Glucagon-like peptides-1 from phylogenetically ancient fish show potent anti-diabetic activities by acting as dual GLP1R and GCGR agonists

Galyna V. Graham; J. Michael Conlon; Yasser H. Abdel-Wahab; Peter R. Flatt

doi:10.1016/j.mce.2018.10.011

Glucagon-like peptides-1 from phylogenetically ancient fish show potent anti-diabetic activities by acting as dual GLP1R and GCGR agonists

Galyna V. Graham, J. Michael Conlon, Yasser H. Abdel-Wahab, Peter R. Flatt

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

7 Citations (Scopus)

Abstract

Glucagon-like peptides-1 (GLP-1)from phylogenetically ancient fish (lamprey, dogfish, ratfish, paddlefish and bowfin) and from a teleost, the rainbow trout produced concentration-dependent stimulations of insulin release from clonal β-cells and isolated mouse islets. Lamprey and paddlefish GLP-1 were the most potent and effective. Incubation of BRIN-BD11 cells with GLP-1 receptor (GLP1R) antagonist, exendin-4 (9–39) attenuated insulinotropic activity of all peptides whereas glucagon receptor (GCGR) antagonist [des-His¹,Pro⁴,Glu⁹] glucagon amide significantly decreased the activities of lamprey and paddlefish GLP-1 only. The GIP receptor antagonist GIP (6–30) Cex-K⁴⁰ [Pal] attenuated the activity of bowfin GLP-1. All peptides (1 μM) produced significant increases in cAMP concentration in CHL cells transfected with GLP1R but only lamprey and paddlefish GLP-1 stimulated cAMP production in HEK293 cells transfected with GCGR. Intraperitoneal administration of lamprey and paddlefish GLP-1 (25 nmol/kg body weight) in mice produced significant decreases in blood glucose and increased insulin concentrations comparable to the effects of human GLP-1. Lamprey and paddlefish GLP-1 display potent insulinotropic activity in vitro and glucose-lowering activity in vivo that is mediated through GLP1R and GCGR so that these peptides may constitute templates for design of new antidiabetic drugs.

Original language	English
Pages (from-to)	54-64
Number of pages	11
Journal	Molecular and Cellular Endocrinology
Volume	480
DOIs	https://doi.org/10.1016/j.mce.2018.10.011
Publication status	Published - Jan 15 2019
Externally published	Yes

Keywords

Antihyperglycaemic
GIP
GLP-1
Glucagon
Insulinotropic
Lamprey
Paddlefish

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Endocrinology

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10.1016/j.mce.2018.10.011

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@article{dc82ed745f604542aaa4a0fcbd861f11,

title = "Glucagon-like peptides-1 from phylogenetically ancient fish show potent anti-diabetic activities by acting as dual GLP1R and GCGR agonists",

abstract = "Glucagon-like peptides-1 (GLP-1)from phylogenetically ancient fish (lamprey, dogfish, ratfish, paddlefish and bowfin) and from a teleost, the rainbow trout produced concentration-dependent stimulations of insulin release from clonal β-cells and isolated mouse islets. Lamprey and paddlefish GLP-1 were the most potent and effective. Incubation of BRIN-BD11 cells with GLP-1 receptor (GLP1R) antagonist, exendin-4 (9–39) attenuated insulinotropic activity of all peptides whereas glucagon receptor (GCGR) antagonist [des-His1,Pro4,Glu9] glucagon amide significantly decreased the activities of lamprey and paddlefish GLP-1 only. The GIP receptor antagonist GIP (6–30) Cex-K40 [Pal] attenuated the activity of bowfin GLP-1. All peptides (1 μM) produced significant increases in cAMP concentration in CHL cells transfected with GLP1R but only lamprey and paddlefish GLP-1 stimulated cAMP production in HEK293 cells transfected with GCGR. Intraperitoneal administration of lamprey and paddlefish GLP-1 (25 nmol/kg body weight) in mice produced significant decreases in blood glucose and increased insulin concentrations comparable to the effects of human GLP-1. Lamprey and paddlefish GLP-1 display potent insulinotropic activity in vitro and glucose-lowering activity in vivo that is mediated through GLP1R and GCGR so that these peptides may constitute templates for design of new antidiabetic drugs.",

keywords = "Antihyperglycaemic, GIP, GLP-1, Glucagon, Insulinotropic, Lamprey, Paddlefish",

author = "Graham, {Galyna V.} and Conlon, {J. Michael} and Abdel-Wahab, {Yasser H.} and Flatt, {Peter R.}",

