IMPROVING METABOLIC ASSESSMENTS IN TYPE-1 DIABETES MELLITUS CLINICAL TRIALS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。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，在大型临床试验的背景下选择可行的试验。选择何种细胞功能指标作为1型糖尿病临床试验的主要结果，取决于在临床试验环境中进行测试的科学有效性需求与实际情况之间的平衡。虽然单独进行空腹c肽测试很容易，并且可能与受刺激的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，大多数研究涉及刺激c肽对非葡萄糖分泌剂的反应。欧洲人最常使用静脉注射胰高血糖素刺激试验。这个测试的优点是时间短（6分钟），但缺点是会引起短暂的恶心。其他人则使用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（大多数研究使用两个小时的测试期，有些则提倡四个小时）。最近的数据表明，在接受胰岛素强化治疗的受试者中，胰高血糖素刺激c肽的下降速度非常缓慢。这是由于生理刺激引起的胰高血糖素刺激试验不敏感，还是由于加强治疗后疾病自然史的变化尚不清楚。在强化治疗出现后进行的研究中，c肽对混合膳食试验的反应似乎也比以前的研究下降得更慢。直接评估剩余细胞功能是一个合适的终点，因为已知1型糖尿病患者的功能保留可以改善血糖控制，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的最佳测量方法是测定c肽（与胰岛素以1:1摩尔比共分泌）。过去几十年的干预研究通常使用c肽测量对液体混合餐的反应（混合餐耐受性试验，MMTT）或静脉注射胰高血糖素作为残余细胞功能的指示。然而，这些或其他测量细胞功能之间的关系还没有得到很好的研究。此外，在可变性、敏感性和对主题的负担方面，一种措施相对于另一种措施的相对优势是未知的。本研究将比较2小时MMTT和胰高血糖素刺激试验（GST）测量刺激c肽反应的可靠性。实验设计：本研究是一项多中心、两组、随机临床试验。对两组进行比较，主要目的是评估MMTT与静脉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进行四次测试。测试随机从MMTT或GST开始。在每次访问中，参与者接受血酮测量，以及MMTT或GST。此外，在第一次就诊时，参与者还测量了胰岛自身抗体和HbA1c。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.