TO COMPARE THE RELIABILITY OF MMTT AND IV GLUCAGON STIMULATION TEST

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。最近的共识研讨会评估了潜在的替代标志物，如对胰岛细胞的免疫反应，HbA 1c，并发症或低血糖的发生率。这些潜在标志物中的每一个都被确定为具有局限性。抗疾病免疫应答的测量尚未显示与临床测量相关。HbA 1c不仅是β细胞分泌的不敏感指标，目前公认的“严格”血糖控制的临床治疗标准也混淆了HbA 1c作为临床试验终点的使用。此外，使用并发症或低血糖的发生率作为主要终点将需要多年或数十年的研究。 相比之下，直接评估残余β细胞功能是一个适当的终点，因为已知T1 D患者β细胞功能的保留可以改善血糖控制并减少低血糖、视网膜病变和肾病。内源性β细胞功能或胰岛素分泌最好通过测定C肽（与胰岛素以1：1摩尔比共分泌）来测量。过去几十年的干预研究通常使用测量对液体混合餐（混合餐耐受性试验; MMTT）或胰高血糖素静脉推注的C肽，作为残余β细胞功能的指示。然而，这些或其他β细胞功能指标之间的关系尚未得到很好的研究。此外，在变异性、敏感性和受试者负担方面，一种措施相对于另一种措施的相对优势尚不清楚。 因此，本提案的总体目标是选择最适合用于T1 D受试者干预研究的代谢检查。此外，还需要确定进行试验的最佳条件。这些选择的重要考虑因素包括了解测试的可变性以及测试对检测β细胞功能变化的敏感性。同样重要的是选择在大型临床试验中实际进行的测试。 总之，TrialNet代谢评估研究比较了MMTT和IV胰高血糖素刺激试验在T1 D中的可靠性，这将极大地促进未来TrialNet预防试验的优化设计和实施。此外，将从广泛的研究网络中获得的数据的种类和数量将在TrialNet范围之外加强对预防T1 D的研究。

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. A recent consensus workshop evaluated potential surrogate markers such as immune responses to islet cells, HbA1c, and rates of complicatons or hypoglycemia. Each of these potential markers was determined to have limitations. Measures of anti-ilset immune responses have not been shown to correlate with clinical measures. HbA1c is not only an insensitive measure of beta cell secretion, the currently accepted clinical treatment standard for "tight" glucose control confounds the use of HbA1c as an endpoint in clinical trials. In addition, use of rates of complications or hypoglycemia as a primary endpoint would require many years or decades of study. In contrast, direct assessment of residual beta cell function is an appropriate endpoint, as retention of beta cell function in patients with T1D is known to result in improved glycemic control and reduced hypoglycemia, retinopathy, and nephropathy. Endogenous beta cell function or insulin secretion is best measured by determination of C-peptide (which is co-secreted with insulin in a 1:1 molar ratio). Intervention studies over the past few decades have usually used measurement of C-peptide in response to a liquid mixed meal (mixed meal tolerance test; MMTT) or an introvenous bolus of glucagon as indicative of residual beta cell function. However, the relationship between these or other measures of beta cell funtion has not been well studied. In addition, the relative advantages of one measure over another in terms of variability, sensitivity and burden to the subject is unknown. The overall goal of this proposal therefore is to select the metabolic test that would be best to use for intervention studies in subjects with T1D. In addition, the optimal conditions for the conduct of the test need to be determined. Important considerations for these choices include knowing the variability of the test and how sensitive the test is to detect changes in beta cell function. Equally important is selecting the test that is practical to conduct in the context of a large clinical trial. In summary, the TrialNet Metabolic Assessment Study comparing the reliabilty of MMTT and IV Glucagon Stimulation Tests in T1D will greatly facilitate the optimal design and implementation of future TrialNet prevention trials. Moreover, the kind and quantity of data that will be derived from the extensive study network will enhance research into the prevention of T1D beyond the realm of TrialNet.