Assessing Beta Cell Loss and Islet Engraftment after Islet Autotransplantation

描述(申请人提供)：胰岛自体移植(IAT)是在慢性胰腺炎患者行全胰腺切除术(TP)时进行的，以预防或减少术后糖尿病。只有40%的患者完全预防了糖尿病。IAT的过程类似于对1型糖尿病患者进行的同种异体胰岛移植，不同之处在于IAT没有排斥或自身免疫，也没有排斥药物的毒性。这两种形式的胰岛移植的成功都受到移植后即刻发生的β细胞团丢失和胰岛植入不佳的限制。然而，我们缺乏一个统一的方法来测量移植后早期移植的胰岛质量，目前还没有直接测量胰岛损失的技术。此外，虽然我们知道急性非特异性炎症等因素可能是早期胰岛丢失的主要中介因素，但我们缺乏任何数据来直接将这些因素与植入的胰岛质量相关联。目前应用的目的是：1)确定哪些代谢试验可以作为移植后90天胰岛植入的最佳标记物，并作为长期结果的替代；2)验证未甲基化胰岛素DNA的测量作为测量胰岛输注后早期胰岛丢失的手段； 3)测量凝血、补体沉积和炎症指标，并将其与胰岛丢失和植入相关联，以确定哪些可能是未来干预的最佳靶点。这项研究是迈向临床试验的关键的第一步，以确定可能改善胰岛植入的新药治疗。为了用新的DRU干预有效地进行小规模的先导试验，我们必须有可靠的早期胰岛植入和胰岛丢失的测量作为这些研究的终点。需要初步数据来确定哪些通路可能是靶向治疗最重要的。为实现这一目标，20名年龄10-65岁的非糖尿病患者接受TP-IAT治疗重症慢性胰腺炎，他们将被纳入并进行前瞻性研究，重点是早期胰岛丢失和胰岛植入的早期措施。患者将在移植后的第一周进行多次抽血，目的是测量输入胰岛时的先天炎症反应和凝血反应(建议的胰岛丢失介质)。在IAT后的第一周和一个月内，将在多个时间点测量β细胞死亡的潜在标记物未甲基化胰岛素DNA水平，以验证该测试作为胰岛丢失的新测量。最后，患者将在移植后90天返回接受详细的代谢测试，包括混合餐耐量测试、静脉葡萄糖耐量测试和葡萄糖增强精氨酸诱导的胰岛素分泌研究。我们将使用这些数据来确定什么测试(S)可能是最有用的胰岛植入测量，以及哪些测试与一年的胰岛素使用结果最相关。这将为代谢方案在未来的临床试验中使用奠定基础。

DESCRIPTION (provided by applicant): Islet autotransplant (IAT) is performed at the time of total pancreatectomy (TP) in patients with chronic pancreatitis, to prevent or minimize postsurgical diabetes. Diabetes is completely prevented in only 40% of patients. The procedure of IAT is similar to allogenic islet transplantation performed in patients with type 1 diabetes, except that in the case of IAT, there is no rejection or autoimmunity, or toxicity from rejection drugs. The success of both forms of islet transplantation is limited by the loss of beta cell mass that occurs in the immediate posttransplant period, and suboptimal islet engraftment. However, we lack a uniform approach to measure engrafted islet mass early after transplant, and no techniques currently exist to directly measure islet loss. Furthermore, while we know that factors such as acute non-specific inflammation likely mediate much of this early islet loss, we lack any data to directly correlate these factors with engrafted islet mass. The aims of the current application are: 1) To determine which metabolic tests may serve as the best marker of islet engraftment at 90 days post-transplant and as a surrogate for long-term outcomes; 2) To validate the measurement of unmethylated insulin DNA-unique to the beta cell and released from dying beta cells into circulation-as a means to measure islet loss early after islet infusion; and 3) To measure and correlate measures of coagulation, complement deposition, and inflammation with islet loss and engraftment to identify which may be the best targets of future interventions. This study is a key first step towards clinical trials to identify new drug therapie that may improve islet engraftment. In order to efficiently conduct small pilot trials with new dru interventions, we must have reliable early measures of islet engraftment and islet loss as endpoints in these studies. Preliminary data is needed to identify which pathways may be most important to target therapeutically. To accomplish this, 20 non-diabetic patients age 10-65 years who are undergoing TP-IAT for management of severe chronic pancreatitis will be enrolled and studied prospectively, with a focus on early islet loss and early measures of islet engraftment. Patients will have multiple blood draws in the first week post-transplant aimed at measuring the innate inflammatory response and coagulation response upon infusion of the islets (proposed mediators of islet loss). A potential marker of beta cell death, the unmethylated insulin DNA level, will be measured at multiple time points over the first week and month after IAT, to validate this test as a novel measure of islet loss. Finally, patients will return for detailed metabolic testing at 90 days post-transplant, including mixed meal tolerance testing, intravenous glucose tolerance testing, and glucose potentiated arginine-induced insulin secretion studies. We will use this data to determine what test(s) may be most useful as a measure of islet engraftment, and which correlate best with 1 year insulin use outcomes. This will set the stage for metabolic protocols to be used in future clinical trials.