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

Nilsson, Cecilia; Hansen, Thomas K.; Rosenquist, Christian; Hartmann, Bolette; Kodra, János T.; Lau, Jesper; Clausen, T.; Raun, Kirsten; Sams, Anette

doi:10.1016/j.ejphar.2016.01.003

Cited by 54 publications

(50 citation statements)

References 33 publications

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“…This first α-CGRP analogue (αAnalogue) is acylated with an albumin-binding fatty acid moiety that allows reversible albumin binding (patent WO 2011/051312 A1). 18,19 It has similar pharmacological properties to the native CGRP peptide, but exhibits prolonged action and improved pharmacokinetic properties with a half-life of >7 hours that benefited a model of type 2 diabetes mellitus. 18,19 The current study demonstrates that the stabilized αAnalogue 18 protects against the development of AngII-induced hypertension and abdominal aortic constriction (AAC)–induced cardiac hypertrophy and heart failure in mice for several weeks.…”

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A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure

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A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure

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“…There is sufficient evidence, spanning nearly two decades, on the influence of CGRP on the secretion of pancreatic and gut hormones, in particular glucagon, somatostatin, and glucagon like peptide (GLP)-1 (26,27,35,36). Intravenous infusion of CGRP in rats results in a dose-dependent increases in basal secretions of glucagon, GLP-1 and GLP-2 (37,38). In the rat pancreas, CGRP is co-localized with somatostatin and is known to stimulate its release, though effect of CGRP on insulin inhibition does not appear to be modulated by the somatostatin pathway (28,39).…”

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confidence: 99%

Calcitonin gene-related peptide: neuroendocrine communication between the pancreas, gut, and brain in regulation of blood glucose

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Background: Calcitonin gene-related peptide (CGRP), a ubiquitous neuropeptide, plays a diverse and intricate role in chronic low-grade inflammation, including conditions such as obesity, type 2 diabetes, and diabetes of the exocrine pancreas. Diabetes of exocrine pancreas is characterised by chronic hyperglycemia and is associated with persistent low-grade inflammation and altered secretion of certain pancreatic and gut hormones. While CGRP may regulate glucose homeostasis and the secretion of pancreatic and gut hormones, its role in chronic hyperglycemia after acute pancreatitis (CHAP) is not known. The aim of this study was to investigate the association between CGRP and CHAP.Methods: Fasting blood samples were collected to measure insulin, HbA1c, CGRP, amylin, C-peptide, glucagon, pancreatic polypeptide (PP), somatostatin, gastric inhibitory peptide, glicentin, glucagon-like peptide-1 and 2, and oxyntomodulin. Modified Poisson regression analysis and linear regression analyses were conducted. Five statistical models were used to adjust for demographic, metabolic, and pancreatitisrelated risk factors.Results: A total of 83 patients were recruited. CGRP was significantly associated with CHAP in all five models (P-trend <0.005). Further, it was significantly associated with oxyntomodulin (P<0.005) and glucagon (P<0.030). Oxyntomodulin and glucagon independently contributed 9.7% and 7%, respectively, to circulating CGRP variance. Other pancreatic and gut hormones were not significantly associated with CGRP.Conclusions: CGRP is involved in regulation of blood glucose in individuals after acute pancreatitis. This may have translational implications in prevention and treatment of diabetes of the exocrine pancreas.

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“…Likewise, Riera et al showed that pharmacologic antagonism of CGRP signaling improved metabolic parameters and potentially inhibits metabolic decline in aged mice (23 months) [44]. In contrast, a recent study demonstrated a beneficial effect of a long acting αCGRP agonist on food intake and body weight in DIO rats [45]. While it is known that pharmacologic agonists may exert different biologic effects, a phenomenon also observed in the case of parathyroid hormone or CT [23] and potentially explaining the findings by Nilsson et al, our study principally confirms the negative effect of endogenous αCGRP on metabolic parameters during DIO.…”

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Differential effects of Calca-derived peptides in male mice with diet-induced obesity

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Key metabolic hormones, such as insulin, leptin, and adiponectin, have been studied extensively in obesity, however the pathophysiologic relevance of the calcitonin family of peptides remains unclear. This family includes calcitonin (CT), its precursor procalcitonin (PCT), and alpha calcitonin-gene related peptide (αCGRP), which are all encoded by the gene Calca. Here, we studied the role of Calca-derived peptides in diet-induced obesity (DIO) by challenging Calcr−/− (encoding the calcitonin receptor, CTR), Calca−/−, and αCGRP−/− mice and their respective littermates with high-fat diet (HFD) feeding for 16 weeks. HFD-induced pathologies were assessed by glucose tolerance, plasma cytokine and lipid markers, expression studies and histology. We found that DIO in mice lacking the CTR resulted in impaired glucose tolerance, features of enhanced nonalcoholic steatohepatitis (NASH) and adipose tissue inflammation compared to wildtype littermates. Furthermore, CTR-deficient mice were characterized by dyslipidemia and elevated HDL levels. In contrast, mice lacking Calca were protected from DIO, NASH and adipose tissue inflammation, and displayed improved glucose tolerance. Mice exclusively lacking αCGRP displayed a significantly less improved DIO phenotype compared to Calca-deficient mice. In summary, we demonstrate that the CT/CTR axis is involved in regulating plasma cholesterol levels while Calca, presumably through PCT, seems to have a detrimental effect in the context of metabolic disease. Our study provides the first comparative analyses of the roles of Calca-derived peptides and the CTR in metabolic disease.

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

Cited by 54 publications

References 33 publications

A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure

A Novel α-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure

Calcitonin gene-related peptide: neuroendocrine communication between the pancreas, gut, and brain in regulation of blood glucose

Differential effects of Calca-derived peptides in male mice with diet-induced obesity

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