Recent technical advances allow detection of several hundred volatile organic compounds (VOCs) in human exhaled air, many of which reflect unidentified endogenous pathways. Our group has previously estimated plasma glucose levels in healthy adults during a standard oral glucose tolerance test via exhaled VOC analysis. As a result of the metabolic characteristics of hyperglycemia in the diabetic (low insulin and increased free fatty acids and ketones), we hypothesized that different exhaled VOC profiles may be present in children with type 1 diabetes mellitus (T1DM) during spontaneous hyperglycemia. Exhaled methyl nitrate strongly correlated specifically with the acute, spontaneous hyperglycemia of T1DM children. Eighteen experiments were conducted among 10 T1DM children. Plasma glucose and exhaled gases were monitored during either constant euglycemia (n ؍ 5) or initial hyperglycemia with gradual correction (n ؍ 13); all subjects received i.v. insulin and glucose as needed. Gas analysis was performed on 1.9-liter breath samples via gas chromatography using electron capture, flame ionization, and mass selective detection. Among the Ϸ100 measured exhaled gases, the kinetic profile of exhaled methyl nitrate, commonly present in room air in the range of 5-10 parts per trillion, was most strongly statistically correlated with that of plasma glucose (P ؍ 0.003-0.001). Indeed, the kinetic profiles of the two variables paralleled each other in 16 of 18 experiments, including repeat subjects who at different times displayed either euglycemia or hyperglycemia.exhaled gases ͉ volatile organic compounds ͉ gas chromatography ͉ plasma glucose T he analysis of volatile organic compounds (VOCs) has been recognized for decades as a diagnostic tool with great potential for application to human breath, and several attempts have been made to use this technique for metabolic monitoring. However, intrinsic difficulties in measurement and analysis have resulted in inconsistent results, severely limiting its practical applicability.Recent advances in VOC analytical technology may have reduced the impact of these technical issues, lowering detection limit of measurable gas concentrations, and increasing the repeatability and stability of measurements. Indeed, in recent years a rising number of studies centered on exhaled VOC clinical applications have been generated (1-5). Most studies, however, are focused on the detection of single disease markers, i.e., exhaled gas profiles constantly present in definite groups of patients, independent of their moment-by-moment metabolic changes. We believe that this approach, while having the potential of detecting important diagnostic markers, greatly underutilizes exhaled gas analysis. Exhaled gas profiles are likely involved in endogenous metabolic processes and are, therefore, constantly changing in response to the extremely complex human endogenous biochemical milieu. The extreme versatility of exhaled gas analysis (combining simultaneous measurements of 100 or more exhaled gases in each ...