title: Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes.
abstract: Glucagon-like peptide 1 (GLP-1) is a potent glucose-lowering agent of potential interest for the treatment of type 2 diabetes. To evaluate actions of NN2211, a long-acting GLP-1 derivative, we examined 11 patients with type 2 diabetes, age 59 +/- 7 years (mean +/- SD), BMI 28.9 +/- 3.0 kg/m(2), HbA(1c) 6.5 +/- 0.6%, in a double-blind, placebo-controlled, crossover design. A single injection (10 microg/kg) of NN2211 was administered at 2300 h, and profiles of circulating insulin, C-peptide, glucose, and glucagon were monitored during the next 16.5 h. A standardized mixed meal was served at 1130 h. Efficacy analyses were performed for the fasting (7-8 h) and mealtime (1130-1530 h) periods. Insulin secretory rates (ISR) were estimated by C-peptide deconvolution analysis. Glucose pulse entrainment (6 mg x kg(-1) x min(-1) every 10 min) was evaluated by 1-min sampled measurements of insulin concentrations from 0930 to 1030 h and subsequent time series analysis of the insulin concentration profiles. All results are given as NN2211 versus placebo; statistical analyses were performed by analysis of variance. In the fasting state, plasma glucose was significantly reduced (6.9 +/- 1.0 vs. 8.1 +/- 1.0 mmol/l; P = 0.004), ISR was increased (179 +/- 70 vs. 163 +/- 66 pmol/min; P = 0.03), and plasma glucagon was unaltered (19 +/- 4 vs. 20 +/- 4 pg/ml; P = 0.17) by NN2211. Meal-related area under the curve (AUC)(1130-1530 h) for glucose was markedly reduced (30.6 +/- 2.4 vs. 39.9 +/- 7.3 mmol x l(-1) x h(-1); P < 0.001), ISR AUC(1130-1530 h) was unchanged (118 +/- 32 vs. 106 +/- 27 nmol; P = 0.13), but the increment (relative to premeal values) was increased (65 +/- 22 vs. 45 +/- 11 nmol; P = 0.04). Glucagon AUC(1130-1530 h) was suppressed (77 +/- 18 vs. 82 +/- 17 pmol x l(-1) x h(-1); P = 0.04). Gastric emptying was significantly delayed as assessed by AUC(1130-1530 h) of 3-ortho-methylglucose (400 +/- 84 vs. 440 +/- 70 mg x l(-1) x h(-1); P = 0.02). During pulse entrainment, there was a tendency to increased high frequency regularity of insulin release as measured by a greater spectral power and autocorrelation coefficient (0.05 < P < 0.10). The pharmacokinetic profile of NN2211, as assessed by blood samplings for up to 63 h postdosing, was as follows: T(1/2) = 10.0 +/- 3.5 h and T(max) = 12.4 +/- 1.7 h. Two patients experienced gastrointestinal side effects on the day of active treatment. In conclusion, the long-acting GLP-1 derivative NN2211 effectively reduces fasting as well as meal-related (approximately 12 h postadministration) glycemia by modifying insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.
authors.affiliation: Medical Department M (Endocrinology and Diabetes), Arhus University Hospital, Arhus, Denmark. cbj@dadlnet.dk
authors.forename: Claus B
authors.initials: CB
authors.lastname: Juhl
authors.forename: Malene
authors.initials: M
authors.lastname: Hollingdal
authors.forename: Jeppe
authors.initials: J
authors.lastname: Sturis
authors.forename: Grethe
authors.initials: G
authors.lastname: Jakobsen
authors.forename: Henrik
authors.initials: H
authors.lastname: Agersø
authors.forename: Johannes
authors.initials: J
authors.lastname: Veldhuis
authors.forename: Niels
authors.initials: N
authors.lastname: Pørksen
authors.forename: Ole
authors.initials: O
authors.lastname: Schmitz
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000032:analysis*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005215:Fasting / Q000097:blood*; D005260:Female; D005934:Glucagon / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D019518:Postprandial Period / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D007328:Insulin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon