Correction of diabetes in an autoimmune model using insulin-secreting liver cells.

1型糖尿病是由分泌胰岛素的胰腺细胞的自身免疫破坏引起的。糖尿病的慢性并发症和缺乏用于移植的供体组织的问题，理论上可以通过从病人自己的细胞中进行工程改造来克服，人造β细胞，即一种非胰岛细胞，能够合成、储存和分泌成熟的胰岛素，以响应代谢刺激，如葡萄糖。这项技术的最终目标是将胰岛素基因直接传递到患者自身的肝细胞中，从而调节胰岛素分泌，以应对葡萄糖和其他刺激胰岛素分泌的物质，在不需要免疫抑制的情况下控制血糖。要做到这一点，必须有可能有效地将胰岛素基因传递到原代肝细胞（来源于动物或人体的细胞）。我们实验室使用非致病性病毒传递系统的结果表明，我们可以通过表达胰岛素和β细胞转录因子NeuroD来逆转化学诱导的糖尿病大鼠的糖尿病。这项研究的目的是在糖尿病的自身免疫模型中重复这一点非肥胖的糖尿病小鼠，它非常接近地模仿了人类糖尿病的发展。我们将确定我们是否可以逆转这些动物的糖尿病，并确定它们对葡萄糖的反应在很长一段时间内是否正常，而不会受到刺激人类糖尿病发展的免疫系统因素的攻击。这项研究计划的结果将导致胰岛素基因传递到大量的初级肝细胞，然后这些细胞将合成、储存和分泌胰岛素来响应葡萄糖。这些细胞可以在不需要免疫抑制的情况下控制患者的血糖水平。

Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. The problems of the chronic complications of diabetes and the lack of donor tissue for transplantation, could theoretically be overcome by engineering from the patient's own cells, an artificial beta cell, i. e. a non-islet cell capable of synthesising, storing and secreting mature insulin in response to metabolic stimuli, such as glucose. The ultimate goal of this technology is to deliver the insulin gene directly to a patient's own liver cells which would regulate insulin secretion in response to glucose and other substances that stimulate insulin secretion, controlling blood glucose without the need for immunosuppression. To accomplish this it must be possible to deliver the insulin gene efficiently to primary liver cells (cells derived from an animal's or human's body). Results from our laboratory using a non-pathogenic viral delivery system indicate that we can reverse diabetes in chemically induced diabetic rats by expression of insulin and a beta cell transcription factor NeuroD. The aim of this study is to repeat this in an auto-immune model of diabetes the nonobese diabetic mouse, which mimicks very closely the development of diabetes in humans. We will determine if we can reverse diabetes in these animals and determine if their response to glucose is normal over an extended period of time, with no attack by the factors of the immune system that stimulate the development of diabetes in man. The results from this research proposal should result in the delivery of the insulin gene to large numbers of primary liver cells that will then synthesise, store and secrete insulin in response to glucose. These cells would control blood glucose levels in patients without the need for immunosuppression.