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Research ArticleENDOCRINE AND REPRODUCTIVE

Pancreatic β-Cell K ATP Channel Activity and Membrane-Binding Studies with Nateglinide: A Comparison with Sulfonylureas and Repaglinide

Shiling Hu, Shuya Wang, Barbara Fanelli, Philip A. Bell, Beth E. Dunning, Sabine Geisse, Rita Schmitz and Brian R. Boettcher
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 444-452;
Shiling Hu
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Shuya Wang
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Barbara Fanelli
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Philip A. Bell
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Beth E. Dunning
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Sabine Geisse
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Rita Schmitz
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Brian R. Boettcher
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Abstract

Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the KATP channel/sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models. Binding studies were carried out with membranes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1 (SUR1). The relative order for displacement of [3H]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide >l-nateglinide > tolbutamide. The results with HEK-293/recombinant human SUR1 cells were similar with the exception that glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [3H]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [3H]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with KATPchannels in rat pancreatic β-cells was investigated with the patch-clamp method. The relative potency for inhibition of theKATP channel was repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect onKATP current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide. These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at theKATP channel.

Footnotes

  • Send reprint requests to: Brian R. Boettcher, Metabolic and Cardiovascular Disease Department, Novartis Institute for Biomedical Research, 556 Morris Ave., Summit, NJ 07901. E-mail:brian.boettcher{at}pharma.novartis.com

  • Abbreviations:
    SUR1
    sulfonylurea receptor 1
    HEK
    human embryonic kidney
    EBNA
    Epstein Barr nuclear antigen 1 gene
    HEK.EBNA[humanSUR1]
    HEK.EBNA cells expressing human SUR1 from the pOriP/Zeo expression plasmid
    RIN-m5F
    rat islet cell tumor β-cell line
    pOriP/Zeo
    expression plasmid containing the oriP origin of replication of the Epstein Barr virus and the zeocin resistance gene
    • Received August 19, 1999.
    • Accepted January 7, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleENDOCRINE AND REPRODUCTIVE

Pancreatic β-Cell K ATP Channel Activity and Membrane-Binding Studies with Nateglinide: A Comparison with Sulfonylureas and Repaglinide

Shiling Hu, Shuya Wang, Barbara Fanelli, Philip A. Bell, Beth E. Dunning, Sabine Geisse, Rita Schmitz and Brian R. Boettcher
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 444-452;

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Research ArticleENDOCRINE AND REPRODUCTIVE

Pancreatic β-Cell K ATP Channel Activity and Membrane-Binding Studies with Nateglinide: A Comparison with Sulfonylureas and Repaglinide

Shiling Hu, Shuya Wang, Barbara Fanelli, Philip A. Bell, Beth E. Dunning, Sabine Geisse, Rita Schmitz and Brian R. Boettcher
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 444-452;
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