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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. 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