title: The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose.
abstract: Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion in a glucose-dependent manner, but its short half-life limits its therapeutic potential. We tested NN2211, a long-acting GLP-1 derivative, in 10 subjects with type 2 diabetes (means +/- SD: age 63 +/- 8 years, BMI 30.1 +/- 4.2 kg/m(2), HbA(1c) 6.5 +/- 0.8%) in a randomized, double-blind, placebo-controlled, crossover study. A single injection (7.5 micro g/kg) of NN2211 or placebo was administered 9 h before the study. beta-cell sensitivity was assessed by a graded glucose infusion protocol, with glucose levels matched over the 5-12 mmol/l range. Insulin secretion rates (ISRs) were estimated by deconvolution of C-peptide levels. Findings were compared with those in 10 nondiabetic volunteers during the same glucose infusion protocol. In type 2 diabetic subjects, NN2211, in comparison with placebo, increased insulin and C-peptide levels, the ISR area under the curve (AUC) (1,130 +/- 150 vs. 668 +/- 106 pmol/kg; P < 0.001), and the slope of ISR versus plasma glucose (1.26 +/- 0.36 vs. 0.54 +/- 0.18 pmol x l[min(-1) x mmol(-1) x kg(-1)]; P < 0.014), with values similar to those of nondiabetic control subjects (ISR AUC 1,206 +/- 99; slope of ISR versus plasma glucose, 1.44 +/- 0.18). The long-acting GLP-1 derivative, NN2211, restored beta-cell responsiveness to physiological hyperglycemia in type 2 diabetic subjects.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0926, USA.
authors.forename: Annette M
authors.initials: AM
authors.lastname: Chang
authors.forename: Grethe
authors.initials: G
authors.lastname: Jakobsen
authors.forename: Jeppe
authors.initials: J
authors.lastname: Sturis
authors.forename: Marla J
authors.initials: MJ
authors.lastname: Smith
authors.forename: Cathie J
authors.initials: CJ
authors.lastname: Bloem
authors.forename: Bob
authors.initials: B
authors.lastname: An
authors.forename: Andrzej
authors.initials: A
authors.lastname: Galecki
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Halter
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005934:Glucagon / Q000031:analogs & derivatives* / Q000502:physiology / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D015309:Glucose Clamp Technique; D006801:Humans; D000069450:Liraglutide; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000502:physiology; D010919:Placebos; D011498:Protein Precursors / Q000502:physiology; D012016:Reference Values
chemical_list: D001786:Blood Glucose; D010446:Peptide Fragments; D010919:Placebos; D011498:Protein Precursors; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon