Assessing Beta Cell Loss and Islet Engraftment after Islet Autotransplantation

评估胰岛自体移植后的β细胞损失和胰岛移植情况

基本信息

批准号：
8851586
负责人：
Melena D. Bellin
金额：
$ 7.6万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851586
关键词：
Acute Address Affect Age Allogenic Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Arginine Autoimmune Diseases Autoimmune Process Autoimmunity Autologous Autologous Transplantation Beta Cell Biological Assay Blood Blood Circulation C-Peptide Cell Death Cell physiology Cells Clinical Trials Clinical Trials Design Coagulation Process Complement DNA Data Deposition Diabetes Mellitus Drug Combinations Engraftment Enrollment Excision Future Glucose Goals Health Hour Individual Inflammation Inflammatory Inflammatory Response Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Intervention Islets of Langerhans Transplantation Measurement Measures Mediating Mediator of activation protein Medical Metabolic Minnesota Multicenter Trials Natural Immunity Operative Surgical Procedures Outcome Outcome Measure Pancreas Pancreatectomy Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Population Procedures Protocols documentation Randomized Clinical Trials Reaction Sampling Serum Staging Stress Techniques Testing Therapeutic Therapeutic Agents Therapeutic Trials Time Total Pancreatectomy Toxic effect Transplantation Universities allotransplant chemokine chronic pancreatitis cytokine design diabetic patient improved innovation insulin secretion intravenous glucose tolerance test islet non-diabetic novel pilot trial prevent primary outcome response success type I diabetic

项目摘要

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.

描述（由申请人提供）：在慢性胰腺炎患者进行全胰腺切除术（TP）时进行胰岛自体移植（IAT），以预防或尽量减少术后糖尿病。只有 40% 的患者能够完全预防糖尿病。 IAT 的过程与 1 型糖尿病患者进行的同种异体胰岛移植相似，不同之处在于 IAT 不存在排斥反应或自身免疫反应，也没有排斥药物的毒性。两种形式的胰岛移植的成功都受到移植后立即发生的β细胞质量损失和胰岛植入不理想的限制。然而，我们缺乏统一的方法来测量移植后早期移植的胰岛质量，并且目前不存在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在很大程度上介导早期胰岛损失，但我们缺乏任何数据将这些因素与植入的胰岛质量直接相关。当前应用的目的是： 1) 确定哪些代谢测试可以作为移植后 90 天胰岛植入的最佳标志并作为长期结果的替代； 2) 验证非甲基化胰岛素 DNA（β 细胞特有的、从垂死的 β 细胞释放到循环中）的测量结果，作为胰岛输注后早期测量胰岛损失的方法； 3) 测量凝血、补体沉积和炎症的测量值并将其与胰岛损失和植入相关联，以确定哪些可能是未来干预的最佳目标。这项研究是临床试验的关键第一步，旨在确定可以改善胰岛移植的新药物疗法。为了有效地进行新的 DRU 干预措施的小型试点试验，我们必须对胰岛植入和胰岛损失进行可靠的早期测量，作为这些研究的终点。需要初步数据来确定哪些途径对于治疗目标来说可能是最重要的。为了实现这一目标，将招募 20 名年龄 10-65 岁、正在接受 TP-IAT 治疗严重慢性胰腺炎的非糖尿病患者并进行前瞻性研究，重点关注早期胰岛丢失和胰岛移植的早期测量。移植后第一周，患者将进行多次抽血，旨在测量胰岛输注后的先天炎症反应和凝血反应（拟议的胰岛丢失介质）。 β 细胞死亡的潜在标志，即非甲基化胰岛素 DNA 水平，将在 IAT 后第一周和第一个月的多个时间点进行测量，以验证该测试作为胰岛损失的新测量方法。最后，患者将在移植后 90 天返回进行详细的代谢测试，包括混合膳食耐受性测试、静脉内葡萄糖耐量测试和葡萄糖强化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哪些测试作为胰岛移植的测量最有用，以及哪些测试与 1 年胰岛素使用结果最相关。这将为未来临床试验中使用的代谢方案奠定基础。