AIRmax as sensitive measure of beta cell function in at-risk individuals

描述(由申请人提供)：在进行预防或推迟1型糖尿病发病的治疗的临床试验中，一个挑战是需要多年测试的大量受试者。这四项旨在预防1型糖尿病的全能试验耗时6-12年完成，涉及对10万多名受试者进行筛查。这种努力的巨大程度实际上限制了可以评估的治疗方法的数量。应对这一挑战的战略包括改进风险分层，以及在1型糖尿病发生之前使用临床和生物学上相关的替代终点。由于设计治疗的目的是延缓或阻止进行性的β细胞功能障碍和破坏，因此β细胞功能的测量预计在这两个方面都是有用的。正如下面进一步讨论的，静脉(IV)或口服葡萄糖的异常反应已经成功地与自身抗体状态一起用于风险分层，从而进入预防1型糖尿病的临床试验的标准。然而，虽然这些指标是疾病的预测指标，但仍有许多胰岛素分泌到静脉血糖明显降低的个体并未进展为1型糖尿病。此外，令人惊讶的是，在1型糖尿病发病前的几年里，口服葡萄糖对C肽的反应几乎没有变化。由于1型糖尿病是由β细胞破坏引起的，这些测量方法无法有力地跟踪疾病的进展，这意味着所用的测量方法不能充分反映β细胞的功能。这项研究的目的是评估另一项衡量胰岛β细胞功能的指标-急性最大胰岛素分泌(AImax)，在1型糖尿病风险人群中。Airmax是一种动态测试，用于测量在存在明显高血糖的情况下对精氨酸的急性胰岛素反应。它被认为是反映β细胞分泌能力的指标。假设Airmax是比目前使用的测试更敏感的β细胞功能指标，其重复性和耐受性使其成为风险分层的合适指标，并在临床试验中作为生物学和临床相关的终点来改变疾病进展。如果是真的，那么确定治疗对高危人群疾病进展的影响的初始临床试验可以使用代谢性代谢终点进行，受试者更少，时间更短，从而允许为后续的最终研究选择治疗方法，并促进将新药物转化为临床使用。 公共卫生相关性：1型糖尿病(T1 DM)是一种儿童和成人的免疫调节疾病，在这种疾病中，产生胰岛素的β细胞完全或几乎完全被破坏，导致终身依赖外源性胰岛素。尽管治疗方法有所改进，但1型糖尿病患者仍面临严重的发病率和早期死亡率；因此，预防疾病的发病将是一个重大的进步。本提案中描述的代谢性代谢生物标记物的验证将有助于测试预防该疾病的新疗法。

DESCRIPTION (provided by applicant): A challenge in the conduct of clinical trials of therapies to prevent or delay the onset of type 1 diabetes is the large numbers of subjects needed to be tested over many years. The four completed fully powered trials aimed to prevent type 1 diabetes took 6-12 years to complete and involved screening more than 100,000 subjects. The enormity of such efforts effectively limits the number of therapies that can be evaluated. Strategies to address this challenge include improved risk stratification and the use of clinically and biologically relevant surrogate endpoints prior to the development of type 1 diabetes. Because therapies are designed with the intent to delay or halt progressive beta cell dysfunction and destruction, measures of beta cell function are expected to be useful in both aspects. As further discussed below, abnormal responses to intravenous (IV) or oral glucose have been successfully used along with autoantibody status for risk stratification and thus entry criteria for clinical trials to prevent type 1 diabetes. Yet, while these measures are predictive o disease, there are many individuals with markedly low insulin secretion to IV glucose who do not progress to type 1 diabetes. Moreover, there is surprisingly little change in c-peptide response to oral glucose in the years prior to type 1 diabetes onset. Since type 1 diabetes results from beta cell destruction, the inability of these measures to robustly track with disease progression implies that the measures used are an inadequate reflection of beta cell function. The aim of this study is to evaluate another measure of beta cell function, acute maximal insulin secretion (AIRmax), in individuals at risk for type 1 diabetes. AIRmax is a dynamic test that measures the acute insulin response to arginine in the presence of marked hyperglycemia. It is considered to reflect beta cell secretory capacity. The hypothesis is that AIRmax is a more sensitive measure of beta cell function than currently used tests and that its reproducibility and tolerability make t a suitable measure for risk stratification and as a biologically and clinically relevant endpoint in clinical trials to alter disease progression. If true, then initial clinical trials to determine th effect of therapies on disease progression in at risk individuals could be conducted using surrogate metabolic endpoints with fewer subjects and for shorter periods of time, thus allowing selection of therapies for subsequent definitive studies and facilitating translation of novel agents into clinical use. PUBLIC HEALTH RELEVANCE: Type 1 diabetes mellitus (T1DM) is an immune-mediated disease of children and adults in which insulin- producing beta cells are completely or near completely destroyed, resulting in life-long dependence on exogenous insulin. Despite improved treatments, individuals with type 1 diabetes still face significant morbidity and early mortality; thus, prevention of the onset of the disease would represent a significant advancement. Validation of surrogate metabolic biomarkers as described in this proposal will facilitate testing of novel therapies to prevent the disease.