Insulin binds to glucagon forming a complex that is hyper-antigenic and inducing complementary antibodies having an idiotype-antiidiotype relationship

We demonstrate using physico-chemical techniques that insulin binds to gluc agon with a Kd of 0.89 micromolar. While such binding is of little signific ance physiologically, it has important immunological consequences. Hormone binding a is mirrored by specific binding between insulin antibody and gluc agon antibody to form idiotype-antiidiotype complexes observable by Ouchter lony immunodiffusion and ELISA. These complexes may provide new insights in to the formation of circulating immune complexes in diabetes. The insulin-g lucagon complex is hyper-antigenic, inducing antibody production at concent rations that do not elicit immune responses from the individual hormones. T he resulting immune response is not primarily against the individual hormon es, but against the complex. In fact, all so-called insulin antibodies test ed (rabbit, guinea pig, mouse and human) show substantially higher affinity for insulin-glucagon complex than for insulin alone, suggesting that this complex is the primary antigen in most, if not all, cases. These results le ad to several testable predictions, including the possibility that glucagon antibody will bind to insulin receptors to cause type 2 (antibody mediated ) insulin resistance.