IMPROVING METABOLIC ASSESSMENTS IN TYPE-1 DIABETES MELLITUS CLINICAL TRIALS

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来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。本研究的目的是选择最适合用于1型糖尿病受试者干预研究的代谢试验，并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。在1型糖尿病临床试验中，选择何种细胞功能测量应作为主要结果，取决于平衡科学有效性的需要与在临床试验环境中进行测试的实际现实。 虽然单独的空腹C肽测试很容易执行，并且可能与刺激的C肽结果很好地相关，但这可能不足以检测治疗的微妙效果。对于临床后诊断，大多数研究涉及对非葡萄糖促分泌素的刺激C肽反应。欧洲人最常使用静脉（IV）胰高血糖素刺激试验。这具有测试时间短（6分钟）的优点，但缺点是会引起短暂的恶心。其他人使用C肽对液体混合餐（Sustacal/Boost）的反应。虽然这不会引起恶心，但确实需要更多的时间（大多数研究使用两小时的测试期，有些人主张四小时）。最近的数据表明，接受强化胰岛素治疗的受试者中胰高血糖素刺激的C肽的下降速率非常缓慢。这是由于超生理刺激导致胰高血糖素刺激试验不敏感，还是由于强化治疗后疾病的自然病程发生变化，目前尚不清楚。与早期研究相比，在强化治疗出现后进行的研究中，对混合餐试验的C肽反应似乎下降得不那么快。 直接评估残留的胰岛细胞功能是一个适当的终点，因为已知1型糖尿病患者的功能保留可改善血糖控制并减少低血糖、视网膜病变和肾病。内源性- 细胞功能或胰岛素分泌最好通过测定C-肽（其与胰岛素以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IV推注的C肽反应作为残余细胞功能的指示。然而，这些或其他衡量细胞功能的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。本研究将比较来自2小时MMTT和胰高血糖素刺激试验（GST）的刺激C肽反应测量值的可靠性。 实验设计：本研究是一项多中心、双臂、随机临床试验。在两组之间进行比较，主要目的是评估MMTT与IV胰高血糖素输注试验的可靠性差异。根据测试顺序分配，每个参与者在有限的时间内接受四次测试。测试随机从MMTT或GST开始。在每次访视时，参与者接受血酮测量，以及MMTT或GST。此外，在第一次访问时，参与者测量了胰岛自身抗体和HbA 1c。每次访问间隔3-10天。

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. The purpose of this study is to select the metabolic test that will be best to use for intervention studies in subjects with Type-1 Diabetes and to determine the optimal conditions for the conduct of the test. Important considerations for these choices include knowing the variability of the test and how sensitive the test is to detect changes in ¿-cell function. Equally important is selecting the test that is practical to conduct in the context of a large clinical trial. The choice of what measure of ¿-cell function should be used as a primary outcome in clinical trials of Type-1 Diabetes depends upon balancing the need for scientific validity with the practical realities of performing the tests in a clinical trial setting. While fasting C-peptide tests alone are easy to perform and may correlate well with stimulated C-peptide results, this may be insufficient to detect subtle effects of therapy. For post-clinical diagnosis, most studies involve a stimulated C-peptide response to non-glucose secretagogues. Europeans have most often used intravenous (IV) glucagon-stimulated testing. This has the advantage of being a short test (6 minutes), but the disadvantage of causing transient nausea. Others have used C-peptide responses to a liquid mixed meal (Sustacal/Boost). Though this does not induce nausea, it does require more time (most studies have used a two-hour testing period and some have advocated four hours). Recent data suggests that the rate of fall of glucagon stimulated C-peptide among subjects receiving intensive insulin treatment is very slow. Whether this is due to insensitivity of the glucagon stimulation test because of supraphysiological stimulation or to a changing natural history of the disease with intensive treatment is not known. C-peptide responses to mixed meal tests also seem to fall less rapidly in studies conducted after the advent of intensive therapy as compared with older investigations. Direct assessment of residual ¿-cell function is an appropriate endpoint, as retention of function in patients with Type-1 Diabetes is known to result in improved glycemic control and reduced hypoglycemia, retinopathy, and nephropathy. Endogenous ¿-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 IV bolus of glucagon as indicative of residual ¿-cell function. However, the relationship between these or other measures of ¿-cell function 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. This study will compare the reliability of measures of stimulated C-peptide response derived from the 2-hour MMTT and the glucagon stimulation test (GST). Experimental Design: The study is a multicenter, two-arm, randomized clinical trial. Comparisons are made between the two groups, with the primary objective of assessing the difference in reliability of the MMTT versus the IV glucagon infusion test. Each participant undergoes four tests within a limited period according to the test sequence assignment. The tests randomly start with either MMTT or GST. At each visit, participants undergo measurement of blood ketones, and either an MMTT or GST. In addition, at the first visit, participants have measurements of islet autoantibodies and HbA1c. Each visit is separated by 3-10 days.