title: Long acting analogue of the calcitonin gene-related peptide induces positive metabolic effects and secretion of the glucagon-like peptide-1.
abstract: The pharmacological potential of Calcitonin gene-related peptide (CGRP) beyond vasodilation is not completely understood and studies are limited by the potent vasodilatory effect and the short half-life of CGRP. In particular, the effects of CGRP on metabolic diseases are not clarified. A peptide analogue of the α form of CGRP (αAnalogue) with prolonged half-life (10.2 ± 0.9h) in rodents was synthesised and used to determine specific metabolic effects in 3 rodent models; normal rats, diet-induced obese rats and the Leptin deficient mouse model (ob/ob mice). The αAnalogue (100 nmol/kg) induced elevated energy expenditure and reduced food intake after single dosing in normal rats. In addition, the αAnalogue increased levels of circulating Glucagon-Like Peptide-1 (GLP-1) by >60% and a specific concentration dependent CGRP-induced GLP-1 secretion was verified in a murine L-cell line. Two weeks treatment of the type 2 diabetic ob/ob mice with the αAnalogue caused reduction in fasting insulin levels (199 ± 36 pM vs 332 ± 68 pM) and a tendency to reduce fasting blood glucose (11.2 ± 1.1mM vs 9.5 ± 0.5mM) and % glycosylated haemoglobin (HbA1c) (5.88 ± 0.17 vs 5.12 ± 0.24), demonstrating a potential anti-diabetic effect. Furthermore, two weeks treatment of diet-induced obese rats with the αAnalogue caused reduction in food intake and a significant decline in body weight (3.6 ± 1.9 gvs. -36 ± 1.1g). We have demonstrated that long-acting CGRP analogues may have a therapeutic potential for the treatment of type 2 diabetes through positive metabolic effects and effect on GLP-1 secretion.
authors.affiliation: Department of Pharmacology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nilsson
authors.affiliation: Department of Protein and Peptide Chemistry Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Thomas Kruse
authors.initials: TK
authors.lastname: Hansen
authors.affiliation: ADME and Assay Technology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenquist
authors.affiliation: Department of Pharmacology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Bolette
authors.initials: B
authors.lastname: Hartmann
authors.affiliation: Department of Protein and Peptide Chemistry Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. Electronic address: JTK@novonordisk.com.
authors.forename: János T
authors.initials: JT
authors.lastname: Kodra
authors.affiliation: Department of Protein and Peptide Chemistry Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Lau
authors.affiliation: Diabetes Biology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Trine Ryberg
authors.initials: TR
authors.lastname: Clausen
authors.affiliation: Department of Pharmacology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Raun
authors.affiliation: Diabetes Biology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Anette
authors.initials: A
authors.lastname: Sams
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D051381:Rats
chemical_list: D052216:Glucagon-Like Peptide 1; D005947:Glucose; D015740:Calcitonin Gene-Related Peptide
keywords: Calcitonin gene-related peptide; Diabetes; Glucagon-Like Peptide-1; Metabolism