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Research ArticleENDOCRINE AND REPRODUCTIVE

A New Hypoglycemic Agent, JTT-608, Evokes Protein Kinase A-Mediated Ca2+ Signaling in Rat Islet β-Cells: Strict Regulation by Glucose, Link to Insulin Release, and Cooperation with Glucagon-Like Peptide-1(7-36)amide and Pituitary Adenylate Cyclase-Activating Polypeptide

Suzuko Hashiguchi, Toshihiko Yada and Terukatsu Arima
Journal of Pharmacology and Experimental Therapeutics January 2001, 296 (1) 22-30;
Suzuko Hashiguchi
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Toshihiko Yada
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Terukatsu Arima
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Abstract

A new nonsulfonylurea oral hypoglycemic agent, JTT-608, has been reported to stimulate insulin release at elevated, but not low, glucose concentrations and consequently not to induce hypoglycemia in rats. Accordingly, this drug is potentially a safer antidiabetic agent than sulfonylureas. To explore the mechanisms underlying this glucose-dependent insulinotropism, the present study investigated the effects of JTT-608 on cytosolic free Ca2+ concentration ([Ca2+]i) and protein kinase A (PKA) activity in rat islet β-cells by microfluorometry using, respectively, fura-2 and a fluorescence PKA substrate, DR II. In the presence of glucose at normal and elevated concentrations (5.0–16.7 mM) JTT-608 (30–1000 μM) concentration dependently increased [Ca2+]i in up to 88% of single β-cells, whereas at lower glucose concentrations (2.8 and 4.2 mM) it had little effect. The [Ca2+]i responses were inhibited under Ca2+-free conditions and by nitrendipine, an L-type Ca2+ channel blocker. JTT-608 rapidly activated PKA and a PKA inhibitor, H89, inhibited [Ca2+]iresponses to JTT-608. JTT-608 also stimulated insulin release from rat islets in a glucose- and Ca2+-dependent manner. The glucose-unresponsive β-cells, which failed to respond to 8.3 mM glucose with increases in [Ca2+]i, were frequently recruited to [Ca2+]i increases by JTT-608. JTT-608 also induced oscillations of [Ca2+]i. Glucagon-like peptide-1(7-36)amide (GLP-1), pituitary adenylate cyclase-activating polypeptide (PACAP), and acetylcholine (ACh) enhanced the action of JTT-608 on [Ca2+]i. In conclusion, JTT-608 evokes PKA-mediated Ca2+ influx and Ca2+ signaling in rat islet β-cells in a glucose-regulated manner, which may account for its glucose-dependent insulinotropism. JTT-608 and neurohormones may cooperatively activate islet β-cells under physiological conditions.

Footnotes

  • Send reprint requests to: Dr. Toshihiko Yada, 2nd Department of Physiology, Jichi Medical School, Minamikawachi, Kawachi, Tochigi 329-0498, Japan. E-mail: tyada{at}jichi.ac.jp

  • This work was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan (to T.Y.).

  • Abbreviations:
    SU
    sulfonylurea
    KATP
    ATP-sensitive K+
    JTT-608
    trans-4-(4-methylcyclohexyl)-4-oxobutyric acid
    GLP-1
    glucagon-like peptide-1(7-36)amide
    ACh
    acetylcholine
    KRB
    Krebs-Ringer bicarbonate buffer
    PKA
    protein kinase A
    PACAP
    pituitary adenylate cyclase-activating polypeptide
    db-cAMP
    dibutyryl adenosine-3′:5′-monophosphate
    H89
    N-[2-(p-bromocinnamylamine)ethyl]-5-isoquinoline-sulfonamide
    • Received January 11, 2000.
    • Accepted September 13, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 1
1 Jan 2001
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A New Hypoglycemic Agent, JTT-608, Evokes Protein Kinase A-Mediated Ca2+ Signaling in Rat Islet β-Cells: Strict Regulation by Glucose, Link to Insulin Release, and Cooperation with Glucagon-Like Peptide-1(7-36)amide and Pituitary Adenylate Cyclase-Activa…
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Research ArticleENDOCRINE AND REPRODUCTIVE

A New Hypoglycemic Agent, JTT-608, Evokes Protein Kinase A-Mediated Ca2+ Signaling in Rat Islet β-Cells: Strict Regulation by Glucose, Link to Insulin Release, and Cooperation with Glucagon-Like Peptide-1(7-36)amide and Pituitary Adenylate Cyclase-Activating Polypeptide

Suzuko Hashiguchi, Toshihiko Yada and Terukatsu Arima
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 22-30;

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Research ArticleENDOCRINE AND REPRODUCTIVE

A New Hypoglycemic Agent, JTT-608, Evokes Protein Kinase A-Mediated Ca2+ Signaling in Rat Islet β-Cells: Strict Regulation by Glucose, Link to Insulin Release, and Cooperation with Glucagon-Like Peptide-1(7-36)amide and Pituitary Adenylate Cyclase-Activating Polypeptide

Suzuko Hashiguchi, Toshihiko Yada and Terukatsu Arima
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 22-30;
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