Development and characterisation of a peptidergic N-and C-terminally stabilised mammalian NPY1R agonist which protects against diabetes induction.
Biochim Biophys Acta Gen Subj
; 1864(5): 129543, 2020 05.
Article
en En
| MEDLINE
| ID: mdl-32007578
ABSTRACT
BACKGROUND:
PYY (1-36) peptides from phylogenetically ancient fish, such as sea lamprey, have previously been shown to function as specific neuropeptide Y1 receptor (NPYR1) agonists. Although, sea lamprey PYY (1-36) is N-terminally stable, we reveal in this study that the peptide is subject to endopeptidase mediated C-terminal dipeptide degradation. In an attempt to prevent this, (d-Arg35)-sea lamprey PYY (1-36) was developed.METHODS:
In vitro bioassays assessed enzymatic stability, insulinostatic activity as well as beta-cell anti-apoptotic actions of (d-Arg35)-sea lamprey PYY (1-36). Follow-up studies examined the impact of twice daily administration of sea lamprey PYY (1-36) or (d-Arg35)-sea lamprey PYY (1-36) in multiple low dose STZ-induced diabetic mice.RESULTS:
(d-Arg35)-sea lamprey PYY (1-36) was fully resistant to plasma enzymatic degradation. The peptide possessed similar significant insulinostatic, as well as positive anti-apoptotic biological actions, as the parent peptide. Sea lamprey PYY (1-36) and (d-Arg35)-sea lamprey PYY (1-36) delayed diabetes progression in STZ mice. Both treatment interventions induced a significant decrease in body weight, food and fluid intake as well as glucose and glucagon concentrations. In addition, glucose tolerance, plasma and pancreatic insulin were partially normalised. (d-Arg35)-sea lamprey PYY (1-36) was significantly more effective than sea lamprey PYY (1-36) in terms of enhancing glucose-stimulate insulin release. Both treatments improved pancreatic islet morphology, linked to decreased apoptosis of beta-cells.CONCLUSION:
We present (d-Arg35)-sea lamprey PYY (1-36) as the first-in-class N- and C-terminally stable PYY (1-36) peptide analogue. GENERALSIGNIFICANCE:
Enzymatically stable, long-acting PYY (1-36) peptides highlight the therapeutic benefits of sustained activation of NPYR1's in diabetes.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos
/
Receptores de Neuropéptido Y
/
Sustancias Protectoras
/
Diabetes Mellitus Experimental
/
Hipoglucemiantes
Tipo de estudio:
Observational_studies
/
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta Gen Subj
Año:
2020
Tipo del documento:
Article
País de afiliación:
Reino Unido