Mechanisms of the Fasting-Induced Increase in Insulin Binding to Rat Adipocytes

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Abstract

Fasting leads to an increase in the ability of adipocytes to bind insulin, and this was accounted for by an increase in the affinity of the receptors for insulin without any change in the number of receptors per cell. Binding affinity can increase because of a decrease in the dissociation rate constant (kd), an increase in the association rate constant (ka), or both. Kinetic studies demonstrated that fasting leads to a striking decrease in the rate at which insulin dissociates from its receptor, and the near two-fold prolongation of the time at which 50% of the bound 125I-insulin dissociates (28±4 vs. 50±5 min) correlated quite well with the two-fold increase in binding affinity. On the other hand, the rate at which insulin associates with its receptor was essentially unchanged. Negatively cooperative interactions between receptors were readily demonstrated in cells from control and fasting animals, and the magnitude and sensitivity of this effect was the same in both groups of cells. It seemed likely that during fasting a change in the concentration of some substrate or hormone could lead to these effects on insulin binding. However, in vitro attempts to recreate the substrate and hormonal changes which occur in fasting produced no evidence to support this idea. In conclusion: (a) fasting leads to an increase in the ability of adipocytes to bind insulin because of an increase in binding affinity; (b) this increase in the affinity of the receptor for insulin was primarily accounted for by a decrease in the rate at which insulin dissociates from its receptors; and (c) fasting did not appreciably alter the negatively cooperative interactions displayed by adipocyte insulin receptors.

Authors

Jerrold M. Olefsky, Masashi Kobayashi