This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: acute metabolic changes induced by ingestion of a standardized dose of glucose will be reflected in discrete patterns of exhaled volatile organic compounds (VOCs). It has been known for centuries that breath contains clues to diseases such as diabetes (acetone) and uremia (isoprene). In the past decade, it has been suggested that exhaled breath gas might be an elegant and non-invasive tool to gain insight into basic mechanisms of pulmonary physiology and pathology. Exhaled nitric oxide has been extensively studied in asthma, and current evidence suggests that it may be a valuable surrogate marker of bronchial inflammatory activity. Pauling and co-workers reported in 1971 that normal human breath contains a complex mixture of several hundred volatile organic compounds (VOCs). New non-invasive, precise and reproducible markers would have the potential to fundamentally improve the diagnosis and individualized therapy of many diseases that involve chronic inflammation, a process known to produce VOCs. Most VOCs are exhaled in pico- to femtomolar concentrations which renders their measurement an analytical challenge. Our research group has been involved in the quantification of atmospheric trace gases since the 1970s. Our analytical system is capable of accurately and precisely quantifying gas concentrations to as low as 20x10-15, or 20 parts per quadrillion by volume (ppqv) [Colman et al., 2001]. Our very low detection limits enable us to observe gases in exhaled breath that have not been previously reported. To date, few if any exhaled breath studies have reported VOC concentrations below 1-2x10-9, or parts per billion by volume (ppbv). Our analytical capabilities will enable us to observe varying concentrations of gases and different types of gases (hydrocarbons, halocarbons, alkyl nitrates, and sulfur gases) that may be markers of disease and/or bodily function. Altered concentrations of VOCs in the exhaled breath are likely to reflect a variety of physiological and pathological conditions, including changes in energy metabolism and stimulation of inflammatory processes. Diabetes is one of the diseases with the largest impact on western society in terms of morbidity, mortality, social cost and deterioration of quality of life. Despite the many advances in diabetes management over the last few decades, the possibility of a permanent cure remains uncertain, and the incidence of the disease (particularly of Type 2 diabbtes, more stongly susceptible to environmemntal modulation) is increasing in western societies at an alarming rate. An important issue associated with diabetes management is the necessity of frequent plasma glucose testing. The current, broadly used fingerstick method, requiring a droplet of blood for each measurement, is uncomfortable, often painful, and expensive (~$1.00 per measurement), often limiting the practical applicability of the physicians suggestion to increase the frequency of testing. Although considerable energy and resources have beenn invested by researchers and drug companies in the attempt to identify non-invasive, low-cost techniques for glucose monitoring, no conclusive results have yet been obtained. The identification of specific exhaled gas patterns correlating with prevailing plasma glucose levels has therefore the potential to create the physiologic basis for a totally new approach to non-ivasive glucose monitoring. Similar glucose concentrations may derive from very different metabolic states, depending on simultaneous concentrations of insulin, ketone bodies, counterregulatory hormones and other glucoregulatory mediators. Because exhaled gas analysis is not based on measurement of one vairable (as other experimental non-invasive techniques are), but on the combination of multiple (indeed potentially hundreds) individual gas concentrations, specific patterns could be idenfitied that would not only determine glycemia, but indeed define a more complex 'metabolic state' (presence or not of chetoacidosis during hyperglycemia, depth of hyperinsulinemia during hypoglycemia, etc.). As a preliminary set of determinations, therefore, with the present study we intend to define the physiological patterns of exhaled VOCs in a group of healthy adult volunteers, at baseline and during the performance of a standard oral glucose tolerance test (OGTT), consisting in the ingestion, after 8 hours of fasting, of 75 grams of glucose. Simultaneous collection of exhaled VOCs and blood for glucose and insulin measurments wil be performed at baseline, and at 2.5, 5, 10, 15, 20, 30, 45, 60, 75, 90, 105 and 120 minutes after glucose ingestion.
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