Non-invasive Assessment of Insulin Resistance

描述（由申请人提供）：本资助的总体目标是开发一种非侵入性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测量方法，适用于大规模筛查研究和糖尿病发展风险患者的个性化预防策略。这种新方法是基于从正常葡萄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。它包括给药一种标准的口服葡萄糖耐量试验溶液，其中含有少量的非放射性（稳定同位素）13c6 -葡萄糖，然后测量呼吸中的13CO2同位素富集程度。在该项目的第一阶段，我们已经建立了这种方法的概念验证和可行性。我们已经证明，该方法与胰岛素抵抗的常用指标的相关性与已发表的这些指标和目前公认的金标准（即葡萄糖钳）具有相似的统计强度。我们也证明了呼气测试作为IGT测量的个体间可重复性是可接受的低，它与OGTT的相关性足够高，允许其发展为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、三个常用指标（HOMA-IR、QUICKI和WBISI）和标准OGTT相比的个体内和个体间变异性；2)评估我们提出的呼吸试验、葡萄糖钳、常见指标和OGTT之间的相关性，这些个体的血糖从正常葡萄糖耐量（NGT）到糖耐量受损（IGT）再到糖尿病，其体重指数（BMI）涵盖了从瘦到肥胖的范围。我们预计，二期研究的成功完成将导致胰岛素抵抗评估的常规方法的发展，以及用于筛查和个体化预防研究的非侵入性IGT测试。在成功完成第二期研究并获得非sbir资助后，我们将建立一个中央设施，生产和销售适当的“测试套件”以及必要的分析专业知识，使所有感兴趣的各方都可以使用该方法进行临床或研究。公共卫生相关性：胰岛素抵抗和糖耐量受损是公共卫生主要关注的严重慢性疾病的早期表现：糖尿病、慢性心脏病、肥胖、高血压等。早期识别对预防很重要。目前评估胰岛素抵抗的“金标准”是所谓的葡萄糖钳，不适合临床对患者的通用管理。目前可用的替代方法，即所谓的共同指数，对于其相应的葡萄糖钳位的任何给定值，显示出很大的个体间变异性，因此，不适合个体化预防目的。在这个SBIR项目的第一阶段，我们已经证明了无创呼吸测试有潜力成为葡萄糖钳的合适替代测试，并作为葡萄糖耐量受损（糖尿病前期）的无创测量。在第二阶段，我们建议开发该测试，并证明其与葡萄糖钳和口服葡萄糖耐量测试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.