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

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

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

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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.

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

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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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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

Keywords

UN SDGs

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