Received for publication November 1, 2005.
Revised April 26, 2006.
Accepted for publication April 26, 2006.

Novel GLP-1 analogue (Val⁸)GLP-1 results in significant improvements of glucose tolerance and pancreatic beta cell function after 3 weeks daily administration in obese diabetic (ob/ob) mice

Abstract

Aims/hypothesis: This study evaluates the antidiabetic potential of an enzyme resistant analogue, (Val⁸)GLP-1. Methods: The effects of daily administration of a novel DPP IV resistant GLP-1 analogue, (Val⁸)GLP-1, on glucose tolerance and pancreatic beta cell function were examined in obese-diabetic ob/ob mice. Results: Acute intraperitoneal administration of (Val⁸)GLP-1 (6.25-25 nmoles/kg) with glucose increased the insulin response and reduced the glycaemic excursion in a dose-dependent manner. The effects of (Val⁸)GLP-1 were greater and longer-lasting than native GLP-1. Once-daily subcutaneous administration of (Val⁸)GLP-1 (25 nmoles/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, (Val⁸)GLP-1 improved glucose tolerance, reduced the glycaemic excursion after feeding, increased the plasma insulin response to glucose and feeding, and improved insulin sensitivity. These effects were consistently greater with (Val⁸)GLP-1 than native GLP-1, and both peptides retained or increased their acute efficacy compared with initial administration. (Val⁸)GLP-1 treatment increased average islet area 1.2-fold without changing the number of islets, resulting in an increased number of larger islets. Conclusions/interpretation: These data demonstrate that (Val⁸)GLP-1 is more effective and longer-acting than native GLP-1 in obese-diabetic ob/ob mice.

Key words: DPP IV, Insulin, Type 2 diabetes, drug therapy, glucagon-like peptide-1 (GLP-1), incretin hormones