Evaluation of the insulin-releasing and glucose-lowering effects of GPR120 activation in pancreatic β-cells.

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Abstract

AIMS: To assess the potency and selectivity of various GPR120 agonists and to determine the cellular localization of GPR120 in clonal β-cells and pancreatic islets.METHODS: Insulin secretion and alterations in intracellular Ca(2+) and cAMP response to glucose and GPR120 agonists, including endogenous agonists α-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and a synthetic analogue (GW-9508), were examined using clonal pancreatic BRIN-BD11 cells, mouse pancreatic islets and in vivo studies using NIH Swiss mice. Cytotoxicity was assessed by lactate dehydrogenase release. Cellular localization of GPR120 was explored by double-staining immunohistochemistry.RESULTS: The most potent and selective GPR120 agonist tested was ALA (half maximum effective concentration 1.2 × 10(-8) mol/l) with a maximum stimulation of insulin secretion of 53% at 10(-4) mol/l (p <0.001) in BRIN-BD11 cells. Stimulation of insulin secretion was also observed with GW-9508 (6.4 × 10(-8) mol/l; 47%), EPA (7.9 × 10(-8) mol/l; 36%) and DHA (1.0 × 10(-7) mol/l; 50%). Results were corroborated by islet studies, with no evidence of cytotoxic effects. Dose-dependent insulin secretion by GPR120 agonists was glucose-sensitive and accompanied by significant elevations of intracellular Ca(2+) and cAMP. Immunocytochemistry showed GPR120 expression on BRIN-BD11 cells and was confined to islet β-cells with no distribution on α-cells. Administration of GPR120 agonists (0.1 µmol/kg body weight) in glucose tolerance studies significantly reduced plasma glucose and augmented insulin release in mice.CONCLUSIONS: These results indicate that GPR120 is expressed on pancreatic β-cells and that agonists at this receptor are potent insulin secretagogues with therapeutic potential for type 2 diabetes.
LanguageEnglish
Pages1128-1139
JournalDiabetes Obesity and Metabolism
Volume16
Issue number11
DOIs
Publication statusPublished - 1 Nov 2014

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Insulin-Secreting Cells
Insulin
Glucose
Islets of Langerhans
alpha-Linolenic Acid
Eicosapentaenoic Acid
Docosahexaenoic Acids
Immunohistochemistry
Insulin Receptor
L-Lactate Dehydrogenase
Type 2 Diabetes Mellitus
Body Weight
Staining and Labeling

Cite this

@article{d1fce8d122c842f19e4e62c1e69e4209,
title = "Evaluation of the insulin-releasing and glucose-lowering effects of GPR120 activation in pancreatic β-cells.",
abstract = "AIMS: To assess the potency and selectivity of various GPR120 agonists and to determine the cellular localization of GPR120 in clonal β-cells and pancreatic islets.METHODS: Insulin secretion and alterations in intracellular Ca(2+) and cAMP response to glucose and GPR120 agonists, including endogenous agonists α-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and a synthetic analogue (GW-9508), were examined using clonal pancreatic BRIN-BD11 cells, mouse pancreatic islets and in vivo studies using NIH Swiss mice. Cytotoxicity was assessed by lactate dehydrogenase release. Cellular localization of GPR120 was explored by double-staining immunohistochemistry.RESULTS: The most potent and selective GPR120 agonist tested was ALA (half maximum effective concentration 1.2 × 10(-8) mol/l) with a maximum stimulation of insulin secretion of 53{\%} at 10(-4) mol/l (p <0.001) in BRIN-BD11 cells. Stimulation of insulin secretion was also observed with GW-9508 (6.4 × 10(-8) mol/l; 47{\%}), EPA (7.9 × 10(-8) mol/l; 36{\%}) and DHA (1.0 × 10(-7) mol/l; 50{\%}). Results were corroborated by islet studies, with no evidence of cytotoxic effects. Dose-dependent insulin secretion by GPR120 agonists was glucose-sensitive and accompanied by significant elevations of intracellular Ca(2+) and cAMP. Immunocytochemistry showed GPR120 expression on BRIN-BD11 cells and was confined to islet β-cells with no distribution on α-cells. Administration of GPR120 agonists (0.1 µmol/kg body weight) in glucose tolerance studies significantly reduced plasma glucose and augmented insulin release in mice.CONCLUSIONS: These results indicate that GPR120 is expressed on pancreatic β-cells and that agonists at this receptor are potent insulin secretagogues with therapeutic potential for type 2 diabetes.",
author = "BM Moran and Yasser Abdel-Wahab and Peter Flatt and Aine McKillop",
year = "2014",
month = "11",
day = "1",
doi = "10.1111/dom.12330",
language = "English",
volume = "16",
pages = "1128--1139",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",
number = "11",

}

TY - JOUR

T1 - Evaluation of the insulin-releasing and glucose-lowering effects of GPR120 activation in pancreatic β-cells.

