The objective of the proposed project is to identify and evaluate novel hypoglycemic agents obtained from a plant used in folk medicine. The ultimate objective is to isolate and structurally characterize one or more natural products with hypoglycemic activity having novel structures and possible novel mechanisms of action from which proprietary analogues exhibiting reduced toxicity and enhanced efficacy can be developed and entered into clinical trials. In Phase I, emphasis will be placed on evaluating the mechanisms of action and toxicity of dioscoretine and its structural cogeners, alkaloids isolated from the roots of Dioscorea dumetorum, a member of the yam family (Dioscoreaceae). This compound has been shown to exhibit potent hypoglycemic activity in normal, glucose- challenged, and alloxanized diabetic animals. The research outlined in this proposal will focus on further mechanistic and toxicological evaluations of non-insulin-independent diabetes, and on the development and evaluation of the proprietary semisynthetic and synthetic analogues in the same animal models.
