Environmental Lead Exposure and Glucose Dysregulation: A Critical Integrative Review of Epidemiological and Mechanistic Evidence.

Environmental lead (Pb) exposure has been proposed as a contributor to glucose dysregulation and type 2 diabetes mellitus (T2DM), but epidemiological consistency, causal interpretation, and human relevance of experimental models remain uncertain. Here, 'integrative' denotes an explicit cross-stream synthesis of human epidemiology, Pb-specific experimental toxicology, and adjacent mechanistic biology under common appraisal dimensions; it does not denote systematic-review status or formal evidence grading. Human findings are mixed and are dominated by cross-sectional studies using a single blood-Pb measurement. Positive associations are more frequent for triglyceride-glucose or other surrogate indices than for incident T2DM, whereas null estimates may reflect either absence of an effect or attenuation from exposure misclassification, restricted contemporary exposure ranges, and insufficient power. Experimental studies directly support impaired β-cell bioenergetics and insulin secretion and increased hepatic gluconeogenesis, but nominal doses, coadministration of a high-fat diet, and incomplete internal-dose reporting limit environmental extrapolation. Pb-specific support for Nrf2-mediated metabolic effects, TXNIP/NLRP3 activation in metabolic tissues, and gut-microbiota mediation remains indirect or preliminary. Real-world coexposure to other metals, particulate matter, and social stressors further limits lead-specific attribution. Overall, Pb is biologically plausible as one contributor to glucose dysregulation under some exposure and susceptibility conditions, but current evidence does not establish an independent causal effect on human T2DM. Prospective, mixture-aware studies with repeated and cumulative Pb biomarkers, adjudicated outcomes, and toxicokinetically anchored experimental designs are needed.