NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs.
Glucagon-like peptide-1 (GLP-1) is an effective anti-diabetic agent, but its metabolic instability makes it therapeutically unsuitable. This study investigated the pharmacodynamics of a long-acting GLP-1 derivative (NN2211: (Arg(34)Lys(26)-(N- epsilon -(gamma-Glu(N-alpha-hexadecanoyl)))-GLP-1(7-37)), after acute and chronic treatment in hyperglycaemic minipigs. During hyperglycaemic glucose clamps, NN2211 (2 micrograms kg(-1) i.v.) treated pigs required more (P < 0.005) glucose than control animals (5.8 +/- 2.1 vs. 2.9 +/- 1.8 mg kg(-1) min(-1)). Insulin excursions were higher (P < 0.01) after NN2211 (15,367 +/- 5,438 vs. 9,014 +/- 2,952 pmol l(-1) min), and glucagon levels were suppressed (P < 0.05). Once-daily injections of NN2211 (3.3 micrograms kg(-1) s.c.) reduced the glucose excursion during an oral glucose tolerance test, to 59 +/- 15% of pre-treatment values by 4 weeks (P < 0.05), without measurable changes in insulin responses. Fructosamine concentrations were unaltered by vehicle, but decreased (from 366 +/- 187 to 302 +/- 114 micromol l(-1), P = 0.14) after 4 weeks of NN2211. Gastric emptying was reduced (P < 0.05) by NN2211. NN2211 acutely increases glucose utilization during a hyperglycaemic glucose clamp and chronic treatment results in better daily metabolic control. Therefore, NN2211, a GLP-1 derivative that can be administered once daily, holds promise as a new anti-diabetic drug with a minimal risk of hypoglycaemia.
Ribel
Ulla
U
Pharmacological Research 1, Health Care Pharmacology, Novo Nordisk A/S, Novo Allé, DK-2880 Bagsvaerd, Denmark. ulr@novonordisk.com
Larsen
Marianne O
MO
Rolin
Bidda
B
Carr
Richard D
RD
Wilken
Michael
M
Sturis
Jeppe
J
Westergaard
Lisbet
L
Deacon
Carolyn F
CF
Knudsen
Lotte Bjerre
LB
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D005934:Glucagon / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D018149:Glucose Intolerance / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D000069450:Liraglutide; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D011498:Protein Precursors / Q000737:chemistry / Q000627:therapeutic use*; D013556:Swine, Miniature
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D011498:Protein Precursors; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon