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Eur J Pharmacol. 2016 Feb 15;773:24-31. doi: 10.1016/j.ejphar.2016.01.003. Epub 2016 Jan 22.

Long acting analogue of the calcitonin gene-related peptide induces positive metabolic effects and secretion of the glucagon-like peptide-1.

Author information

1
Department of Pharmacology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
2
Department of Protein and Peptide Chemistry Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
3
ADME and Assay Technology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
4
Department of Protein and Peptide Chemistry Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. Electronic address: JTK@novonordisk.com.
5
Diabetes Biology Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.

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.

KEYWORDS:

Calcitonin gene-related peptide; Diabetes; Glucagon-Like Peptide-1; Metabolism

PMID:
26808305
DOI:
10.1016/j.ejphar.2016.01.003
[Indexed for MEDLINE]

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