A novel DPP-IV-resistant analog of glucagon-like peptide-1 (GLP-1): KGLP-1 alone or in combination with long-acting PLGA microspheres.

Abstract Glucagon-like peptide-1 (GLP-1) is an important hormone peptide secreted from the gastrointestinal tract in response to nutrient ingestion. Its multifaceted actions make GLP-1 attractive as a candidate for the treatment of type 2 diabetes mellitus. However, its main limitation is an extremely short half-life, which is due to rapid inactivation by a ubiquitous enzyme, dipeptidyl peptidase-IV (DPP-IV). Therefore, here we describe the development of a novel GLP-1 analog, designated KGLP-1. Initial in vitro experiments revealed that KGLP-1 bound to and activated GLP-1R with similar efficacy as native GLP-1. Importantly, KGLP-1 showed marked resistance to inactivation by DPP-IV. Further in vivo studies confirmed that KGLP-1 had antihyperglycemic and insulinotropic actions after intraperitoneal injection to KM mice and alloxan-induced diabetic mice. Finally, we prepared KGLP-1-loaded poly ( d , l -lactic-co-glycolic acid) microspheres (PLGA MS) using the solid in oil in oil (s/o/o) solvent extraction method, which achieved controlled release and biological efficacy over a period of 10 days after a single subcutaneous injection in alloxan-induced diabetic rats.