Glucagon-like peptide-1 delivery for treatment of type 2 diabetes.

摘要

Glucagon-like peptide-1 (GLP-1) is an insulinotropic hormone that increases insulin secretion in a glucose-dependent manner. Insulin secretion is only increased when concentrations of glucose is high and not at low to normal concentrations of glucose, therefore avoiding hypoglycemic episodes. In spite of its many remarkable advantages as a therapeutic agent for diabetes, GLP-1 is not immediately clinically applicable because of its extremely short half-life. The purpose of this research was to design an effective way of GLP-1 delivery for therapeutic use of GLP-1. The first half of the research studied the effects of GLP-1 delivery using a thermosensitive biodegradable triblock copolymer. The second half of this research was to design a new and effective GLP-1 delivery system for therapeutic use for type 2 diabetes treatment based upon construction of GLP-1 plasmid and its delivery.; The effect of GLP-1 delivery system using biodegradable injectable polymer was studied. The results from the I release experiment did show steady amount of GLP-1 released from PLGA-PEG-PLGA triblock copolymer formulation with zinc-complexed GLP-1 depot more than ten days after loading. As a result from the animal experiment with the type 2 diabetic model, it was evident that the GLP-1 released from the thermosensitive biodegradable hydrogel formulation was bioactive as it stimulated insulin secretion in vivo. Therefore, it was concluded that it is feasible to use PLGA-PEG-PLGA triblock copolymer formulation with zinc-complexed GLP-1 as a 2 week delivery system, making it a twice-a-month injection depot.; For less frequent and more convenient administration of GLP-1, the GLP-1 gene delivery system was attempted in this study. Since no reactive hypoglycemia occurs even with higher concentrations of GLP-1, a potent promoter/enhancer was used in this system. It has been established that GLP-1 gene delivery significantly decreased blood glucose levels in a type 2 diabetic animal model. The results showed that delivered GLP-1 gene stimulated insulin secretion, indicating that GLP-1 gene delivery also represents a promising candidate for treatment of type 2 diabetes.