Glucagon-related peptides from phylogenetically ancient fish reveal new approaches to the development of dual GCGR and GLP1R agonists for Type 2 diabetes therapy

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Abstract

The insulinotropic and antihyperglycaemic properties of glucagons from the sea lamprey (Petromyzontiformes), paddlefish (Acipenseriformes) and trout (Teleostei) and oxyntomodulin from dogfish (Elasmobranchii) and ratfish (Holocephali) are compared with those of human glucagon and GLP-1 in mammalian test systems. All fish peptides produced concentration-dependent stimulation of insulin release from BRIN-BD11 rat and 1.1 B4 human clonal β-cells and isolated mouse islets. Paddlefish glucagon was the most potent and effective peptide. The insulinotropic activity of paddlefish glucagon was significantly (P < 0.01) decreased after incubating BRIN-BD11 cells with the GLP1R antagonist, exendin-4(9-39) and the GCGR antagonist [des-His1,Pro4 ,Glu9] glucagon amide but GIPR antagonist, GIP(6-30)Cex-K40[Pal] was without effect. Paddlefish and lamprey glucagons and dogfish oxyntomodulin (10 nmol/L) produced significant (P < 0.01) increases in cAMP concentration in Chinese hamster lung (CHL) cells transfected with GLP1R and human embryonic kidney (HEK293) cells transfected with GCGR. The insulinotropic activity of paddlefish glucagon was attenuated in CRISPR/Cas9-engineered GLP1R knock-out INS-1 cells but not in GIPR knock-out cells. Intraperitoneal administration of all fish peptides, except ratfish oxyntomodulin, to mice together with a glucose load produced significant (P < 0.05) decreases in plasma glucose concentrations and paddlefish glucagon produced a greater release of insulin compared with GLP-1. Paddlefish glucagon shares the sequences Glu15-Glu16 and Glu24-Trp25-Leu26-Lys27-Asn28-Gly29 with the potent GLP1R agonist, exendin-4 so may be regarded as a naturally occurring, dual-agonist hybrid peptide that may serve as a template design of new drugs for type 2 diabetes therapy.
LanguageEnglish
Article numberxx
Pagesxx
JournalPeptides
Volumexx
Issue numberxx
DOIs
Publication statusPublished - 1 Nov 2018

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Medical problems
Glucagon
Fish
Type 2 Diabetes Mellitus
Fishes
Peptides
Oxyntomodulin
Dogfish
Lampreys
Glucagon-Like Peptide 1
Therapeutics
Clustered Regularly Interspaced Short Palindromic Repeats
Petromyzon
Elasmobranchii
Insulin
Glucose
Trout
HEK293 Cells
Drug Design
Cricetulus

Keywords

  • insulinotropic
  • antidiabetic
  • glucagon
  • Glucagon like peptide 1 (GLP-1)
  • Oxyntomodulin
  • exendin 4
  • Paddlefish

Cite this

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title = "Glucagon-related peptides from phylogenetically ancient fish reveal new approaches to the development of dual GCGR and GLP1R agonists for Type 2 diabetes therapy",
abstract = "The insulinotropic and antihyperglycaemic properties of glucagons from the sea lamprey (Petromyzontiformes), paddlefish (Acipenseriformes) and trout (Teleostei) and oxyntomodulin from dogfish (Elasmobranchii) and ratfish (Holocephali) are compared with those of human glucagon and GLP-1 in mammalian test systems. All fish peptides produced concentration-dependent stimulation of insulin release from BRIN-BD11 rat and 1.1 B4 human clonal β-cells and isolated mouse islets. Paddlefish glucagon was the most potent and effective peptide. The insulinotropic activity of paddlefish glucagon was significantly (P < 0.01) decreased after incubating BRIN-BD11 cells with the GLP1R antagonist, exendin-4(9-39) and the GCGR antagonist [des-His1,Pro4 ,Glu9] glucagon amide but GIPR antagonist, GIP(6-30)Cex-K40[Pal] was without effect. Paddlefish and lamprey glucagons and dogfish oxyntomodulin (10 nmol/L) produced significant (P < 0.01) increases in cAMP concentration in Chinese hamster lung (CHL) cells transfected with GLP1R and human embryonic kidney (HEK293) cells transfected with GCGR. The insulinotropic activity of paddlefish glucagon was attenuated in CRISPR/Cas9-engineered GLP1R knock-out INS-1 cells but not in GIPR knock-out cells. Intraperitoneal administration of all fish peptides, except ratfish oxyntomodulin, to mice together with a glucose load produced significant (P < 0.05) decreases in plasma glucose concentrations and paddlefish glucagon produced a greater release of insulin compared with GLP-1. Paddlefish glucagon shares the sequences Glu15-Glu16 and Glu24-Trp25-Leu26-Lys27-Asn28-Gly29 with the potent GLP1R agonist, exendin-4 so may be regarded as a naturally occurring, dual-agonist hybrid peptide that may serve as a template design of new drugs for type 2 diabetes therapy.",
keywords = "insulinotropic, antidiabetic, glucagon, Glucagon like peptide 1 (GLP-1), Oxyntomodulin, exendin 4, Paddlefish",
author = "Galyna Graham and JM Conlon and Yasser Abdel-Wahab and PR Flatt",
year = "2018",
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T1 - Glucagon-related peptides from phylogenetically ancient fish reveal new approaches to the development of dual GCGR and GLP1R agonists for Type 2 diabetes therapy

