxia. Hypoxia-inducible factor-1α (HIF-1α) is the functional subunit of the HIF-1 transcription factor and plays a central role in regulating cellular adaptive responses to low oxygen tension. HIF-1α orchestrates these adaptive responses by regulating downstream effectors such as vascular endothelial growth factor (VEGF), which is essential for vascular integrity and metabolic homeostasis. However, while these molecular pathways are well-defined in vitro, there is a lack of a comprehensive synthesis of their circulating levels in type 2 diabetes mellitus (T2DM) patients. This gap in systemic evidence necessitates a rigorous meta-analysis to provide a definitive quantitative assessment.

METHODS

We conducted a systematic search of major English and Chinese databases (PubMed, Embase, Cochrane Library, Web of Science, Wanfang, CNKI, VIP, and CBM) from inception through September 27, 2025. Cross-sectional studies evaluating peripheral blood protein levels of HIF-1α and VEGF in T2DM patients versus healthy controls were included. Data synthesis was performed using standardized mean differences (SMD) with 95% confidence intervals (CI). Heterogeneity and stability of the results were assessed via subgroup analysis, sensitivity analysis, and Egger's test.

RESULTS

Thirty studies were included, comprising 6,400 T2DM patients and 2,994 healthy controls. Meta-analysis revealed significantly elevated peripheral blood levels of both HIF-1α and VEGF in T2DM patients compared to healthy controls. Subgroup analyses confirmed the robustness of these trends across all stratified populations. Sensitivity analyses demonstrated that the findings were robust, and Egger's test indicated no evidence of significant publication bias.

CONCLUSIONS

The distinct expression profiles of elevated HIF-1α and VEGF underscore their potential involvement in the pathophysiology of T2DM. Our meta-analysis confirms that T2DM is consistently associated with elevated circulating levels of both HIF-1α and VEGF. While these findings underscore the involvement of this molecular axis in T2DM pathophysiology, they do not support their current use as clinical biomarkers or therapeutic targets. The cross-sectional design of the included studies precludes causal inference. Future prospective and mechanistic research is essential to determine their potential utility.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251164744.