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Research ArticleEndocrine and Diabetes

TAK-875, an Orally Available G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist, Enhances Glucose-Dependent Insulin Secretion and Improves Both Postprandial and Fasting Hyperglycemia in Type 2 Diabetic Rats

Yoshiyuki Tsujihata, Ryo Ito, Masami Suzuki, Ayako Harada, Nobuyuki Negoro, Tsuneo Yasuma, Yu Momose and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics October 2011, 339 (1) 228-237; DOI: https://doi.org/10.1124/jpet.111.183772
Yoshiyuki Tsujihata
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Ryo Ito
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Masami Suzuki
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Ayako Harada
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Nobuyuki Negoro
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Tsuneo Yasuma
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Yu Momose
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Koji Takeuchi
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Abstract

G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA1) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1–10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.

Footnotes

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

    doi:10.1124/jpet.111.183772.

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

  • ABBREVIATIONS:

    FFA
    free fatty acid
    CHO
    Chinese hamster ovary
    GPR40/FFA1
    G protein-coupled receptor 40/free fatty acid receptor 1
    hGPR40
    human GPR40
    IP
    inositol monophosphate
    IP3
    inositol 1,4,5-triphosphate
    [Ca2+]i
    intracellular calcium concentration
    BSA
    bovine serum albumin
    DMSO
    dimethyl sulfoxide
    TAK-875
    [(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate
    SD
    Sprague-Dawley
    ZDF
    Zucker diabetic fatty
    ZL
    Zucker lean
    DDP-4
    dipeptidyl peptidase-4
    GLP-1
    glucagon-like peptide-1
    ER
    endoplasmic reticulum
    ELISA
    enzyme-linked immunosorbent assay
    KRBH
    Krebs-Ringer-bicarbonate HEPES buffer.

  • Received May 18, 2011.
  • Accepted July 12, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 1
1 Oct 2011
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Research ArticleEndocrine and Diabetes

GPR40 Agonist as a Potential Antidiabetic Drug

Yoshiyuki Tsujihata, Ryo Ito, Masami Suzuki, Ayako Harada, Nobuyuki Negoro, Tsuneo Yasuma, Yu Momose and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics October 1, 2011, 339 (1) 228-237; DOI: https://doi.org/10.1124/jpet.111.183772

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Research ArticleEndocrine and Diabetes

GPR40 Agonist as a Potential Antidiabetic Drug

Yoshiyuki Tsujihata, Ryo Ito, Masami Suzuki, Ayako Harada, Nobuyuki Negoro, Tsuneo Yasuma, Yu Momose and Koji Takeuchi
Journal of Pharmacology and Experimental Therapeutics October 1, 2011, 339 (1) 228-237; DOI: https://doi.org/10.1124/jpet.111.183772
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