GLUCAGON-LIKE PEPTIDE-1 CAN REVERSE THE AGE-RELATED DECLINE IN GLUCOSE-TOLERANCE IN RATS

Wistar rats develop glucose intolerance and have a diminished insulin response to glucose with age. The aim of this study was to investigate if these changes were reversible with glucagon-like peptide-1 (GLP-1) , a peptide that we have previously shown could increase insulin mRNA and total insulin content in insulinoma cells. We infused 1.5 pmol kg( -1).min(-1) GLP-1 subcutaneously using ALZET microesmotic pumps into 2 2-mo-old Wistar rats for 48 h. Rat infused with either GLP-1 or saline were then subjected to an intraperitoneal glucose (1 g/kg body weight ) tolerance test, 2 h after removing the pump. 15 min after the intrap eritoneal glucose, GLP-1-treated animals had lower plasma glucose leve ls (9.04+/-0.92 mmol/liter, P < 0.01) than saline-treated animals (11. 61+/-0.23 mmol/liter). At 30 min the plasma glucose was still lower in the GLP-1-treated animals (8.61+/-0.39 mmol/liter, P < 0.05) than sal ine-treated animals (10.36+/-0.43 mmol/liter). This decrease in glucos e levels was reflected in the higher insulin levels attained in the GL P-1-treated animals (936+/-163 pmol/liter vs. 395+/-51 pmol/liter, GLP -1 vs. saline, respectively, P < 0.01), detected 15 min after glucose injection. GLP-1 treatment also increased pancreatic insulin, GLUT2, a nd glucokinase mRNA in the old rats. The effects of GLP-1 were abolish ed by simultaneous infusion of exendin [9-39], a specific antagonist o f GLP-1. GLP-1 is therefore able to reverse some of the known defects that arise in the beta cell of the pancreas of Wistar rats, not only b y increasing insulin secretion but also by inducing significant change s at the molecular level.