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：
10328905
负责人：
Melena D. Bellin
金额：
$ 63.92万
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/10328905
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 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 Health Services Accessibility 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 Severities Source Testing Time Total Pancreatectomy acute pancreatitis chronic pancreatitis clinical care clinically significant cohort counterregulation diabetes management diabetes risk duodenectomy endoplasmic reticulum stress glucagon-like peptide 1 glucose monitor glycemic control graft function improved improved functioning 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.

抽象的用胰岛自养植物（TPIAT）进行总胰腺切除术（TPIAT），以治疗严重的，棘手的疼痛慢性胰腺炎，用于患有医疗或内窥镜疗法失败的患者。 TP营救了来源疼痛，而IAT降低了术后糖尿病的风险或严重程度； 1年后，多达40％的患者是 OFF胰岛素和几乎90％的胰岛功能（C肽阳性）。但是，长期知之甚少胰岛移植的功能。需要严格的研究以确定哪些比例维持胰岛长期功能以及胰岛功能是否改善血糖控制并减少糖尿病并发症这个人口。这在临床护理中具有很高的影响潜力：目前有些患者被拒绝由于缺乏严格的研究，IAT的覆盖范围确定了IAT的益处。此外，我们知道关于肠道解剖学和相关激素（GLP-1）和α细胞失调（胰高血糖素）的变化如何变化中间移植的胰岛影响长期血糖调节。低血糖越来越多 TPIAT报道，夸张的增加响应和/或缺陷的读写症。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的机制在5 - 20年以外的患者中，血糖控制（肠降低的马酮轴，反调节骑马） tpiat。该研究的总体目的是确定IAT的长期益处。为了评估胰岛移植功能，我们将使用混合餐耐受性测试（MMTT）中的C肽水平作为内源性胰岛的标记功能。我们将至少有200名参与者参加这项横断面研究，他们是TPIAT 5 - 20年用于慢性或复发性急性胰腺炎。该研究的第一个目的是确定在TPIAT后5 - 20年保持胰岛移植功能，并确定MMTT的C肽水平是否与并发的血糖控制措施有关。第二个目的是确定胰岛移植是否是否功能与糖尿病特异性并发症成反比（严重低血糖症，糖尿病患者酮症酸中毒，微血管疾病）。第三个目的是确定其他机制影响TPIAT的长期血糖控制，包括增加功能，α细胞功能和β的标记细胞应激。作为探索性目的，我们将招募一个仅在TP出发的5 - 20年的患者子组要经历相同的测试协议，以与没有移植功能的TPIAT接收者进行比较。这研究的意义在于其在需要TP时直接影响临床护理和进入IAT的潜力。我们假设胰岛移植功能可以改善血糖控制，并减少糖尿病并发症不是独立胰岛素的接受者，而是功能失调的增加和反调节反应会影响低血糖风险。