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


CONCLUSIONS
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.
Wang
Q
Q
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Brubaker
P L
PL
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003920:Diabetes Mellitus / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000517:prevention & control; D007328:Insulin / Q000032:analysis; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010446:Peptide Fragments / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use; D011498:Protein Precursors / Q000627:therapeutic use*; D014688:Venoms
D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide