Volatile Organic Compounds in Exhaled Breath as Diagnostic Biomarkers for Diabetes: Advances, Limitations and Future Directions

Diabetes mellitus remains a major global health challenge, and the invasiveness, cost, and logistical constraints of current diagnostic methods limit early detection and effective monitoring. Breathomics, the analysis of volatile organic compounds (VOCs) in exhaled breath, has emerged as a promising non-invasive approach for diabetes detection and metabolic monitoring. Breath VOCs reflect a range of interconnected physiological processes involved in diabetes pathophysiology, including altered glucose and lipid metabolism, ketogenesis, oxidative stress, inflammation, and host–microbiome interactions. This review summarizes current evidence on diabetes-associated breath VOCs, with emphasis on ketone-related compounds, alcohols, hydrocarbons, aldehydes, and sulfur-containing metabolites. We also examine analytical technologies used for VOC detection, from mass spectrometry–based platforms to sensor-based systems and emerging point-of-care devices, alongside statistical and machine learning approaches for identifying complex breath signatures. Importantly, interpreting breath VOC profiles remains challenging due to the high dimensionality of VOC datasets and the influence of physiological, environmental, and behavioral confounders. Breath-based diagnostics, therefore, involve substantial analytical and computational complexity, as disease-related signals must be distinguished from background biological variability and external contamination. Clinical applications in diabetes screening, glycemic monitoring, and risk assessment are discussed, including emerging studies in low-resource and special population settings. However, significant barriers to clinical translation remain, including biological variability, methodological heterogeneity, difficulties in interpreting complex VOC patterns, and the lack of large-scale validation and regulatory approval. Future directions should prioritise standardization of breath sampling and analysis, integration with multi-omics and digital health frameworks, and robust multicenter clinical validation. Overall, this review provides a balanced assessment of the opportunities and challenges of breath-based diagnostics and positions breathomics as a promising complementary tool in precision diabetology rather than a replacement for established biochemical testing.