Novel Glucagon-Uke Peptide-1 (GLP-1) Analog (Val~8)GLP-1 Results in Significant Improvements of Glucose Tolerance and Pancreatic beta-Cell Function after 3-Week Daily Administration in Obese Diabetic (ob/ob) Mice

摘要

This study evaluates the antidiabetic potential of an enzyme-resistant analog,(Val~8)GLP-1.The effects of daily administration of a novel dipeptidyl peptidase IV-resistant glucagon-like peptide-1 (GLP-1) analog,(Val~8)GLP-1,on glucose tolerance and pancreatic beta-cell function were examined in obese-diabetic (ob/ob) mice.Acute intraperitoneal administration of (Val~8)GLP-1 (6.25-25 nmol/kg) with glucose increased the insulin response and reduced the glycemic excursion in a dose-dependent manner.The effects of (Val~8)GLP-1 were greater and longer lasting than native GLP-1.Once-daily subcutaneous administration of (Val~8)GLP-1 (25 nmol/kg) for 21 days reduced plasma glucose concentrations,increased plasma insulin,and reduced body weight more than native GLP-1 without a significant change in daily food intake.Furthermore,(Val~8)GLP-1 improved glucose tolerance,reduced the glycemic excursion after feeding,increased the plasma insulin response to glucose and feeding,and improved insulin sensitivity.These effects were consistently greater with (Val~8)GLP-1 than with native GLP-1,and both peptides retained or increased their acute efficacy compared with initial administration.(Val~8)GLP-1 treatment increased average islet area 1.2-fold without changing the number of islets,resulting in an increased number of larger islets.These data demonstrate that (Val~8)GLP-1 is more effective and longer acting than native GLP-1 in obese-diabetic ob/ob mice.