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Background: Although altered metabolism has long been known to affect human breath, generating clinically usable metabolic tests from exhaled compounds has proven challenging. If developed, a breath-based lipid test would greatly simplify management of diabetes and serious pathological conditions (e.g., obesity, familial hyperlipidemia, and coronary artery disease), in which systemic lipid levels are a critical risk factor for onset and development of future cardiovascular events. Methods: We, therefore, induced controlled fluctuations of plasma lipids (insulin-induced lipid suppression or intravenous infusion of Intralipid) during 4-h in vivo experiments on 23 healthy volunteers (12 males/11 females, 28.0 ± 0.3 years) to find correlations between exhaled volatile organic compounds and plasma lipids. In each subject, plasma triglycerides (TG) and free fatty acids (FFA) concentrations were both directly measured and calculated via individualized prediction equations based on the multiple linear regression analysis of a cluster of 4 gases. In the lipid infusion protocol, we also generated common prediction equations using a maximum of 10 gases. Results: This analysis yielded strong correlations between measured and predicted values during both lipid suppression ( r = 0.97 for TG; r = 0.90 for FFA) and lipid infusion ( r = 0.97 for TG; r = 0.94 for FFA) studies. In our most accurate common prediction model, measured and predicted TG and FFA values also displayed very strong statistical agreement ( r = 0.86 and r = 0.81, respectively). Conclusions: Our results demonstrate the feasibility of measuring plasma lipids through breath analysis. Optimization of this technology may ultimately lead to the development of portable breath analyzers for plasma lipids, replacing blood-based bioassays.

Effective management of diabetes mellitus, affecting tens of millions of patients, requires frequent assessment of plasma glucose. Patient compliance for sufficient testing is often reduced by the unpleasantness of current methodologies, which require blood samples and often cause pain and skin callusing. We propose that the analysis of volatile organic compounds (VOCs) in exhaled breath can be used as a novel, alternative, noninvasive means to monitor glycemia in these patients. Seventeen healthy (9 females and 8 males, 28.0 ± 1.0 yr) and eight type 1 diabetic (T1DM) volunteers (5 females and 3 males, 25.8 ± 1.7 yr) were enrolled in a 240-min triphasic intravenous dextrose infusion protocol (baseline, hyperglycemia, euglycemia-hyperinsulinemia). In T1DM patients, insulin was also administered (using differing protocols on 2 repeated visits to separate the effects of insulinemia on breath composition). Exhaled breath and room air samples were collected at 12 time points, and concentrations of ∼100 VOCs were determined by gas chromatography and matched with direct plasma glucose measurements. Standard least squares regression was used on several subsets of exhaled gases to generate multilinear models to predict plasma glucose for each subject. Plasma glucose estimates based on two groups of four gases each ( cluster A: acetone, methyl nitrate, ethanol, and ethyl benzene; cluster B: 2-pentyl nitrate, propane, methanol, and acetone) displayed very strong correlations with glucose concentrations (0.883 and 0.869 for clusters A and B, respectively) across nearly 300 measurements. Our study demonstrates the feasibility to accurately predict glycemia through exhaled breath analysis over a broad range of clinically relevant concentrations in both healthy and T1DM subjects.