Because of prior immunohistochemical findings of insulin, gamma globulin and complement components in diabetic microangiopathy, the in vitro interaction of insulin and IgG was studied. When native insulin and purified IgG were reacted under mild reducing conditions, a precipitate formed which was highly reactive with serum complement. Neither insulin nor IgG alone, reduced under the same conditions, demonstrated significant complement fixing activity. Maximal complement fixing activity was obtained from such a mixture at 30° C. in approximately one hour, the time of appearance of a visible precipitate. The presence of both insulin and IgG in the complement fixing precipitate was demonstrated by Ouchterlony analysis and by use of radio-labeled insulin and IgG. The tracer experiments indicated a precipitate composition of approximately 80 per cent insulin and 20 per cent IgG by weight. The utilization of complement components was similar to that obtained with IgG altered by heat aggregation or reaction with antigen. Complement fixation was not affected by alleviation of the precipitate, indicating that free sulfhydryl groups are not necessary. This interaction of denatured insulin and IgG to form a complement fixing complex offers a possible explanation for the presence of these components in micro-angiopathic lesions and may be a contributing factor to the pathogenesis of diabetic microangiopathy. Although complement is activated by an immunoglobulin insulin complex, this mechanism would be considered an immune bypass since specific antibody to insulin is not required.

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