| Overview: The long-term goal of the Diabetes Section is to devise new approaches to the treatment of type II diabetes that are safe and effective, especially in the elderly patients with diabetes. Significant advances have been made in three distinct areas. First, we actively looked at the molecular mechanisms underlying the effect of incretins on insulin secretion and insulin action; second, we investigated the effect of the incretin glucagon-like peptide (GLP) as a potential trophic factor in aging; and third, we were successful at finding new ways to potentially enhance insulin receptor signalling by the design of potent peptide-based inhibitors of protein-tyrosine phosphatases. Among the major lines of inquiry being pursued are the study of the effects of acute and chronic treatments of various cell lines in culture (derived from pancreas, fat and skeletal muscle) with GLP on (1) physiological functions; (2) the transcription rate and stability of specific mRNAs that are regulatable by GLP; and (3) the level of expression of various glucose transporter proteins. GLP can be used as a trophic factor in old or diabetic animal models to study its therapeutic potentials. Furthermore, the future directions arising from our results with the peptide-based inhibitors of protein tyrosine phosphatases are several. First, we will pursue the identification, isolation and characterization of physiologically relevant protein tyrosine phosphatases acting on specific substrates, as well as the preparation of selective, high affinity inhibitors of the insulin receptor phosphatase(s). New studies will be directed at introducing a series of synthetic peptide analogues into live cells in which a variety of metabolic and mitogenic effectors of insulin action will be investigated. This approach can ultimately be extended by administrating such compounds in animals at different ages and animals with acquired and genetic forms of Type II diabetes, to help restore insulin responsiveness. |
