Further Evidence for Functional Heterogeneity of Adipocyte Insulin Receptors*

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Abstract
Dissociation of [125I]iodoinsulin from adipocyte insulin receptors was studied in the presence or absence of the insulin derivatives, desoctapeptide insulin and desalanine desasparagine insulin. When cells were allowed to associate with a tracer concentration (10-10 M) of [125I]iodoinsulin and dissociation was studied in either insulin-free buffer or buffer containing 100 ng/ml unlabeled insulin, dissociation was accelerated in the presence of unlabeled insulin. This is consistent with negatively cooperative site-site interactions. On the other hand, when dissociation studies were performed in the presence of high concentrations of desoctapeptide insulin or desalanine desasparagine insulin, dissociation rates were slower than those observed in insulin-free buffer. In marked contrast, when cells were allowed to achieve a high fractional receptor occupancy by associating with high concentrations of either desoctapeptide insulin or desalanine desasparagine insulin, subsequent dissociation rates were greatly enhanced. Thus, insulin derivatives which failed to induce the negative cooperative effect can lead to enhanced [125I]iodoinsulin dissociation, if high fractional receptor occupancy is achieved during the association phase of the experiment. This is consistent with the hypothesis that adipocyte receptors exist in functionally distinct, high affinity, low capacity and low affinity, high capacity states. Thus, when association is performed with [125I]iodoinsulin plus high concentrations of unlabeled insulin, dissociation rates are enhanced because most of the [125I]iodoinsulin binds to the low affinity (fast dissociating) sites, due to saturation of the high affinity, low capacity sites.