The most common complication of diabetes is neuropathy, which occurs, in approximately 60 percent of all diabetic patients. Our work has generated a new theory: that glucose-mediated apoptosis contributes to the development of diabetic neuropathy and that interrupting the death pathway with insulin-like growth factor-I (IGF-I) could afford a new means of therapy. This application aims to understand how glucose kills and IGF-I rescues neurons in both cell culture and animal models of diabetic neuropathy. We speculate high glucose promotes the formation of reactive oxygen species (ROS). Mt membrane depolarization (MMD) then occurs in direct response to glucose, ROS or dimerization of the anti-apoptotic protein Bcl-xL with the pro-apoptotic proteins Bax/Bak. In each case, there is release of Mt cytochrome c into the cytosol and activation of the caspase cascade. It is unknown if caspases can be directly cleaved by ROS, or which initiator (-8 or -9) or downstream effector (-3 through -7) caspases are involved in the cascade. IGF-I may interrupt cell death at one or more points in the pathway. Human neuroblastoma cells, primary sensory neurons and mouse models are used to test this model. We have 4 aims: 1. Characterize ROS formation and the point of IGF-I protection following glucose exposure 2. Characterize the roles of Bcl proteins and determine the point of IGF-I protection following glucose exposure 3. Characterize the caspase cascade and determine the point of IGF-I protection following glucose exposure 4. Use genetically altered mice to characterize the death pathway in clinical diabetic neuropathy and determine the point of IGF-I protection
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