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Research ArticleArticle

The Sulfonylurea Glimepiride Regulates Intracellular Routing of the Insulin-Receptor Complexes through Their Interaction with Specific Protein Kinase C Isoforms

Marta Letizia Hribal, Rossella D'Alfonso, Barbara Giovannone, Davide Lauro, Yong Yu Liu, Patrizia Borboni, Massimo Federici, Renato Lauro and Giorgio Sesti
Molecular Pharmacology February 2001, 59 (2) 322-330; DOI: https://doi.org/10.1124/mol.59.2.322
Marta Letizia Hribal
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Rossella D'Alfonso
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Barbara Giovannone
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Davide Lauro
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Yong Yu Liu
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Patrizia Borboni
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Massimo Federici
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Renato Lauro
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Giorgio Sesti
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Abstract

Sulfonylureas may stimulate glucose metabolism by protein kinase C (PKC) activation. Because interaction of insulin receptors with PKC plays an important role in controlling the intracellular sorting of the insulin-receptor complex, we investigated the possibility that the sulfonylurea glimepiride may influence intracellular routing of insulin and its receptor through a mechanism involving PKC, and that changes in these processes may be associated with improved insulin action. Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. By contrast, glimepiride significantly increased intracellular dissociation of the insulin-receptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-induced receptor down-regulation. Association of PKC-βII and -ε with insulin receptors was increased in glimepiride-treated cells. Selective depletion of cellular PKC-βII and -ε by exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) or treatment of cells with PKC-βII inhibitor G06976 reversed the effect of glimepiride on intracellular insulin-receptor processing. Glimepiride increased the effects of insulin on glucose incorporation into glycogen by enhancing both sensitivity and maximal efficacy of insulin. Exposing cells to TPA or G06976 inhibitor reversed these effects. Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and improved insulin action. These data suggest a novel mechanism of action of sulfonylurea, which may have a therapeutic impact on the treatment of type 2 diabetes.

Footnotes

    • Received May 11, 2000.
    • Accepted October 18, 2000.
  • Send reprint requests to: Giorgio Sesti, MD, Dipartimento di Medicina Interna, Università di Roma-“Tor Vergata”, Via Tor Vergata, 135, 00133 Roma, Italy. E-mail: sesti{at}uniroma2.it

  • This work was supported in part by grants from Hoechst Marion Roussel and Consiglio Nazionale delle Ricerche Grant 96.03724.CT14.

  • M.L.H. and R.D. contributed equally to this work.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (2)
Molecular Pharmacology
Vol. 59, Issue 2
1 Feb 2001
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Research ArticleArticle

The Sulfonylurea Glimepiride Regulates Intracellular Routing of the Insulin-Receptor Complexes through Their Interaction with Specific Protein Kinase C Isoforms

Marta Letizia Hribal, Rossella D'Alfonso, Barbara Giovannone, Davide Lauro, Yong Yu Liu, Patrizia Borboni, Massimo Federici, Renato Lauro and Giorgio Sesti
Molecular Pharmacology February 1, 2001, 59 (2) 322-330; DOI: https://doi.org/10.1124/mol.59.2.322

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Research ArticleArticle

The Sulfonylurea Glimepiride Regulates Intracellular Routing of the Insulin-Receptor Complexes through Their Interaction with Specific Protein Kinase C Isoforms

Marta Letizia Hribal, Rossella D'Alfonso, Barbara Giovannone, Davide Lauro, Yong Yu Liu, Patrizia Borboni, Massimo Federici, Renato Lauro and Giorgio Sesti
Molecular Pharmacology February 1, 2001, 59 (2) 322-330; DOI: https://doi.org/10.1124/mol.59.2.322
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