A new long-acting GLP-1 derivative KTP ameliorates hyperglycemia and dyslipidemia and improves pancreas and fatty liver in db/db mice

Glucagon-like peptide-1 (GLP-1) is a polypeptide incretin hormone that glucose-dependently promotes the secretion and synthesis of insulin. However, its half-life is extremely short. To enhance its half-life, we developed a long-acting GLP-1 derivative KTP with controlled release, designed on the basis of another GLP-1 derivative GP62. The kinetics and bioactivity of KTP were evaluated in Sprague Dawley (SD) rats. Long-term treatment of KTP was performed in db/db mice. Mice were treated twice daily with subcutaneous injections of KTP (1.2 mg/kg body weight), Exendin-4 (0.1 mg/kg body weight) or vehicle (phosphate buffered saline (PBS), pH 7.4) for 60 d. KTP had a longer half-life, as well as further increasing the secretion and production of insulin and reducing blood glucose concentrations, than GP62. Long-term treatment with KTP also induced anorexia, decreased water and food intake, decreased weight gain, improved blood glucose and blood lipid and ameliorated pancreatic damage and fatty liver in db/db mice.