Long-Term Islet Function and Impact after Total Pancreatectomy with Islet Autotransplant (LIFT)

全胰腺切除术联合胰岛自体移植 (LIFT) 后的长期胰岛功能和影响

基本信息

批准号：
10540722
负责人：
Melena D. Bellin
金额：
$ 63.52万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10540722
关键词：
Alpha Cell Anatomy Autologous Transplantation Beta Cell Blinded Blood Glucose C-Peptide Cell physiology Cellular Stress Chronic Clinical Closure by clamp Complex Complications of Diabetes Mellitus Continuous Glucose Monitor Cross-Sectional Studies Data Diabetes Mellitus Diabetic Ketoacidosis Diabetic Retinopathy Dose Early treatment Enrollment Event Excision Face Functional disorder Fund Raising Future Glucagon Glycosylated hemoglobin A Goals Hormonal Hormones Hospitalization Hypoglycemia Impairment Insulin Insurance Intractable Pain Islets of Langerhans Transplantation Kidney Diseases L Cells Measurement Measures Mediating Medicaid Medical Medicare Microvascular Dysfunction Neuropathy Operative Surgical Procedures Opioid Outcome Pain Pancreas Participant Patients Physicians Population Postoperative Period Procedures Production Proinsulin Protocols documentation Quality of life Recurrence Regulation Reporting Research Retinal Diseases Risk Risk Reduction Severities Source Testing Time Total Pancreatectomy acute pancreatitis chronic pancreatitis clinical care clinically significant cohort counterregulation diabetes management duodenectomy endoplasmic reticulum stress glucagon-like peptide 1 glycemic control graft function improved incretin hormone insulin secretion islet macrovascular disease pain relief patient subsets preservation prevent public health relevance reconstruction recruit response

项目摘要

Abstract Total pancreatectomy with islet autotransplant (TPIAT) is performed to treat the severe, intractable pain of chronic pancreatitis for patients who have failed medical or endoscopic therapies. The TP relieves the source of pain, while the IAT reduces risk or severity of post-operative diabetes; after 1 year, up to 40% of patients are off insulin and nearly 90% have islet function (C-peptide positive). However, little is known about the long-term function of the islet graft. Rigorous studies are needed to determine what proportion of patients maintain islet function long term and whether islet function improves glycemic control and reduces diabetes complications in this population. This carries high potential for impact in clinical care: currently some patients are denied coverage for IAT due to lack of rigorous studies establishing the benefit of IAT. Furthermore, we know little about how changes in gut anatomy and associated hormones (GLP-1) and alpha cell dysregulation (glucagon) of intraportally transplanted islets impact long-term glycemic regulation. Hypoglycemia has been increasingly reported after TPIAT, with exaggerated incretin response and/or defective glucagon counterregulation suggested as possible mechanisms. We propose to study islet function, glycemic control, diabetes complications, and mechanisms impacting glycemic control (incretin hormone axis, counterregulatory hormones) in patients who are 5-20 years out from TPIAT. The study’s overall aim is to determine the long-term benefit of IAT. To assess islet graft function, we will use C-peptide levels from mixed meal tolerance testing (MMTT) as the marker of endogenous islet function. We will enroll at least 200 participants in this cross-sectional study, who are 5-20 years after TPIAT for chronic or recurrent acute pancreatitis. The study's first aim is to determine the proportion of patients who maintain islet graft function 5-20 years after TPIAT and to determine whether C-peptide levels from a MMTT are associated with concurrent glycemic control measures. The second aim is to determine whether islet graft function is inversely associated with diabetes-specific complications (severe hypoglycemia, diabetic ketoacidosis, and micro- or macrovascular disease). The third aim is to determine other mechanisms that impact long-term glycemic control in TPIAT, including incretin function, alpha cell function, and markers of beta cell stress. As an exploratory aim we will recruit a subgroup of patients who are 5-20 years out from TP alone to undergo the same testing protocol for comparison with TPIAT recipients without and with graft function. This study's significance lies in its potential to directly impact clinical care and access to IAT when TP is needed. We hypothesize that islet graft function improves glycemic control and reduces diabetes complications even in recipients who are not insulin-independent, but that dysfunctional incretin and counter-regulatory responses will impact hypoglycemia risk.

抽象的进行全胰腺切除术联合胰岛自体移植 (TPIAT) 是为了治疗严重、顽固性疼痛对于药物或内镜治疗失败的慢性胰腺炎患者来说，TP 可以缓解其根源。疼痛，虽然 IAT 降低了术后 1 年后患糖尿病的风险或严重程度，但高达 40% 的患者出现这种情况；停用胰岛素，近 90% 具有胰岛功能（C 肽阳性），但对其长期影响知之甚少。需要进行严格的研究来确定保留胰岛的患者比例。长期功能以及胰岛功能是否可以改善血糖控制并减少糖尿病并发症这对临床护理具有很大的影响潜力：目前，一些患者被拒绝接受治疗。由于缺乏严格的研究来证明 IAT 的好处，因此我们对 IAT 的覆盖范围也知之甚少。关于肠道解剖结构和相关激素 (GLP-1) 以及 α 细胞失调（胰高血糖素）的变化门静脉移植胰岛对长期血糖调节的影响越来越大。 TPIAT 后报告，肠促胰岛素反应过度和/或胰高血糖素反调节有缺陷建议作为可能的机制。我们建议研究胰岛功能、血糖控制、糖尿病并发症以及影响机制 5-20 年后患者的血糖控制（肠促胰岛素激素轴、反调节激素） TPIAT。该研究的总体目标是确定 IAT 的长期益处，我们评估胰岛移植物的功能。将使用混合膳食耐受性测试 (MMTT) 中的 C 肽水平作为内源性胰岛的标记我们将招募至少 200 名 TPIAT 后 5-20 年的参与者参与这项横断面研究。该研究的首要目的是确定患有慢性或复发性急性胰腺炎的患者比例。 TPIAT 后 5-20 年维持胰岛移植物功能，并确定 MMTT 中的 C 肽水平是否与同时进行的血糖控制措施相关的第二个目的是确定是否进行胰岛移植。功能与糖尿病特异性并发症（严重低血糖、糖尿病第三个目标是确定其他机制。影响 TPIAT 的长期血糖控制，包括肠促胰素功能、α 细胞功能和 β 标记物作为探索性目标，我们将招募一组距 TP 还剩 5-20 年的患者。接受相同的测试方案，以与无移植功能和有移植功能的 TPIAT 受者进行比较。该研究的意义在于它有可能直接影响临床护理和需要 TP 时获得 IAT 的机会。我们的重点是胰岛移植功能可以改善血糖控制并减少糖尿病并发症，即使在不依赖胰岛素，但肠促胰岛素功能失调和反调节反应的接受者会影响低血糖风险。