The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice.
NN2211 is a long-acting, metabolically stable glucagon-like peptide-1 (GLP-1) derivative designed for once daily administration in humans. NN2211 dose dependently reduced the glycemic levels in ob/ob mice, with antihyperglycemic activity still evident 24 h postdose. Apart from an initial reduction in food intake, there were no significant differences between NN2211 and vehicle treatment, and body weight was not affected. Histological examination revealed that beta-cell proliferation and mass were not increased significantly in ob/ob mice with NN2211, although there was a strong tendency for increased proliferation. In db/db mice, exendin-4 and NN2211 decreased blood glucose compared with vehicle, but NN2211 had a longer duration of action. Food intake was lowered only on day 1 with both compounds, and body weight was unaffected. beta-Cell proliferation rate and mass were significantly increased with NN2211, but with exendin-4, only the beta-cell proliferation rate was significantly increased. In conclusion, NN2211 reduced blood glucose after acute and chronic treatment in ob/ob and db/db mice and was associated with increased beta-cell mass and proliferation in db/db mice. NN2211 is currently in phase 2 clinical development.
Rolin
Bidda
B
Novo Nordisk, DK-2880 Bagsvaerd, Denmark. bidr@novonordisk.com
Larsen
Marianne O
MO
Gotfredsen
Carsten F
CF
Deacon
Carolyn F
CF
Carr
Richard D
RD
Wilken
Michael
M
Knudsen
Lotte Bjerre
LB
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004435:Eating / Q000187:drug effects; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D006943:Hyperglycemia / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000166:cytology*; D000069450:Liraglutide; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism; D014688:Venoms
D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide