Elevated peripheral HIF-1α levels associated with higher fasting glucose and HbA1c in patients with type 2 diabetes mellitus

ImportanceElucidating the role of hypoxia-inducible factor-1α (HIF-1α) in pancreatic β-cell dysfunction is essential for understanding the pathophysiology of type 2 diabetes mellitus (T2DM) and improving clinical risk assessment.ObjectiveTo evaluate associations between protein expression level of HIF-1α in peripheral blood and key glycemic parameters—fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin (FINS), and the homeostatic model assessment of insulin resistance (HOMA-IR)—in patients with T2DM.Data sourcesPubMed, Embase, Cochrane Library, Web of Science (WOS), Wanfang, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Service System (SinoMed) were searched from inception to July 28, 2025, for Chinese and English publications.Study selectionObservational studies examining the relationship between HIF-1α levels and glycemic outcomes in T2DM populations.Data extraction and synthesisTwo reviewers independently extracted data and assessed study quality using AHRQ criteria. Random-effects meta-analysis was used to calculate mean differences (MD) with 95% confidence intervals (CI).Main outcomes and measuresDifferences in FPG, HbA1c, FINS, and HOMA-IR between high and low HIF-1α groups with T2DM.ResultsThirty-six studies (n = 5,979) were included. Elevated peripheral HIF-1α was significantly associated with increased FPG (MD = 1.13, 95% CI [0.59, 1.67]), HbA1c (MD = 0.93, 95% CI [0.63, 1.24]), FINS (MD = 1.13, 95% CI [0.24, 2.02]), and HOMA-IR (MD = 1.40, 95% CI [0.62, 2.18]). Subgroup analysis indicated that geographic location significantly modified the FPG association (p = 0.0105). Sensitivity analyses confirmed the robustness of these findings.ConclusionElevated peripheral HIF-1α levels correlate with impaired β-cell function and increased insulin resistance. The discordance between elevated systemic levels and known tissue-specific reductions suggests that peripheral HIF-1α may reflect a compensatory response to hypoxia rather than a primary driver of T2DM pathogenesis.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251118501, CRD420251118501.