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Research ArticleEndocrine and Diabetes

The Effects of TAK-875, a Selective G Protein-Coupled Receptor 40/Free Fatty Acid 1 Agonist, on Insulin and Glucagon Secretion in Isolated Rat and Human Islets

Hiroaki Yashiro, Yoshiyuki Tsujihata, Koji Takeuchi, Masatoshi Hazama, Paul R. V. Johnson and Patrik Rorsman
Journal of Pharmacology and Experimental Therapeutics February 2012, 340 (2) 483-489; DOI: https://doi.org/10.1124/jpet.111.187708
Hiroaki Yashiro
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Yoshiyuki Tsujihata
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Koji Takeuchi
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Masatoshi Hazama
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Paul R. V. Johnson
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Patrik Rorsman
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Abstract

G protein-coupled receptor 40 (GPR40)/free fatty acid 1 (FFA1) is a G protein-coupled receptor involved in free fatty acid-induced insulin secretion. To analyze the effect of our novel GPR40/FFA1-selective agonist, [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate (TAK-875), on insulin and glucagon secretion, we performed hormone secretion assays and measured intracellular Ca2+ concentration ([Ca2+]i) in both human and rat islets. Insulin and glucagon secretion were measured in static and dynamic conditions by using groups of isolated rat and human pancreatic islets. [Ca2+]i was recorded by using confocal microscopy. GPR40/FFA1 expression was measured by quantitative polymerase chain reaction. In both human and rat islets, TAK-875 enhanced glucose-induced insulin secretion in a glucose-dependent manner. The stimulatory effect of TAK-875 was similar to that produced by glucagon-like peptide-1 and correlated with the elevation of β-cell [Ca2+]i. TAK-875 was without effect on glucagon secretion at both 1 and 16 mM glucose in human islets. These data indicate that GPR40/FFA1 influences mainly insulin secretion in a glucose-dependent manner. The β-cell-specific action of TAK-875 in human islets may represent a therapeutically useful feature that allows plasma glucose control without compromising counter-regulation of glucagon secretion, thus minimizing the risk of hypoglycemia.

Footnotes

  • This study was conducted with financial support from the Takeda Pharmaceutical Company.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.187708.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    FFA
    free fatty acid
    GLP-1
    glucagon-like peptide-1
    GLP-1R
    GLP-1 receptor
    GPR40
    G protein-coupled receptor 40
    PCR
    polymerase chain reaction
    DMSO
    dimethyl sulfoxide
    RIA
    radioimmunoassay
    KRBH
    Krebs-Ringer-bicarbonate HEPES buffer
    BSA
    bovine serum albumin
    SUR1
    sulfonylurea receptor 1
    AUC
    area under the curve
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    AU
    arbitrary units
    GLU
    glucose
    TAK-875
    [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate.

  • Received September 14, 2011.
  • Accepted November 18, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 2
1 Feb 2012
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Research ArticleEndocrine and Diabetes

TAK-875 Enhances Insulin Release in Human Islets

Hiroaki Yashiro, Yoshiyuki Tsujihata, Koji Takeuchi, Masatoshi Hazama, Paul R. V. Johnson and Patrik Rorsman
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 483-489; DOI: https://doi.org/10.1124/jpet.111.187708

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Research ArticleEndocrine and Diabetes

TAK-875 Enhances Insulin Release in Human Islets

Hiroaki Yashiro, Yoshiyuki Tsujihata, Koji Takeuchi, Masatoshi Hazama, Paul R. V. Johnson and Patrik Rorsman
Journal of Pharmacology and Experimental Therapeutics February 1, 2012, 340 (2) 483-489; DOI: https://doi.org/10.1124/jpet.111.187708
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