This proposal aims to develop novel insulin molecules possessing superior activity. There is great clinical demand for these analogues. 3.2 Million Australians suffer from diabetes and pre-diabetes and it is widely considered the world's fastest growing disease. We have modified the structure of the insulin molecule to enhance its stability in the body and to improve its formulation stability to enable prolonged storage and transport to remote locations. Fast and slow acting derivatives, and orally acting analogues, will be designed, synthesised and evaluated. These structural analogues will also provide missing fundamental knowledge about the structure-activity relationship between insulin and its receptor.