A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation

Aims/hypothesis Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes. Methods This study evaluated N -acetyl-glucagon, ( d -Ser 2 )glucagon and an analogue of ( d -Ser 2 )glucagon with the addition of nine amino acids from t...

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Veröffentlicht in:Diabetologia 2014-09, Vol.57 (9), p.1927-1936
Hauptverfasser: Lynch, Aisling M., Pathak, Nupur, Pathak, Varun, O’Harte, Finbarr P. M., Flatt, Peter R., Irwin, Nigel, Gault, Victor A.
Format: Artikel
Sprache:eng
Schlagworte:
Amino acids
Animals
Biological and medical sciences
Blood Glucose - metabolism
Body Weight
Diabetes
Diabetes Mellitus - drug therapy
Diabetes Mellitus - etiology
Diabetes Mellitus - metabolism
Diabetes. Impaired glucose tolerance
Dipeptidyl Peptidase 4 - therapeutic use
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Glucagon
Glucagon - analogs & derivatives
Glucagon - metabolism
Glucagon - therapeutic use
Glucagon-Like Peptide-1 Receptor
Glucose
Homeostasis
Human Physiology
Hypoglycemic Agents - therapeutic use
Insulin
Internal Medicine
Male
Medical sciences
Medicine
Medicine & Public Health
Metabolic Diseases
Metabolism
Mice
Mice, Knockout
Obesity
Obesity - complications
Obesity - metabolism
Polypeptides
Receptors, Glucagon - metabolism
Weight control
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Zusammenfassung:Aims/hypothesis Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes. Methods This study evaluated N -acetyl-glucagon, ( d -Ser 2 )glucagon and an analogue of ( d -Ser 2 )glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely ( d -Ser 2 )glucagon-exe. Results All analogues were resistant to dipeptidyl peptidase IV degradation. N -Acetyl-glucagon lacked acute insulinotropic effects in BRIN BD11 cells, whereas ( d -Ser 2 )glucagon and ( d -Ser 2 )glucagon-exe evoked significant ( p  
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-014-3296-7