BIOMARKERS OF GLUCOSE METABOLISM IN EXHALED BREATH

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们提出了一种创新的方法，血糖和相关变量的非侵入性监测领域，检测和定量的微量挥发性有机化合物（VOCs）在呼出的人的呼吸作为内源性代谢的生物标志物。 呼出气体代表了一组理想的潜在生物标志物，因为它们可以从几乎任何患者中轻松且无创地收集。 虽然挥发性有机化合物的潜力已经被认识了几十年，并已作出了几次尝试，利用它们进行代谢监测，在测量和分析的内在困难，导致不一致的结果，严重限制了他们的实用性。 然而，分析技术的最新进展可能已经减少了这些问题，如果不是解决了这些问题的话，并导致对这种方法的新的兴趣，以指数方式增加了对其应用的研究。 这些进展的最大贡献者是舍伍德·罗兰博士和唐纳德·布莱克博士，他们是世界著名的大气化学家和这一应用的共同研究者（罗兰博士因其在大气气体成分方面的发现而获得1995年诺贝尔化学奖）。 罗兰/布莱克实验室现在可以可靠地测量气体浓度低至10份/千分之四，这是世界上无与伦比的灵敏度。 在过去的3年中，该实验室与UCI GCRC代谢核心之间的合作产生了一系列显著的观察结果（见初步结果），包括根据呼出的VOC曲线重建健康成人OGTT期间的血糖曲线，以及在T1 DM儿童高血糖症纠正期间跟踪血糖。 虽然有趣，但这些观察结果是在预先存在的实验方案中作为辅助发现进行的，增加必要的对照研究并通过标准糖尿病管理中预期的代谢改变范围彻底定义呼出气体模式的可能性有限。 我们认为，为了揭示这种方法的全部潜力，需要进行一系列严格控制的基础研究，详细建议如下。 总体目标： a）定义健康受试者和1型糖尿病（T1 DM）患者在血浆葡萄糖、胰岛素和游离脂肪酸（FFA）浓度的不同组合期间的呼出气体特征。 B）鉴定呼出气体分布与血浆葡萄糖、胰岛素、葡萄糖/胰岛素比、FFA、酮和氧化应激标志物之间的相关性。 c）生成预测算法，从气体分布图中估计我们感兴趣的变量的循环浓度。 这些总目标将在下列具体条件下实现： 具体目标1：快速诱导高血糖症，纠正高血糖症，正常血糖（正常血糖和高血糖都会发生，伴或不伴高胰岛素血症，高胰岛素血症会发生，伴或不伴循环FFA抑制） 具体目标#2：单次血糖水平延长（3小时高血糖、正常/高胰岛素血症、低血糖） 具体目标#3：生理性餐后高血糖症（单次高碳水化合物餐或多次小餐给药后）

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)