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

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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.