Pancreas and Islet Transplantation in Humans

描述（由申请人提供）：本项目的前提是，常规使用肝内部位进行胰岛移植是导致移植受者低血糖期间β细胞和α细胞功能异常的关键因素。我们的方法是研究慢性胰腺炎患者在肝和非肝部位接受全胰腺切除术和自体胰岛移植（TP/AIT）的肝内胰岛功能。使用自体胰岛受体进行代谢研究具有巨大的优势，可以在没有免疫抑制剂（β细胞毒性）和1型糖尿病自身免疫状态混淆的情况下检查胰岛功能。本项目的具体目标是：具体目标1：确定最初成功的TP/AIT受者随着时间的推移产生β细胞功能下降和高血糖的机制。我们将研究TP/AIT受者在肝脏和非肝脏部位成功接受自体胰岛，通过刺激胰岛素、c肽和胰高血糖素对静脉注射（IV）葡萄糖和精氨酸的反应来测量胰岛分泌；葡萄糖增强精氨酸诱导的胰岛素分泌的功能性β细胞质量胰岛素敏感性是通过升血糖钳和高血糖钳来实现的。具体目的2：确定TP/AIT受体具有难治性α细胞功能和低血糖反调节缺陷的机制。我们将使用带胰高血糖素冲洗的放射性标记（3H）降糖钳研究TP/AIT受者72小时后的反调节激素反应，以记录糖原消耗情况。禁食;有或没有注入生长抑素的饮食性低血糖；运动诱导的低血糖，骑自行车时达到峰值Vo2的40%。我们设想这些结果将提供新的见解，不仅可以改善TP/AIT受者的预后，还可以改善1型糖尿病患者同种异体移植的预后。

DESCRIPTION (provided by applicant): This project is based upon the premise that conventional use of the intrahepatic site for islet transplantation is a key factor in abnormal function of beta-cells and alpha-cells during hypoglycemia in transplant recipients. Our approach is to study intrahepatic islet function in patients with chronic pancreatitis who undergo total pancreatectomy and autoislet transplantation (TP/AIT) in both hepatic and nonhepatic sites. Use of autoislet recipients for metabolic studies carries the huge advantage of examining islet function in a setting without the confounding problems of immunosuppressive agents that are beta-cell toxic and the autoimmune state of type 1 diabetes. The specific aims of this project are: Specific Aim #1: To identify the mechanism(s) through which initially successful TP/AIT recipients develop decreased beta-cell function and hyperglycemia over time. We will study TP/AIT recipients who have successfully received autoislets in hepatic and non-hepatic sites through use of measures of islet secretion by stimulation of insulin, C-peptide, and glucagon responses to intravenous (IV) glucose and arginine; functional beta-cell mass by glucose potentiation of arginine-induced insulin secretion; and insulin sensitivity by euglycemic, hyperglycemic clamps. Specific Aim #2: To identify the mechanism(s) through which TP/AIT recipients have refractory alpha-cell function and deficient counter-regulation of hypoglycemia. We will study counter-regulatory hormonal responses in TP/AIT recipients using the radio-labeled (3H)-hypoglycemic clamps with glucagon flush to document glycogen depletion after 72 hr. fasts; meal-induced hypoglycemia with and without somatostatin infusion; and exercise- induced hypoglycemia with bicycle at 40% of peak Vo2. We envision the results will provide novel insights that will pertain not only to improving outcomes in TP/AIT recipients but also insights that will improve outcomes in alloislet transplantation for type 1 diabetic patients.