The diabetes exposome: interplay of environmental and genetic determinants in diabetes.

Diabetes mellitus arises from complex interactions between biological susceptibility and diverse environmental influences that extend beyond traditional "genes versus lifestyle" models. The exposome is defined as the aggregate of non-genetic environmental exposures and their biological consequences across the life course. It provides a systems-level framework to evaluate this interaction, spanning chemical, physical, social, and behavioral domains while integrating them with internal molecular responses to decode how environments shape metabolic health. Emerging assessment strategies, including exposome-wide association studies (ExWAS), high-resolution mass spectrometry-based biomonitoring, geospatial and remote-sensing platforms, and wearable exposure sensors, enable characterization of multi-exposure profiles rather than single agents in isolation. Within exposome domains, air pollution, endocrine-disrupting chemicals, food-borne contaminants, exposome characteristics of the built environment, and chronic psychosocial stress have each been shown to contribute to the development and progression of both type 1 and type 2 diabetes. These diverse exposures often share common pathogenic mechanisms of chronic low-grade inflammation, oxidative and nitrosative stress, alterations in the gut microbiome, and epigenetic changes that ultimately lead to glucose dysregulation. Recent progress in metabolomics, lipidomics, and epigenomics is elucidating the "internal exposome," providing molecular fingerprints that encode prior exposure and detect early metabolic disruption. This integrated approach argues for a paradigm adjustment in diabetes prevention from behavior-centered strategies to those that also target upstream environmental determinants. Exposomic information can improve risk prediction, inform precision public health and medical practice, and inform policy regarding air pollution, chemical use, urban planning, and food systems. This review summarizes the current state of knowledge of the exposome in diabetes, describing its conceptual underpinnings, major tools of assessment, major epidemiologic findings, and biological mechanisms, and identifying the key challenges and opportunities for exposomics to inform effective approaches to diabetes prevention and planetary health.