BIOMARKERS OF GLUCOSE METABOLISM IN EXHALED BREATH

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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. We propose an innovative approach to the field of non-invasive monitoring of blood glucose and related variables, the detection and quantification of trace amounts of Volatile Organic Compounds (VOCs) in exhaled human breath as biomarkers endogenous metabolism. Exhaled gases represent an ideal set of potential biomarkers, as they can be collected easily and non-invasively from virtually any patient. While the potential of VOCs has been recognized for decades and several attempts have been made to utilize them for metabolic monitoring, intrinsic difficulties in measurement and analysis have resulted in inconsistent results, severely limiting their practical applicability. Recent advances in analytical technology, however, may have reduced, if not solved, these problems, and resulted in renewed interest in this methodology, with an exponentially rising number of studies focusing on its applications. Among the greatest contributors to these advances are Drs. Sherwood Rowland and Donald Blake, world renowned atmospheric chemists and co-investigators in this application (for his discoveries in atmospheric gas composition, Dr. Rowland was awarded the 1995 Nobel Prize for Chemistry). The Rowland/Blake laboratory can now reliably measure gas concentrations as low as 10 parts/quadrillion, a sensitivity unequalled worldwide. During the last 3 years, a collaboration between this lab and the UCI GCRC Metabolic Core has resulted in a series of remarkable observation (see preliminary results), including the reconstruction, from exhaled VOCs profiles, of plasma glucose curves during OGTT in healthy adults, and the tracking of blood glucose during correction of hyperglycemia in T1DM children. While intriguing, these observations were made as ancillary findings during pre-existing experimental protocols, with limited possibility to add necessary control studies and thoroughly define exhaled gas patterns through the range of metabolic alteration that can be expected in standard diabetes management. We believe that to reveal the full potential of this methodology, a series of carefully controlled, basic studies are needed, as proposed in detail below. General aims: a) To define exhaled breath gas profiles, in healthy subjects and patients with Type 1 Diabetes (T1DM) during different combinations of plasma glucose, insulin and free fatty acid (FFA) concentrations. b) To identify correlations between exhaled gas profiles and plasma glucose, insulin, glucose/insulin ratio, FFAs, ketones and oxidative stress markers. c) To generate predictive algorithms to estimate, from gas profiles, circulating concentrations of our variables of interest. These general aims will be pursued in the following specific conditions: Specific aim # 1: Rapid induction of hyperglycemia, its correction, euglycemia (both eugly- and hyper-glycemia will occur with or without hyperinsulinemia, and hyperinsulinemia will occur with and without suppression of circulating FFAs) Specific aim # 2: Single prolonged glycemic levels (3 h of hyperglycemia, normo-/hyperinsulinemic euglycemia, hypoglycemia) Specific aim # 3: Physiological post-prandial hyperglycemia (following administration of a single high-carbohydrate meal, or multiple small meals)