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Inhibition of insulin receptor phosphorylation by indomethacin

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Abstract

Insulin stimulated phosphorylation of tyrosine residues by the insulin receptor kinase may be part of a signalling mechanism associated with insulin's action. We report that indomethacin inhibited the phosphorylation of the β-subunit of the solubilized adipocyte insulin receptor. Indomethacin also inhibited several insulin-sensitive processes in intact rat adipocytes. Indomethacin (1 mM) inhibited basal phosphorylation of the β-subunit of the solubilized insulin receptor by 6007o and insulin-stimulated phosphorylation by 30%. In adipocytes, indomethacin inhibited basal 3-0-[methyl-14C]-methyl-D glucose transport by 50070 (P < 0.01), D-[6-14C]-glucose oxidation by 5007o (P < 0.01), D-[6-14C]-glucose conversion to lipid by 30010 (P < 0.01), and D-[1-14C]-glucose conversion to lipid by 6007o (P<0.01). Similarly, indomethacin inhibited insulin-stimulated 3-0-[methyl-14C]-methyl-D-glucose transport by 75070 (P<0.01), D-[6-14C]-glucose oxidation by 20% (P<0.05), D-[1-14C]-glucose oxidation by 35070 (P<0.01), D-[6-14C] glucose conversion to lipid by 25010 (P<0.01), and D-[1-14C] glucose conversion to lipid by 4501o (P<0.01). In contrast, insulin binding to its receptor, basal D-[1-14C]-glucose oxidation and both basal and insulin-stimulated activation of glycogen synthase were unaffected by indomethacin. Thus, indomethacin partially inhibited autophosphorylation of the solubilized insulin receptor on tyrosine and partially inhibited some but not all of insulin's actions. This supports the hypothesis that insulin's metabolic effects are linked to activation of the insulin receptor protein kinase and indicates that there may be heterogeneity in the mechanisms of intracellular metabolic control by insulin.

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Authors and Affiliations

  1. Department of Pharmacology, The University of Virginia School of Medicine, 22908, Charlottesville, Virginia, USA

    Carl D. Malchoff, Joseph L. Messina, Valery Gordon, Shinri Tamura & Joseph Larner

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  1. Carl D. Malchoff
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  2. Joseph L. Messina
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  3. Valery Gordon
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  4. Shinri Tamura
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  5. Joseph Larner
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Malchoff, C.D., Messina, J.L., Gordon, V. et al. Inhibition of insulin receptor phosphorylation by indomethacin. Mol Cell Biochem 69, 83–90 (1985). https://doi.org/10.1007/BF00225930

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  • DOI: https://doi.org/10.1007/BF00225930

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