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

摘要 全胰腺切除加自体胰岛移植(TPIAT)用于治疗严重的顽固性胰腺癌疼痛。 慢性胰腺炎，用于内科或内窥镜治疗失败的患者。从源头上解脱 疼痛，而IAT降低了术后糖尿病的风险或严重程度；一年后，多达40%的患者 停用胰岛素，近90%有胰岛功能(C肽阳性)。然而，人们对长期情况知之甚少。 胰岛移植物的功能。需要进行严格的研究来确定维持胰岛的患者比例 长期功能和胰岛功能是否改善血糖控制和减少糖尿病并发症 这群人。这在临床护理中具有很高的潜在影响：目前一些患者被拒绝 由于缺乏确定IAT益处的严格研究，因此覆盖了IAT的覆盖面。此外，我们知道的很少 关于肠道解剖和相关激素(GLP-1)和α细胞失调(胰高血糖素)的变化 门脉内移植的胰岛会影响长期的血糖调节。低血糖的情况越来越严重 TPIAT后报告，胰岛素反应夸大和/或胰高血糖素反调节缺陷 建议作为可能的机制。 我们建议研究胰岛功能、血糖控制、糖尿病并发症及其影响机制。 5-20岁以下患者的血糖控制(胰岛素激素轴、逆调节激素) TIPIAT。这项研究的总体目标是确定IAT的长期益处。为了评估胰岛移植的功能，我们 将混合餐耐量试验的C-肽水平作为内源性胰岛的标志物 功能。我们将招募至少200名参与者参加这项横断面研究，他们是TPIAT后5-20年的人 适用于慢性或复发性急性胰腺炎。这项研究的第一个目标是确定 在TPIAT后5-20年维持胰岛移植物功能，并测定MMTT法测定的C-肽水平 与同时采取的血糖控制措施有关。第二个目标是确定胰岛移植物 功能与糖尿病特有的并发症(严重低血糖、糖尿病 酮症酸中毒和微血管或大血管疾病)。第三个目标是确定其他机制 对TPIAT患者长期血糖控制的影响，包括胰岛素功能、α细胞功能和β-标记物 细胞压力。作为一项探索性目标，我们将招募一组仅离开TP 5-20年的患者 接受相同的检测方案，与无移植物功能和有移植物功能的TPIAT受者进行比较。这 这项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。 我们假设，胰岛移植功能改善了血糖控制，减少了糖尿病并发症，即使在 非胰岛素依赖型受者，但存在胰岛素分泌功能障碍和逆调节反应 会影响低血糖风险。

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.