AU - Graham, Galyna

AU - Conlon, JM

AU - Abdel-Wahab, Yasser

AU - Flatt, PR

PY - 2018/11/1

Y1 - 2018/11/1

N2 - The insulinotropic and antihyperglycaemic properties of glucagons from the sea lamprey (Petromyzontiformes), paddlefish (Acipenseriformes) and trout (Teleostei) and oxyntomodulin from dogfish (Elasmobranchii) and ratfish (Holocephali) are compared with those of human glucagon and GLP-1 in mammalian test systems. All fish peptides produced concentration-dependent stimulation of insulin release from BRIN-BD11 rat and 1.1 B4 human clonal β-cells and isolated mouse islets. Paddlefish glucagon was the most potent and effective peptide. The insulinotropic activity of paddlefish glucagon was significantly (P < 0.01) decreased after incubating BRIN-BD11 cells with the GLP1R antagonist, exendin-4(9-39) and the GCGR antagonist [des-His1,Pro4 ,Glu9] glucagon amide but GIPR antagonist, GIP(6-30)Cex-K40[Pal] was without effect. Paddlefish and lamprey glucagons and dogfish oxyntomodulin (10 nmol/L) produced significant (P < 0.01) increases in cAMP concentration in Chinese hamster lung (CHL) cells transfected with GLP1R and human embryonic kidney (HEK293) cells transfected with GCGR. The insulinotropic activity of paddlefish glucagon was attenuated in CRISPR/Cas9-engineered GLP1R knock-out INS-1 cells but not in GIPR knock-out cells. Intraperitoneal administration of all fish peptides, except ratfish oxyntomodulin, to mice together with a glucose load produced significant (P < 0.05) decreases in plasma glucose concentrations and paddlefish glucagon produced a greater release of insulin compared with GLP-1. Paddlefish glucagon shares the sequences Glu15-Glu16 and Glu24-Trp25-Leu26-Lys27-Asn28-Gly29 with the potent GLP1R agonist, exendin-4 so may be regarded as a naturally occurring, dual-agonist hybrid peptide that may serve as a template design of new drugs for type 2 diabetes therapy.

AB - The insulinotropic and antihyperglycaemic properties of glucagons from the sea lamprey (Petromyzontiformes), paddlefish (Acipenseriformes) and trout (Teleostei) and oxyntomodulin from dogfish (Elasmobranchii) and ratfish (Holocephali) are compared with those of human glucagon and GLP-1 in mammalian test systems. All fish peptides produced concentration-dependent stimulation of insulin release from BRIN-BD11 rat and 1.1 B4 human clonal β-cells and isolated mouse islets. Paddlefish glucagon was the most potent and effective peptide. The insulinotropic activity of paddlefish glucagon was significantly (P < 0.01) decreased after incubating BRIN-BD11 cells with the GLP1R antagonist, exendin-4(9-39) and the GCGR antagonist [des-His1,Pro4 ,Glu9] glucagon amide but GIPR antagonist, GIP(6-30)Cex-K40[Pal] was without effect. Paddlefish and lamprey glucagons and dogfish oxyntomodulin (10 nmol/L) produced significant (P < 0.01) increases in cAMP concentration in Chinese hamster lung (CHL) cells transfected with GLP1R and human embryonic kidney (HEK293) cells transfected with GCGR. The insulinotropic activity of paddlefish glucagon was attenuated in CRISPR/Cas9-engineered GLP1R knock-out INS-1 cells but not in GIPR knock-out cells. Intraperitoneal administration of all fish peptides, except ratfish oxyntomodulin, to mice together with a glucose load produced significant (P < 0.05) decreases in plasma glucose concentrations and paddlefish glucagon produced a greater release of insulin compared with GLP-1. Paddlefish glucagon shares the sequences Glu15-Glu16 and Glu24-Trp25-Leu26-Lys27-Asn28-Gly29 with the potent GLP1R agonist, exendin-4 so may be regarded as a naturally occurring, dual-agonist hybrid peptide that may serve as a template design of new drugs for type 2 diabetes therapy.

KW - insulinotropic

KW - antidiabetic

KW - glucagon

KW - Glucagon like peptide 1 (GLP-1)

KW - Oxyntomodulin

KW - exendin 4

KW - Paddlefish

U2 - 10.1016/j.peptides.2018.10.013

DO - 10.1016/j.peptides.2018.10.013

M3 - Article

VL - xx

SP - xx

JO - Peptides

T2 - Peptides

JF - Peptides

SN - 0196-9781

IS - xx

M1 - xx

ER -