Non-invasive Assessment of Insulin Resistance

描述(由申请人提供)：这笔赠款的总体目标是开发一种非侵入性的方法来评估胰岛素抵抗和糖耐量受损(IGT)，作为糖尿病前期的一种衡量标准，适用于大规模筛查研究和有糖尿病风险的患者的个性化预防策略。这一新方法是基于从正常糖耐量到糖耐量受损再到糖尿病过程中全身燃料利用组合的已知变化。它包括服用标准的口服葡萄糖耐量测试液，该溶液另外还含有少量的非放射性(稳定同位素)13C6-葡萄糖，然后测量呼气13CO2同位素浓缩。在该项目的第一阶段，我们已经确定了该方法的概念验证和可行性。我们已经证明，该方法与常见的胰岛素抵抗指数的相关性与已发表的这些指数和目前公认的金标准即葡萄糖钳夹相比较，具有相似的统计强度。我们还证明，呼气试验作为IGT的一种测量方法，其个体间的重复性是可以接受的，它与OGTT的相关性足够高，足以使其成为IGT的非侵入性测试。在第二阶段，我们将进行一系列临床研究，以：1)评估我们的方法与葡萄糖钳夹方法、三种常见指数(HOMA-IR、QUICKI和WBISI)以及标准OGTT之间的个体内和个体间变异性；以及2)评估我们建议的呼气试验、葡萄糖钳夹、常见指数和OGTT之间的相关性，这些患者的血糖范围从正常糖耐量(NGT)、糖耐量受损(IGT)到糖尿病，且身体质量指数(BMI)涵盖从瘦到肥胖的范围。我们预计，第二阶段研究的成功完成将导致开发一种评估胰岛素抵抗的常规方法和一种非侵入性的IGT检测方法，用于筛查和个体化预防研究。在成功完成第二阶段研究后，在非SBIR资助下，我们将建立一个中央设施，生产和销售适当的“检测试剂盒(S)”以及必要的分析专业知识-使该方法可供所有感兴趣的各方用于临床或研究目的。与公共卫生相关：胰岛素抵抗和糖耐量受损是严重的慢性疾病的早期表现，这些疾病主要涉及公众健康：糖尿病、慢性心脏病、肥胖症、高血压等。及早认识到这些疾病对于预防非常重要。目前，评估胰岛素抵抗的“金标准”是所谓的葡萄糖钳夹法，这并不适用于患者的一般临床治疗。目前可用的替代方法，即所谓的共同指数，对于相应的葡萄糖钳钳的任何给定值，都显示出很大的个体间变异性，因此不适合于个体化预防目的。在SBIR计划的第一阶段，我们已经证明，无创呼气测试有可能成为葡萄糖钳夹的合适替代测试，并作为糖耐量受损(糖尿病前期)的非侵入性测量。在第二阶段，我们建议开发这项测试，并证明它与葡萄糖钳夹试验和口服葡萄糖耐量试验都具有高度的线性相关性。

DESCRIPTION (provided by applicant): The overall objective of this grant is to develop a non-invasive method for assessment of insulin resistance and impaired glucose tolerance (IGT) as a measure of pre-diabetes suitable for application to large-scale screening studies and to individualized preventive strategies in patients at risk for development of diabetes. This new approach is based on the known alterations in the mix of whole-body fuel utilization that occurs during progression from normal glucose tolerance to impaired glucose tolerance to diabetes. It involves administration of a standard oral glucose tolerance test solution that contains, in addition, a small quantity of the non-radioactive (stable isotope) 13C6-glucose, followed by measurement of breath 13CO2 isotope enrichment. During Phase-I of this project, we have established the proof-of-concept and feasibility of this approach. We have demonstrated that the correlation of the said method with the common indices of insulin resistance possesses similar statistical strength compared with those published for these indices and the currently accepted gold standard, i.e. the glucose-clamp. We have also demonstrated that inter-individual reproducibility of the breath test as a measure of IGT is acceptably low and its correlation with OGTT sufficiently high to permit its development as a non-invasive test of IGT. During Phase-II, we will conduct a number of clinical investigations to: 1) evaluate the intra- and inter-individual variability of our method compared to the glucose-clamp, the three common indices (HOMA-IR, QUICKI, and WBISI), and the standard OGTT; and 2) to evaluate the correlation between our proposed breath test, the glucose-clamp, common indices, and OGTT in individuals whose glycemia ranges from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to diabetes and whose body mass index (BMI) covers the range from lean to obese. We anticipate that successful completion of the Phase-II research will lead to the development of a routine method for assessment of insulin resistance and a non-invasive test of IGT for application to screening and individualized preventive studies. After successful completion of Phase-II research and with non-SBIR funding, we will establish a central facility to produce and market appropriate "test kit(s)" along with the necessary analytical expertise - making the method available to all interested parties for clinical or research purposes. PUBLIC HEALTH RELEVANCE: Insulin resistance and impaired glucose tolerance are early manifestations of serious chronic disorders of major concern to public health: diabetes, chronic heart disease, obesity, hypertension, etc. Their early recognition is important for preventive purposes. Currently, the "Gold Standard" for assessing insulin resistance is the so-called glucose-clamp, which is not suitable for general-purpose clinical management of patients. The surrogate methods available currently, the so-called Common indices show large inter- individual variability's for any given value of their corresponding glucose-clamp and, thus, are not suitable for individualized preventive purposes. During Phase-I of this SBIR program, we have demonstrated that a non- invasive Breath Test has the potential to be a suitable surrogate test for the glucose-clamp and as a non- invasive measure of impaired glucose tolerance (pre-diabetes). During Phase-II, we propose to develop this test and to demonstrate its high linear correlation with both the glucose-clamp and oral glucose tolerance test.