A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice

Galyna Graham; Andrew Mc Closkey; Yasser Abdel-Wahab; JM Conlon; PR Flatt

doi:10.1016/j.mce.2019.110584

A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice

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Abstract

Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala ²]palmitoyl-lamprey GLP-1 and [D-Ala ²]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal β-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala ²]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet β-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes.

Original language	English
Article number	110584
Journal	Molecular and Cellular Endocrinology
Volume	499
Early online date	17 Sept 2019
DOIs	https://doi.org/10.1016/j.mce.2019.110584
Publication status	Published (in print/issue) - 1 Jan 2020

Bibliographical note

Funding Information:
The authors wish to thank Bernard Thorens (University of Lausanne, Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University, USA) for glucagon receptor-transfected HEK293?cells, and Jaqueline Naylor (MedImmune, Cambridge, UK) for CRISPR/Cas9-engineered INS-1?cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang (Broad Institute, MIT) and pU6-(BbsI)_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn (Broad Institute, MIT). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL), and Ulster University Strategic Funding.

Funding Information:
The authors wish to thank Bernard Thorens ( University of Lausanne , Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University , USA) for glucagon receptor-transfected HEK293 cells, and Jaqueline Naylor ( MedImmune , Cambridge, UK) for CRISPR/Cas9-engineered INS-1 cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang ( Broad Institute , MIT ) and pU6-( Bbs I)_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn ( Broad Institute , MIT ). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL) , and Ulster University Strategic Funding.

Publisher Copyright:
© 2019 Elsevier B.V.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Dual agonist
Insulinotropic
Lamprey GLP-1
Obesity
Paddlefish GLP-1
Type 2 diabetes

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10.1016/j.mce.2019.110584

Lamprey-paddlefish GLP-1 analoguesAuthor Accepted Manuscript, 2.87 MB

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title = "A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice",

abstract = "Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala 2]palmitoyl-lamprey GLP-1 and [D-Ala 2]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal β-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala 2]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet β-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes. ",

keywords = "Dual agonist, Insulinotropic, Lamprey GLP-1, Obesity, Paddlefish GLP-1, Type 2 diabetes",

author = "Galyna Graham and \{Mc Closkey\}, Andrew and Yasser Abdel-Wahab and JM Conlon and PR Flatt",

note = "Funding Information: The authors wish to thank Bernard Thorens (University of Lausanne, Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University, USA) for glucagon receptor-transfected HEK293?cells, and Jaqueline Naylor (MedImmune, Cambridge, UK) for CRISPR/Cas9-engineered INS-1?cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang (Broad Institute, MIT) and pU6-(BbsI)\_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn (Broad Institute, MIT). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL), and Ulster University Strategic Funding. Funding Information: The authors wish to thank Bernard Thorens ( University of Lausanne , Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University , USA) for glucagon receptor-transfected HEK293 cells, and Jaqueline Naylor ( MedImmune , Cambridge, UK) for CRISPR/Cas9-engineered INS-1 cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang ( Broad Institute , MIT ) and pU6-( Bbs I)\_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn ( Broad Institute , MIT ). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL) , and Ulster University Strategic Funding. Publisher Copyright: {\textcopyright} 2019 Elsevier B.V. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2020",

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doi = "10.1016/j.mce.2019.110584",

language = "English",

volume = "499",

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A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice. / Graham, Galyna; Mc Closkey, Andrew ; Abdel-Wahab, Yasser et al.
In: Molecular and Cellular Endocrinology, Vol. 499, 110584, 01.01.2020.

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

TY - JOUR

T1 - A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice

AU - Graham, Galyna

AU - Mc Closkey, Andrew

AU - Abdel-Wahab, Yasser

AU - Conlon, JM

AU - Flatt, PR

N1 - Funding Information: The authors wish to thank Bernard Thorens (University of Lausanne, Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University, USA) for glucagon receptor-transfected HEK293?cells, and Jaqueline Naylor (MedImmune, Cambridge, UK) for CRISPR/Cas9-engineered INS-1?cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang (Broad Institute, MIT) and pU6-(BbsI)_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn (Broad Institute, MIT). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL), and Ulster University Strategic Funding. Funding Information: The authors wish to thank Bernard Thorens ( University of Lausanne , Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University , USA) for glucagon receptor-transfected HEK293 cells, and Jaqueline Naylor ( MedImmune , Cambridge, UK) for CRISPR/Cas9-engineered INS-1 cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang ( Broad Institute , MIT ) and pU6-( Bbs I)_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn ( Broad Institute , MIT ). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL) , and Ulster University Strategic Funding. Publisher Copyright: © 2019 Elsevier B.V. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala 2]palmitoyl-lamprey GLP-1 and [D-Ala 2]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal β-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala 2]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet β-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes.

AB - Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala 2]palmitoyl-lamprey GLP-1 and [D-Ala 2]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal β-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala 2]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet β-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes.

KW - Dual agonist

KW - Insulinotropic

KW - Lamprey GLP-1

KW - Obesity

KW - Paddlefish GLP-1

KW - Type 2 diabetes

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UR - https://pure.ulster.ac.uk/en/publications/a-long-acting-dual-agonist-analogue-of-lamprey-glp-1-shows-potent

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DO - 10.1016/j.mce.2019.110584

M3 - Article

C2 - 31539596

SN - 0303-7207

VL - 499

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

M1 - 110584

ER -

A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

Other files and links

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Evaluation of GPR55 and GPR120 as novel therapeutic targets for the treatment of type 2 diabetes

Insulinotropic and glucose-lowering peptides from phylogenetically ancient fish with potential for therapy of type 2 diabetes

Yasser Abdel-Wahab

Cite this

A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Student theses

Evaluation of GPR55 and GPR120 as novel therapeutic targets for the treatment of type 2 diabetes

Insulinotropic and glucose-lowering peptides from phylogenetically ancient fish with potential for therapy of type 2 diabetes

Profiles

Yasser Abdel-Wahab

Cite this