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. The study was supported by the Northern Ireland Department of Education and Learning (DEL), and Ulster University Strategic Funding. Publisher Copyright: {\textcopyright} 2018 Elsevier B.V.",

year = "2019",

month = jan,

day = "15",

doi = "10.1016/j.mce.2018.10.011",

language = "English",

volume = "480",

pages = "54--64",

journal = "Molecular and Cellular Endocrinology",

issn = "0303-7207",

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T1 - Glucagon-like peptides-1 from phylogenetically ancient fish show potent anti-diabetic activities by acting as dual GLP1R and GCGR agonists

AU - Graham, Galyna V.

AU - Conlon, J. Michael

AU - Abdel-Wahab, Yasser H.

AU - Flatt, Peter R.

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. The study was supported by the Northern Ireland Department of Education and Learning (DEL), and Ulster University Strategic Funding. Publisher Copyright: © 2018 Elsevier B.V.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Glucagon-like peptides-1 (GLP-1)from phylogenetically ancient fish (lamprey, dogfish, ratfish, paddlefish and bowfin) and from a teleost, the rainbow trout produced concentration-dependent stimulations of insulin release from clonal β-cells and isolated mouse islets. Lamprey and paddlefish GLP-1 were the most potent and effective. Incubation of BRIN-BD11 cells with GLP-1 receptor (GLP1R) antagonist, exendin-4 (9–39) attenuated insulinotropic activity of all peptides whereas glucagon receptor (GCGR) antagonist [des-His1,Pro4,Glu9] glucagon amide significantly decreased the activities of lamprey and paddlefish GLP-1 only. The GIP receptor antagonist GIP (6–30) Cex-K40 [Pal] attenuated the activity of bowfin GLP-1. All peptides (1 μM) produced significant increases in cAMP concentration in CHL cells transfected with GLP1R but only lamprey and paddlefish GLP-1 stimulated cAMP production in HEK293 cells transfected with GCGR. Intraperitoneal administration of lamprey and paddlefish GLP-1 (25 nmol/kg body weight) in mice produced significant decreases in blood glucose and increased insulin concentrations comparable to the effects of human GLP-1. Lamprey and paddlefish GLP-1 display potent insulinotropic activity in vitro and glucose-lowering activity in vivo that is mediated through GLP1R and GCGR so that these peptides may constitute templates for design of new antidiabetic drugs.

AB - Glucagon-like peptides-1 (GLP-1)from phylogenetically ancient fish (lamprey, dogfish, ratfish, paddlefish and bowfin) and from a teleost, the rainbow trout produced concentration-dependent stimulations of insulin release from clonal β-cells and isolated mouse islets. Lamprey and paddlefish GLP-1 were the most potent and effective. Incubation of BRIN-BD11 cells with GLP-1 receptor (GLP1R) antagonist, exendin-4 (9–39) attenuated insulinotropic activity of all peptides whereas glucagon receptor (GCGR) antagonist [des-His1,Pro4,Glu9] glucagon amide significantly decreased the activities of lamprey and paddlefish GLP-1 only. The GIP receptor antagonist GIP (6–30) Cex-K40 [Pal] attenuated the activity of bowfin GLP-1. All peptides (1 μM) produced significant increases in cAMP concentration in CHL cells transfected with GLP1R but only lamprey and paddlefish GLP-1 stimulated cAMP production in HEK293 cells transfected with GCGR. Intraperitoneal administration of lamprey and paddlefish GLP-1 (25 nmol/kg body weight) in mice produced significant decreases in blood glucose and increased insulin concentrations comparable to the effects of human GLP-1. Lamprey and paddlefish GLP-1 display potent insulinotropic activity in vitro and glucose-lowering activity in vivo that is mediated through GLP1R and GCGR so that these peptides may constitute templates for design of new antidiabetic drugs.

KW - Antihyperglycaemic

KW - GIP

KW - GLP-1

KW - Glucagon

KW - Insulinotropic

KW - Lamprey

KW - Paddlefish

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U2 - 10.1016/j.mce.2018.10.011

DO - 10.1016/j.mce.2018.10.011

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SN - 0303-7207

VL - 480

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JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

ER -

Glucagon-like peptides-1 from phylogenetically ancient fish show potent anti-diabetic activities by acting as dual GLP1R and GCGR agonists

Abstract

Keywords

ASJC Scopus subject areas

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