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

Diabetologia. 2002 Sep;45(9):1263-73. doi: 10.1007/s00125-002-0828-3. Epub 2002 Apr 26.


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 micro g/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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism*
  • Cell Division / drug effects
  • Diabetes Mellitus / prevention & control*
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Exenatide
  • Female
  • Glucagon / therapeutic use*
  • Glucagon-Like Peptide 1
  • Glucose Tolerance Test
  • Hyperglycemia / prevention & control
  • Insulin / analysis
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Peptide Fragments / therapeutic use*
  • Peptides / therapeutic use
  • Protein Precursors / therapeutic use*
  • Venoms*


  • Blood Glucose
  • Insulin
  • Peptide Fragments
  • Peptides
  • Protein Precursors
  • Venoms
  • Glucagon-Like Peptide 1
  • Glucagon
  • Exenatide