PANCREAS AND ISLET TRANSPLANTATION

这项提案所述工作的总目标是增加我们的 了解成功的胰腺和胰腺的代谢后果 胰岛移植在I型糖尿病患者中的应用 健康人半胰腺切除的长期代谢后果 捐赠者。我们会特别重视我们的长期跟进工作 成功接受胰腺移植的受者和半移植的受者 胰腺切除的捐赠者和获得急需的洞察力 胰岛移植通常失败的原因是尽管使用了 相同的免疫抑制药物方案用于成功的胰腺 移植。具体目标是： L)提供系列性、长期性、横断性和时效性 胰岛α和β细胞功能的前瞻性评估， I型糖尿病的血糖调节和低血糖的反调节 成功接受胰腺移植的糖尿病患者。我们假设 胰腺移植将提供长期和稳定的 血糖正常化。 2)确定半胰腺切除的长期代谢后果 关于胰岛素分泌储备，胰岛素介导的葡萄糖处置，以及 正常献血者体内葡萄糖介导的葡萄糖代谢 葡萄糖耐量。我们假设胰岛素分泌储备减少 献血者通过胰岛素和/或补偿性增加进行调整 外周和/或肝组织中的葡萄糖敏感性。 3)确定同种异体胰岛β细胞移植失败 功能发生在移植后早期的植入期 在可能出现经典免疫排斥之前，或之后当 血管化移植物的免疫排斥反应可能是 胰岛功能衰竭。我们假设初始植入的失败是一种 关于小岛的主要和以前未被认识到的解释部分 失败了。 4)提供正常血糖和正常血糖长期代谢评估 自体胰岛移植治疗慢性胰腺炎的非胰岛素依赖型受体 I型糖尿病患者和同种异体胰岛移植。我们假设 一旦胰岛移植被证明成功了一年多， 血糖的长期稳定正常化将随之而来。 实现这些目标的研究设计和方法将包括 包括葡萄糖和血红蛋白A1C在内的各种代谢测量 胰岛素、C-肽和胰升糖素分泌的测量； 放射性同位素膳食研究；低血糖、高胰岛素钳夹研究； 精氨酸诱导的胰岛素分泌的葡萄糖增强作用的研究 同时和不同时进行的正常血糖、高胰岛素钳夹试验 生长抑素输注；以及肌肉中GLUT-4转运体的水平。 我们预计这些研究将提供深入的新陈代谢评估。 糖代谢的变化和低血糖的反调节 胰腺移植受者和半胰腺切除供者 这将为同种异体胰岛移植的机制提供新的见解。 失败了。

The overall goal of the work described in this proposal is to increase our understanding of the metabolic consequences of successful pancreas and islet transplantation in Type I diabetic patients, and to ascertain the long term metabolic consequences of hemi-pancreatectomy in healthy human donors. Special emphasis will be given to our long term follow up of recipients of successful pancreas transplantation and of hemi- pancreatectomized donors and to gaining critically needed insights into the reasons why islet transplantation usually falls, despite the use of the identical immunosuppressive drug regimen used for successful pancreas transplantation. The specific aims are: l) To provide serial, long term, cross-sectional and time-related prospective assessments of pancreatic islet alpha and beta cell function, regulation of glycemia, and counterregulation of hypoglycemia in Type I diabetic recipients of successful pancreas transplantation. We hypothesize that pancreas transplantation will provide long-term and stable normalization of glycemia. 2) To determine the long term metabolic consequences of hemipancreatectomy on insulin secretory reserve, insulin-mediated glucose disposal, and glucose-mediated glucose disposal in healthy human donors with normal glucose tolerance. We hypothesize that decreased insulin secretory reserve in donors is adjusted for by compensatory increases in insulin and/or glucose sensitivity in peripheral and/or hepatic tissues. 3) To determine whether failure of allografted pancreatic islet beta cell function occurs early post-transplantation during the engraftment period before classic immunologic rejection is likely, or later when immunorejection of a vascularized graft is the likely explanation for islet failure. We hypothesize that failure of initial engraftment is a major and previously under-recognized part of the explanation for islet failure. 4) To provide long term metabolic assessments of normoglycemic and insulin-independent recipients of islet autografts in chronic pancreatitis patients and islet allografts in Type I diabetic patients. We hypothesize that once islet transplantation has proven successful for over one year, long-term and stable normalization of glycemia will ensue. The research design and methods for achieving these goals will include a variety of metabolic measurements including glucose and hemoglobin A1C levels; measurements of insulin, C-peptide, and glucagon secretion; radioisotopic meal studies; hypoglycemic, hyperinsulinemic clamp studies; studies of glucose potentiation of arginine-induced insulin secretion; euglycemic, hyperinsulineniic clamp studies with and without concurrent somatostatin infusion; and muscle levels of GLUT-4 transporter. We anticipate these studies will provide an in-depth metabolic assessment of glucose metabolism and counterregulation of hypoglycemia in successful recipients of pancreas transplantation and hemi-pancreatectomized donors and will provide new insights into the mechanisms of islet allograft failure.