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

Sarah Craig; Victor A Gault; Christina Shiels; Gerd Hamscher; Nigel Irwin

doi:10.1016/j.bbagen.2021.129917

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

Sarah Craig, Victor A Gault, Christina Shiels, Gerd Hamscher, Nigel Irwin

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

89 Downloads (Pure)

Abstract

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. [Abstract copyright: Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.]

Original language	English
Article number	129917
Pages (from-to)	129917
Number of pages	7
Journal	BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume	1865
Issue number	8
Early online date	5 May 2021
DOIs	https://doi.org/10.1016/j.bbagen.2021.129917
Publication status	Published (in print/issue) - 1 Aug 2021

Bibliographical note

Funding Information:
These studies were supported by Department for the Economy, Northern Ireland and Ulster University Selective Research Funding.

Publisher Copyright:
© 2021 The Author(s)

Keywords

GIP
GLP-1
Insulin secretion
JMV-449
Neurotensin

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bbagen.2021.129917Licence: CC BY

bph.15485Final published version, 1.22 MBLicence: CC BY

Cite this

Craig, S., Gault, V. A., Shiels, C., Hamscher, G., & Irwin, N. (2021). 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. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1865(8), 129917. Article 129917. https://doi.org/10.1016/j.bbagen.2021.129917

@article{a53abd97998d4dd799f656144359a62a,

title = "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",

abstract = "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. [Abstract copyright: Copyright {\textcopyright} 2021 The Author(s). Published by Elsevier B.V. All rights reserved.]",

keywords = "GIP, GLP-1, Insulin secretion, JMV-449, Neurotensin",

author = "Sarah Craig and Gault, {Victor A} and Christina Shiels and Gerd Hamscher and Nigel Irwin",

note = "Funding Information: These studies were supported by Department for the Economy, Northern Ireland and Ulster University Selective Research Funding. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = aug,

day = "1",

doi = "10.1016/j.bbagen.2021.129917",

language = "English",

volume = "1865",

pages = "129917",

journal = "BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS",

issn = "0304-4165",

publisher = "Elsevier",

number = "8",

}

Craig, S, Gault, VA, Shiels, C, Hamscher, G & Irwin, N 2021, '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', BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, vol. 1865, no. 8, 129917, pp. 129917. https://doi.org/10.1016/j.bbagen.2021.129917

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. / Craig, Sarah; Gault, Victor A; Shiels, Christina et al.
In: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, Vol. 1865, No. 8, 129917, 01.08.2021, p. 129917.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Craig, Sarah

AU - Gault, Victor A

AU - Shiels, Christina

AU - Hamscher, Gerd

AU - Irwin, Nigel

PY - 2021/8/1

Y1 - 2021/8/1

N2 - 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. [Abstract copyright: Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.]

AB - 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. [Abstract copyright: Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.]

KW - GIP

KW - GLP-1

KW - Insulin secretion

KW - JMV-449

KW - Neurotensin

UR - http://www.scopus.com/inward/record.url?scp=85105561815&partnerID=8YFLogxK

U2 - 10.1016/j.bbagen.2021.129917

DO - 10.1016/j.bbagen.2021.129917

M3 - Article

C2 - 33964357

SN - 0304-4165

VL - 1865

SP - 129917

JO - BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

JF - BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

IS - 8

M1 - 129917

ER -

Craig S, Gault VA, Shiels C, Hamscher G, Irwin N. 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. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS. 2021 Aug 1;1865(8):129917. 129917. Epub 2021 May 5. doi: 10.1016/j.bbagen.2021.129917

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this