, Volume 45, Issue 9, pp 1263-1273
Date: 26 Apr 2002

Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice

Abstract

Aims/hypothesis. Glucagon-like peptide-1 ameliorates the symptoms of diabetes through stimulation of insulin secretion and enhancement of beta-cell mass. We have therefore investigated the effects of glucagon-like peptide-1 on the development of diabetes, using db/db mice as a model of Type II diabetes.

Methods. The potent glucagon-like peptide-1 analogue Exendin-4 or vehicle (control) was administered (i.p.; 1 nmol/kg) to obese 6-week old db/db mice daily for 14 days (n=10).

Results. By 8 weeks of age, control db/db mice developed hyperglycaemia (fasting: 10.4±0.5 mmol/l), hyperinsulinaemia and impaired glucose tolerance. However, Exendin-4 treatment prevented hyperglycaemia (fasting: 6.1±1.0 mmol/l, p<0.01), with reduced plasma insulin concentrations (p<0.001) and improved glucose tolerance (p<0.05). Peripheral insulin sensitivity was not affected. However, insulin release in vivo and in vitro from the perfused pancreas was improved by Exendin-4, as were pancreatic insulin concentrations (0.54±0.02 vs 0.32±0.01 µg/mg protein, p<0.05). These changes occurred in conjunction with increased beta-cell mass (3.01±0.31 vs 2.22±0.22 mg, p<0.05) and proliferation (BrdU+ beta-cells: 1.08±0.20 vs 0.47±0.11%, p<0.05), as well as decreased apoptosis (Tunel+ beta-cells: 0.37±0.06 vs 1.20±0.21%). Western blot demonstrated increased expression of Akt1 (by fivefold, p<0.01) and p44 MAP kinase (by sixfold, p<0.01), and decreased activation of caspase-3 (by 30%, p<0.05).

Conclusion/interpretation. Our results suggest that Ex4 treatment delays the onset of diabetes in 6–8 week old db/db mice, through a mechanism involving Akt1 and expansion of the functional beta-cell mass.

Electronic Publication