Autoreactive antibodies control blood glucose by regulating insulin homeostasis

Significance The random nature of antibody repertoire generation includes the potential of producing autoantibodies recognizing self-structures. It is believed that establishing immunological tolerance and prevention of autoimmune diseases require the removal of antibody specificities recognizing self. Using insulin as a common and physiologically important autoantigen, we show that anti-insulin antibodies associated with autoimmune diabetes can readily be detected in mice and humans and are involved in the physiological regulation of blood glucose levels. Importantly, human high-affinity, anti-insulin IgM antibodies protect insulin from autoimmune degradation by anti-insulin IgG antibodies. Thus, in contrast to the proposed negative selection, self-recognition and the production of highly autoreactive IgM antibodies are important for tolerance induction.