Review
The clinical potential of exhaled breath analysis for diabetes mellitus

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Abstract

Various compounds in present human breath have long been loosely associated with pathological states (including acetone smell in uncontrolled diabetes). Only recently, however, the precise measurement of exhaled volatile organic compounds (VOCs) and aerosolized particles was made possible at extremely low concentrations by advances in several analytical methodologies, described in detail in the international literature and each suitable for specific subsets of exhaled compounds. Exhaled gases may be generated endogenously (in the pulmonary tract, blood, or peripheral tissues), as metabolic by-products of human cells or colonizing micro-organisms, or may be inhaled as atmospheric pollutants; growing evidence indicates that several of these molecules have distinct cell-to-cell signaling functions. Independent of origin and physiological role, exhaled VOCs are attractive candidates as biomarkers of cellular activity/metabolism, and could be incorporated in future non-invasive clinical testing devices. Indeed, several recent studies reported altered exhaled gas profiles in dysmetabolic conditions and relatively accurate predictions of glucose concentrations, at least in controlled experimental conditions, for healthy and diabetic subjects over a broad range of glycemic values. Optimization of this methodology and validation in large-scale trials under a wider range of conditions is needed to determine its true potential to transition into practical clinical use.

Section snippets

Introduction to breath analysis

Breath analysis has long been recognized as a potentially powerful tool for the diagnosis and study of medical diseases. Even in ancient times, physicians recognized that certain breath odors were associated with specific pathological states. For instance, renal failure became associated with a ‘fishy’ smell and diabetes with a ‘fruity’ smell. In the 19th century, Nebelthau found acetone in the breath of diabetics, and Anstie that exhaled ethanol was a byproduct of alcohol metabolism. Yet the

Sources of breath gases

VOCs and aerosolized particles in the human breath arise from many sources including inhaled room air, airways surfaces, blood, and peripheral tissues throughout the body. While much is yet to be learned about the role of these gases, some appear to be by-products of biochemical reactions while others may be produced for specific physiological roles, such as cell-to-cell signaling. Production of other gases may only be present, or greatly amplified, during infections or other pathological

Features of diabetes that can potentially influence breath testing

Understanding key physical differences induced by diabetes may be a necessary prerequisite to accurate breath-based measurement of diabetes-related metabolic variables. While a “universal” test applicable to both healthy and diabetic populations would be ideal, changes in the lungs and metabolism occurring in diabetic patients may affect breath composition in characteristic ways. On one hand, these changes may be useful for diagnostic purposes; on the other hand, they may also require specific

Conclusions

In summary, breath analysis methods appears on the verge of major breakthroughs that will hopefully exponentially accelerate the transition of past theoretical concepts into practical clinical devices relevant to diabetic populations. However, much still remains to be discovered regarding the origins, pathways, and pathophysiological roles of breath components; fortunately, many new analytical tools that can isolate VOC production from specific cells and tissues are available to now help answer

Grant support

TDC Minh is supported by a National Institutes of Health/National Institute of Diabetes (NIH/NIDDK) Kirschstein Predoctoral Fellowship (F30-DK-088401). PR Galassetti is supported by an NIH/NIDDK Mid-Career Development Grant (K24-DK-085223). Other support was provided by NIH/National Center for Research Resources (NCRR) (UL1-RR031985), American Diabetes Association (ADA) (#7-08-CR-22), Juvenile Diabetes Research Foundation (JDRF) (#7-08-CR-22).

Conflict of interest

There are no conflicts of interest.

Acknowledgements

This work was supported by NIH F30-DK-088401, NIH K24-DK-085223, NIH UL1-RR031985, ADA #7-08-CR-22, and JDRF #7-08-CR-22.

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