NN2211: a long-acting glucagon-like peptide-1 derivative with antidiabetic 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 along-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 mug 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 (15367 +/- 5438 vs. 9014 +/- 2952 pmol l(-1) min), and glucagon levels were suppressed (P<0.05). Once-daily injections of NN2211 (3.3 mug 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 mumol 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. (C) 2002 Elsevier Science B.V. All rights reserved.