PANCREAS AND ISLET TRANSPLANTATION IN HUMANS

描述(申请人提供)：这些研究的总体目标是更好地了解正在服用免疫抑制药物的成功胰腺和胰岛移植受者的胰腺β细胞和α细胞功能，并更好地确定半胰腺切除对胰腺节段供者的代谢影响。拟议工作的总目的是继续我们对胰腺移植受者和供者的长期跟踪，并启动对1型糖尿病肝内自体胰岛移植受者的新研究，重点是了解最初成功的同种异体胰岛移植受者后来发展为胰岛衰竭的原因；免疫抑制药物对β细胞有毒的作用机制；以及更好地了解肝脏内α细胞在低血糖期间未能分泌胰高血糖素的原因。这项建议的具体目标是： 具体目标#1.继续长期、纵向研究成功的胰腺移植受者和胰腺节段活体供者的胰岛素分泌储备和对低血糖的逆调节激素反应，以确定胰岛β细胞和α细胞功能是稳定的还是随着时间的推移而恶化。 具体目的#2.确定1型糖尿病患者成功的同种异体胰岛移植后血糖控制的恶化是否与自身免疫性疾病的复发、和/或免疫抑制药物的毒性作用、和/或移植胰岛的数量和质量以及/或肥胖和胰岛素抵抗的发展有关。 具体目标#3：利用人的分离胰岛，确定免疫抑制药物浓度与胰岛激素分泌、细胞凋亡和细胞复制的不良生物反应关系。 具体目的#4：确定成功接受同种异体胰岛治疗的1型糖尿病患者是否始终缺乏对低血糖的胰高血糖素反应，以及肾上腺素对低血糖反应的持续恢复。 具体目的#5.确定低血糖时正常发生的胰升糖素反应是否依赖于相邻的β细胞分泌的胰岛素减少作为“关闭”信号。 胰腺和胰岛受体以及半胰腺切除供者的代谢测试将在华盛顿大学和明尼苏达大学GCRC‘s进行。这些方法将包括精氨酸诱导的胰岛素分泌的葡萄糖增强，正常血糖高胰岛素钳夹和低血糖高胰岛素钳夹。实验室方法将包括分离的人胰岛和研究胰岛素启动子活性、胰岛素mRNA水平、胰岛素含量和胰岛素分泌。低血糖时胰升糖素释放的机制以及在没有β细胞的情况下它的消失将在SpragueDawley大鼠身上进行研究。

DESCRIPTION (provided by applicant): The overall objective of these studies is to better understand pancreatic beta and alpha cell function in human recipients of successful pancreas and islet transplantation who are taking immunosuppressive drugs and to better ascertain metabolic consequences of hemi-pancreatectomy in human donors of pancreatic segments. The general intent of the work proposed is to continue our long term follow up of recipients and donors of pancreas transplantation and to initiate new studies of type 1 diabetic recipients of intrahepatic autoislet transplantation with a major emphasis on developing an understanding why initially successful alloislet recipients later develop islet failure; the mechanism of action by which immunosuppressive drugs are toxic to beta cells; and developing a better understanding of the failure of the intrahepatic alpha cell to secrete glucagon during hypoglycemia. The Specific Aims for this proposal are: Specific Aim # 1. To continue long-term, longitudinal studies of insulin secretory reserve and counterregulatory hormonal responses to hypoglycemia in successful recipients of pancreas transplants and in living donors of pancreatic segments to determine whether islet beta cell and alpha cell function are stable or undergo deterioration with time. Specific Aim # 2. To determine whether deterioration in glycemic control after successful alloislet transplantation in type 1 diabetic patients is related to resurgence of autoimmune disease, and/or toxic effects of immunosuppressive drugs, and/or the quantity and quality of islets transplanted and/or the development of obesity and insulin resistance. Specific Aim # 3. To determine, using human isolated islets, the immunosuppressive drug concentration-adverse biologic response relationships for islet hormonal secretion, apoptosis, and cellular replication. Specific Aim #4. To determine whether the glucagon response to hypoglycemia is consistently absent and the epinephrine response to hypoglycemia is consistently restored in successful type 1 diabetic recipients of alloislets. Specific Aim # 5. To determine whether the glucagon response that normally occurs during hypoglycemia is dependent on a decrease in insulin secretion from adjacent beta cells as a "switch off' signal. The metabolic testing of pancreas and islet recipients as well as hemi-pancreatectomized donors will take place at the University of Washington and the University of Minnesota GCRC's. The methods will include glucose potentiation of arginine induced insulin secretion, euglycemic hyperinsulinemic clamps, and hypoglycemic hyperinsulinemic clamps. The laboratory methods will include isolated human islets and studies of insulin promoter activity, insulin mRNA levels, insulin content, and insulin secretion. Studies of the mechanism of glucagon release during hypoglycemia and its disappearance in the absence of beta cells will be conducted in Sprague Dawley rats.