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

描述（由申请人提供）：在进行预防或延迟1型糖尿病发作的治疗的临床试验中的一个挑战是需要对大量受试者进行多年的测试。这四项旨在预防1型糖尿病的完全有效的试验花了6-12年时间完成，涉及筛选超过10万名受试者。这种努力的局限性有效地限制了可以评估的治疗方法的数量。应对这一挑战的策略包括改善风险分层，以及在发生1型糖尿病之前使用临床和生物学相关的替代终点。由于治疗的设计目的是延迟或停止进行性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有用。如下文进一步讨论的，对静脉内（IV）或口服葡萄糖的异常反应已与自身抗体状态一起沿着成功地用于风险分层，从而用于预防1型糖尿病的临床试验的进入标准。然而，虽然这些措施是预测疾病，但有许多人具有显著低的胰岛素分泌到IV葡萄糖，他们不会发展为1型糖尿病。此外，令人惊讶的是，在1型糖尿病发病前几年，c肽对口服葡萄糖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，这些测量无法稳健地跟踪疾病进展意味着所使用的测量不足以反映β细胞功能。本研究的目的是评估β细胞功能的另一种测量方法，急性最大胰岛素分泌（AIRmax），在1型糖尿病风险个体中。AIRmax是一种动态试验，用于测量在存在显著高血糖的情况下精氨酸对急性胰岛素的反应。它被认为反映了β细胞分泌能力。假设AIRmax是一种比目前使用的测试更敏感的β细胞功能指标，其重现性和耐受性使其成为风险分层的合适指标，并作为临床试验中改变疾病进展的生物学和临床相关终点。如果是真的，那么可以使用替代代谢终点，在更少的受试者和更短的时间内进行初始临床试验，以确定治疗对风险个体疾病进展的影响，从而允许为后续确定性研究选择治疗，并促进新药转化为临床应用。 公共卫生相关性：1型糖尿病（T1 DM）是儿童和成人的免疫介导的疾病，其中产生胰岛素的β细胞完全或接近完全被破坏，导致对外源性胰岛素的终身依赖。尽管治疗方法有所改进，但1型糖尿病患者仍面临显著的发病率和早期死亡率;因此，预防疾病的发作将代表着重大的进步。本提案中描述的替代代谢生物标志物的验证将有助于测试预防疾病的新疗法。

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.