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ENDOCRINE AND DIABETES

Novel Glucagon-Like Peptide-1 (GLP-1) Analog (Val⁸)GLP-1 Results in Significant Improvements of Glucose Tolerance and Pancreatic -Cell Function after 3-Week Daily Administration in Obese Diabetic (ob/ob) Mice

School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland (K.S.L., N.I., F.P.M.O., P.R.F.); School of Biological Sciences, Queen's University of Belfast, Belfast, Northern Ireland (B.D.G., P.H., B.G.); and School of Life and Health Sciences, Aston University, Birmingham, United Kingdom (C.J.B.)

This study evaluates the antidiabetic potential of an enzyme-resistant analog, (Val⁸)GLP-1. The effects of daily administration of a novel dipeptidyl peptidase IV-resistant glucagon-like peptide-1 (GLP-1) analog, (Val⁸)GLP-1, on glucose tolerance and pancreatic -cell function were examined in obese-diabetic (ob/ob) mice. Acute intraperitoneal administration of (Val⁸)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 (Val⁸)GLP-1 were greater and longer lasting than native GLP-1. Once-daily subcutaneous administration of (Val⁸)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, (Val⁸)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 (Val⁸)GLP-1 than with 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. These data demonstrate that (Val⁸)GLP-1 is more effective and longer acting than native GLP-1 in obese-diabetic ob/ob mice.

Address correspondence to: Dr. Brian Green, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. E-mail: b.green{at}ulster.ac.uk