Indomethacin inhibits endocytosis and degradation of insulin

Indomethacin inhibits autophosphorylation of the insulin receptor. The lack of a consensus as to whether phosphorylation of the insulin receptor is necessary for its endocytosis prompted an investigation into the effects of indomethacin on the uptake and subcellular processing of insulin in the perfused rat liver. Indomethacin did not affect total uptake of insulin by the liver, but there was a concentration dependent inhibition of transfer from the plasma membrane to the endosomes (1mM, 32% inhibition; 5mM, 90% inhibition). Compartmental analysis showed the endocytic rate constant to be inhibited by 82% at 5mM indomethacin (0.0084 to 0.0015 sec-1). The similarity between the level of inhibition of autophosphorylation and the inhibition of endocytosis suggest that phosphorylation of the receptor is necessary for endocytosis. Indomethacin at 5mM completely abolished efflux of insulin degradation products from the perfused liver, suggesting that internalisation is an absolute requirement for degradation.