New Insights into the Relationship Between Microplastics and Diabetes from the Perspective of the Gut–Liver Axis and Macrophage Regulation

Microplastics (MPs) are increasingly recognized as a global environmental threat. Emerging evidence suggests they may have metabolic consequences. In this review, we synthesize current findings from animal and in vitro studies to propose a mechanistic framework linking MP exposure to type 2 diabetes mellitus (T2DM). This framework is uniquely centered on the gut–liver axis and macrophage-centric immune networks. We systematically delineate evidence suggesting that MPs can compromise intestinal barrier integrity, instigate gut dysbiosis, and promote pro-inflammatory M1 polarization of macrophages in experimental models. This immune activation is proposed to subsequently amplify hepatic inflammation, potentially contributing to systemic insulin resistance (IR) and pancreatic β-cell dysfunction. We emphasize that while this pathway is biologically plausible, direct causal evidence in humans remains limited and is a critical knowledge gap. Integrating multi-level evidence from animal models and in vitro systems, we delve into the trans-organ immunometabolic effects of MPs within adipose tissue, pancreas, and skeletal muscle, establishing their role as a novel class of “metabolic disruptors.” Critically, we assess the key controversies and knowledge gaps pertaining to dose–response relationships, particle-specific toxicity (size, polymer type, and additives), the effects of complex environmental mixtures, and the urgent need for robust human validation. We advocate for future research priorities, including multi-omics integration, advanced organ-on-a-chip platforms, prospective cohort studies, and targeted intervention strategies, to propel this field from mechanistic exploration toward clinical and public health relevance. Finally, this synthesis underscores that mitigating the production and environmental release of MPs, alongside developing strategies to impede their bioavailability and accumulation, represents a crucial public health imperative for the prevention of environment-related metabolic diseases.