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

I型糖尿病是由胰腺中分泌胰岛素的β细胞的自身免疫破坏引起的。从理论上讲，糖尿病的慢性并发症和缺乏移植供体组织的问题可以通过从患者自己的细胞中进行改造来克服，人造β细胞是一种非胰岛细胞，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给患者自己的肝细胞，该细胞将对葡萄糖和其他刺激胰岛素分泌的物质做出反应，调节胰岛素的分泌，控制血糖，而不需要免疫抑制。要做到这一点，必须有可能将胰岛素基因高效地输送到原代肝细胞(来自动物或人体的细胞)。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NeuD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-非肥胖型糖尿病小鼠中重复这一点，该模型非常接近于人类糖尿病的发展。我们将确定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较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应该会导致将胰岛素基因传递到大量的原代肝细胞，这些细胞随后会合成、储存和分泌胰岛素，以响应葡萄糖。这些细胞可以控制患者的血糖水平，而不需要免疫抑制。

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.