447. AP20187-Inducible Insulin-Like Effects in Diabetic Muscle and Liver Transduced with AAV
Authors: Gabriella Cotugno, Pietro Formisano, Ferdinando Giacco, VictorM. Rivera, Francesco Beguinot, Alberto Auricchio
Journal: Molecular Therapy (2006)

Diabetes Mellitus, characterized by insulin deficiency (type I) or resistance (type II), derives from insulin action impairments in hormone target tissues: muscle, liver and adipocytes. Insulin regulates metabolism and glucose homeostasis through binding to a specific membrane receptor (IR) with tyrosine kinase activity. Induction of the insulin receptor signaling in hormone target cells may represent a tool to rescue glucose homeostasis in both insulin and insulin receptor deficiencies. Recently we have described that homodimerization of the chimeric insulin receptor LFv2IRE induced by the small dimerizer drug AP20187 results in insulin like actions in hepatocytes trasduced with adeno-associated viral vectors (AAV). Here we show that AAV-mediated LFv2IRE expression in murine muscle and liver followed by systemic AP20187 administration results in reversible homodimerization and tyrosine-phosphorylation of the chimeric receptor which peaks 6 hours after drug administration. More importantly AAV vectors expressing LFv2IRE were administered to muscle and liver of the Non-Obese Diabetic (NOD) murine model of type I Diabetes. Significant increases in hepatic glycogen content were observed following AP20187 systemic administration to AAV-treated NOD mice. The analysis of glucose uptake from diabetic muscle transduced with AAV following AP20187 administration is in progress. The ability of the LFv2IRE-AP20187 system to induce insulin-like actions in hormone target tissues in diabetic mice can be further exploited to obtain glucose homeostasis thus representing a potential novel therapeutic strategy for pathological conditions due to either insulin deficiency or resistance. Diabetes Mellitus, characterized by insulin deficiency (type I) or resistance (type II), derives from insulin action impairments in hormone target tissues: muscle, liver and adipocytes. Insulin regulates metabolism and glucose homeostasis through binding to a specific membrane receptor (IR) with tyrosine kinase activity. Induction of the insulin receptor signaling in hormone target cells may represent a tool to rescue glucose homeostasis in both insulin and insulin receptor deficiencies. Recently we have described that homodimerization of the chimeric insulin receptor LFv2IRE induced by the small dimerizer drug AP20187 results in insulin like actions in hepatocytes trasduced with adeno-associated viral vectors (AAV). Here we show that AAV-mediated LFv2IRE expression in murine muscle and liver followed by systemic AP20187 administration results in reversible homodimerization and tyrosine-phosphorylation of the chimeric receptor which peaks 6 hours after drug administration. More importantly AAV vectors expressing LFv2IRE were administered to muscle and liver of the Non-Obese Diabetic (NOD) murine model of type I Diabetes. Significant increases in hepatic glycogen content were observed following AP20187 systemic administration to AAV-treated NOD mice. The analysis of glucose uptake from diabetic muscle transduced with AAV following AP20187 administration is in progress. The ability of the LFv2IRE-AP20187 system to induce insulin-like actions in hormone target tissues in diabetic mice can be further exploited to obtain glucose homeostasis thus representing a potential novel therapeutic strategy for pathological conditions due to either insulin deficiency or resistance.