Comparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control.
GIP
GLP-1
Insulin secretion
JMV-449
Neurotensin
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
05
03
2021
revised:
29
04
2021
accepted:
03
05
2021
pubmed:
9
5
2021
medline:
10
9
2021
entrez:
8
5
2021
Statut:
ppublish
Résumé
Neurotensin receptor activation augments the biosctivity of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). JMV-449, a C-terminal neurotensin-like fragment with a reduced peptide bond, represents a neurotensin receptor agonist. The present study assessed the actions of JMV-449 on pancreatic beta-cells alone, and in combination with GIP and GLP-1. Further studies examined the impact of JMV-449 and incretin mimetics on glucose homeostasis and appetite control in mice. JMV-449 was resistant to plasma enzyme degradation and induced noticeable dose-dependent insulin-releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV-449 augmented (P < 0.05) the insulinotropic actions of both hormones, as well as enhancing (P < 0.001) insulin secretory activity of both incretin peptides. JMV-449 also increased beta-cell proliferation and induced significant benefits on beta-cell survival in response to cytokine-induced apoptosis. JMV-449 (25 nmol/kg) inhibited (P < 0.05-P < 0.001) food intake in overnight fasted lean mice, and enhanced (P < 0.01) the appetite supressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV-449 evoked glucose lowering actions, but more interestingly significantly augmented (P < 0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics. In terms of glucose-induced insulin secretion, only GIP receptor signalling was associated with increases in insulin concentrations, and this was not enhanced by JMV-449. JMV-449 is a neurotensin receptor agonist that positively augments key aspects of the biological action profile of GIP and GLP-1. These observations emphasise the, yet untapped, therapeutic potential of combined neurotensin and incretin receptor signalling for diabetes.
Sections du résumé
BACKGROUND
Neurotensin receptor activation augments the biosctivity of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). JMV-449, a C-terminal neurotensin-like fragment with a reduced peptide bond, represents a neurotensin receptor agonist.
METHODS
The present study assessed the actions of JMV-449 on pancreatic beta-cells alone, and in combination with GIP and GLP-1. Further studies examined the impact of JMV-449 and incretin mimetics on glucose homeostasis and appetite control in mice.
RESULTS
JMV-449 was resistant to plasma enzyme degradation and induced noticeable dose-dependent insulin-releasing actions in BRIN-BD11 beta-cells. In combination with either GIP or GLP-1, JMV-449 augmented (P < 0.05) the insulinotropic actions of both hormones, as well as enhancing (P < 0.001) insulin secretory activity of both incretin peptides. JMV-449 also increased beta-cell proliferation and induced significant benefits on beta-cell survival in response to cytokine-induced apoptosis. JMV-449 (25 nmol/kg) inhibited (P < 0.05-P < 0.001) food intake in overnight fasted lean mice, and enhanced (P < 0.01) the appetite supressing effects of an enzymatically stable GLP-1 mimetic. When injected co-jointly with glucose, JMV-449 evoked glucose lowering actions, but more interestingly significantly augmented (P < 0.05) the glucose lowering effects of established long-acting GIP and GLP-1 receptor mimetics. In terms of glucose-induced insulin secretion, only GIP receptor signalling was associated with increases in insulin concentrations, and this was not enhanced by JMV-449.
CONCLUSION
JMV-449 is a neurotensin receptor agonist that positively augments key aspects of the biological action profile of GIP and GLP-1.
GENERAL SIGNIFICANCE
These observations emphasise the, yet untapped, therapeutic potential of combined neurotensin and incretin receptor signalling for diabetes.
Identifiants
pubmed: 33964357
pii: S0304-4165(21)00075-1
doi: 10.1016/j.bbagen.2021.129917
pii:
doi:
Substances chimiques
Blood Glucose
0
Incretins
0
Oligopeptides
0
Receptors, Neurotensin
0
JMV 449
139026-66-7
Neurotensin
39379-15-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
129917Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.