INSULIN RECEPTOR IN VERTEBRATES IS FUNCTIONALLY MORE CONSERVED DURING EVOLUTION THAN INSULIN ITSELF

The characteristics of the insulin-receptor interaction have been examined in different species of vertebrates, including mammals (man, rat, mouse, and guinea pig), birds (turkey and chicken), amphibians (frog), and bony fish (trout). We found that low vertebrates, such as frogs and fish, have insulin receptors that by multiple function criteria are very similar to those of birds and mammals. Thus, a sharp pH dependence of binding was observed with both mammalian (optimum, 7.8—8.0) and nonmammalian (optimum, 7.2—7.6) receptors. The effect of temperature on association, dissociation, and steady state binding was also very similar. In general, at higher temperatures (30—37 C) binding was faster than at lower temperature (4 C), but at steady state the level of binding was inversely related to the temperature. Further, in all of the species examined, analysis of equilibrium binding data produced curvilinear Scatchard plots, and unlabeled insulin accelerated the dissociation of labeled insulin compatible with insulin-induced negatively cooperative site-site interaction among the receptors. Even more striking was the finding that the affinities of the insulin receptors for the various insulins and analogs were about the same in all of the species examined. In all species tested, chicken insulin bound to the receptor with a higher affinity than pork insulin, which bound better than fish insulin, guinea pig insulin, and the modified insulin derivatives. This difference in affinity reflects the relative biological potency of each insulin in inducing insulin-like effects in mammalian tissues. Thus, the homologous insulin in a given species often bound less well to its own receptor than did insulin of other species. In general, the concentration of insulin receptors was reciprocally correlated with the biopotency of the homologous insulin. For example, the guinea pig (which has a low affinity insulin) has partially compensated by having the highest concentration of insulin receptors on its cells, while the chicken and turkey (which have superpotent insulins) have the lowest receptor concentration.y marked similarity in binding properties, insulin receptors from different species were blocked by one very potent serum containing antibodies to the insulin receptor (serum B-2), suggesting some structural similarities as well. However, with other antisera, differences in immunoreactivity were observed. These data suggest that the insulin receptor has been functionally well conserved over a period of evolution of 400 million yr. Some structural changes in the receptor have occurred, as evidenced by changes in immunoreactivity, but these appear to be in regions of the molecule not critical for its insulin-binding properties. © 1979 by The Endocrine Society.