Insulin-dependent diabetes mellitus (IDDM) is characterized by a severe deficiency of insulin secondary to the autoimmune destruction of pancreatic beta cells. Current treatment for IDDM includes multiple daily insulin injections and specialized regimens of diet and exercise. Occasional lapses in patient compliance can result in acute episodes of ketoacidosis that can be fatal, and alternative long-term strategies such as islet cell transplantation or implantation of insulin infusion pumps are currently under active investigation. The liver is a key organ in maintaining glucose homeostasis in response to insulin and in ketogenesis during severe insulin deficiency. An adjuvant treatment for IDDM is hepatic insulin gene expression, whereby insulin is produced following transfer of the insulin gene into parenchymal cells of the liver. We have previously shown that the administration of a recombinant retroviral vector expressing the rat preproinsulin-1 cDNA to streptozotocin-induced diabetic rats can completely prevent ketoacidosis and normalize their fasting blood glucose levels. Further experiments performed with a recombinant retroviral vector expressing a form of the rat preproinsulin-1 cDNA engineered to allow its processing to mature insulin in hepatocytes have defined the therapeutic window that will prevent ketoacidosis without significant risk of hypoglycemia secondary to hyperinsulinemia. The objectives of the current proposal are: 1) To obtain similar therapeutic results using non-invasive alternatives to the surgical partial hepatectomy that was necessary to achieve significant retrovirus-mediated transduction of hepatocytes in the previous studies; 2) To achieve some form of regulated insulin expression, so that insulin expression is induced under conditions of hyperglycemia and suppressed under conditions of hyperinsulinemia. Such regulation is not intended to restore the rapid physiological control of insulin secretion that normally occurs in response to changes in blood glucose levels, but rather to serve as a safeguard against prolonged periods of hyper- or hypoglycemia. Finally, using the naturally-occurring BB Worcester rat model of diabetes, the hypothesis that a recombinant retroviral vector incorporating these features of insulin expression and regulation can be used to prevent both the acute and chronic complications of IDDM will be rigorously tested. Successful conduct of the proposed research will lead to the development of a novel modality for adjuvant treatment of IDDM in humans.
