Evidence for modulation of insulin action and degradation independently of insulin binding.

The interrelationships between insulin binding, action, and degradation were investigated in isolated hepatocytes with the aid of an insulin-receptor antibody (IRA) preparation that does not affect insulin binding. These IRA have insulin-like effects as determined by their ability to stimulate [14C]acetate incorporation into lipids. However, this effect is less than that of insulin; and in the presence of insulin and IRA, the effects of insulin are partially inhibited. The IRA have no effect on lipogenesis stimulated by postreceptor insulin "mimickers." The IRA also significantly inhibit insulin degradation. However, they do not affect insulin degradation in the presence of a large excess of unlabeled hormone. Taken together these data demonstrate that insulin action and degradation can be modulated independently of binding and suggest that the IRA partially inhibit insulin action and degradation through a portion of the insulin receptor that is not a determinant of insulin binding. It is possible, however, that there exist in the antiserum heterogeneous antibodies that bind to nonreceptor sites on the plasma membrane and mediate some of the phenomena observed.