AU - Moran, BM

AU - Abdel-Wahab, Yasser

AU - Flatt, Peter

AU - McKillop, Aine

PY - 2014/11/1

Y1 - 2014/11/1

N2 - AIMS: To assess the potency and selectivity of various GPR120 agonists and to determine the cellular localization of GPR120 in clonal β-cells and pancreatic islets.METHODS: Insulin secretion and alterations in intracellular Ca(2+) and cAMP response to glucose and GPR120 agonists, including endogenous agonists α-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and a synthetic analogue (GW-9508), were examined using clonal pancreatic BRIN-BD11 cells, mouse pancreatic islets and in vivo studies using NIH Swiss mice. Cytotoxicity was assessed by lactate dehydrogenase release. Cellular localization of GPR120 was explored by double-staining immunohistochemistry.RESULTS: The most potent and selective GPR120 agonist tested was ALA (half maximum effective concentration 1.2 × 10(-8) mol/l) with a maximum stimulation of insulin secretion of 53% at 10(-4) mol/l (p <0.001) in BRIN-BD11 cells. Stimulation of insulin secretion was also observed with GW-9508 (6.4 × 10(-8) mol/l; 47%), EPA (7.9 × 10(-8) mol/l; 36%) and DHA (1.0 × 10(-7) mol/l; 50%). Results were corroborated by islet studies, with no evidence of cytotoxic effects. Dose-dependent insulin secretion by GPR120 agonists was glucose-sensitive and accompanied by significant elevations of intracellular Ca(2+) and cAMP. Immunocytochemistry showed GPR120 expression on BRIN-BD11 cells and was confined to islet β-cells with no distribution on α-cells. Administration of GPR120 agonists (0.1 µmol/kg body weight) in glucose tolerance studies significantly reduced plasma glucose and augmented insulin release in mice.CONCLUSIONS: These results indicate that GPR120 is expressed on pancreatic β-cells and that agonists at this receptor are potent insulin secretagogues with therapeutic potential for type 2 diabetes.

AB - AIMS: To assess the potency and selectivity of various GPR120 agonists and to determine the cellular localization of GPR120 in clonal β-cells and pancreatic islets.METHODS: Insulin secretion and alterations in intracellular Ca(2+) and cAMP response to glucose and GPR120 agonists, including endogenous agonists α-linolenic acid (ALA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and a synthetic analogue (GW-9508), were examined using clonal pancreatic BRIN-BD11 cells, mouse pancreatic islets and in vivo studies using NIH Swiss mice. Cytotoxicity was assessed by lactate dehydrogenase release. Cellular localization of GPR120 was explored by double-staining immunohistochemistry.RESULTS: The most potent and selective GPR120 agonist tested was ALA (half maximum effective concentration 1.2 × 10(-8) mol/l) with a maximum stimulation of insulin secretion of 53% at 10(-4) mol/l (p <0.001) in BRIN-BD11 cells. Stimulation of insulin secretion was also observed with GW-9508 (6.4 × 10(-8) mol/l; 47%), EPA (7.9 × 10(-8) mol/l; 36%) and DHA (1.0 × 10(-7) mol/l; 50%). Results were corroborated by islet studies, with no evidence of cytotoxic effects. Dose-dependent insulin secretion by GPR120 agonists was glucose-sensitive and accompanied by significant elevations of intracellular Ca(2+) and cAMP. Immunocytochemistry showed GPR120 expression on BRIN-BD11 cells and was confined to islet β-cells with no distribution on α-cells. Administration of GPR120 agonists (0.1 µmol/kg body weight) in glucose tolerance studies significantly reduced plasma glucose and augmented insulin release in mice.CONCLUSIONS: These results indicate that GPR120 is expressed on pancreatic β-cells and that agonists at this receptor are potent insulin secretagogues with therapeutic potential for type 2 diabetes.

U2 - 10.1111/dom.12330

DO - 10.1111/dom.12330

M3 - Article

VL - 16

SP - 1128

EP - 1139

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 11

ER -