The role of circulating immune complexes in the pathogenesis of diabetes mellitus.

We have studied soluble immune complexes (IC) in the sera of both insulin-dependent and non-insulin-dependent diabetics by a variety of non-specific techniques and also by a method that detects specifically insulin-anti-insulin IC. Our screening studies, detailed in the first section of this work, showed that insulin-anti-insulin IC appear not to be the only type of IC present in diabetics. Non-specific screening tests gave practically identical percentages of positive results in insulin-dependent and non-insulin-dependent diabetics. However, the agreement between different screening tests was poor. We propose the use of 'IC scores' (numerical expressions of the general trend of several screening tests performed with one given serum sample) for the statistical analysis of correlations between the presence of soluble IC and clinical evidence of diabetic microangiopathy. As expected, the use of 'scores' minimized false positive or negatives and considerably enhanced statistical correlations between levels of IC and proteinuria, nephropathy, retinopathy, peripheral neuropathy, and peripheral vasculopathy. The second section of this report describes our isolation studies, which provided definitive proof for the existence of soluble insulin-anti-insulin IC and allowed us to carry out the first successful studies of the biological properties of soluble IC purified from the sera of diabetic patients, as detailed in the third section of this report. Such IC-induced platelet aggregation and activation which in vivo could lead to the development of microvascular lesions could explain, at least in part, the abnormalities in platelet function seen in diabetics. Although the precise mechanisms by which soluble IC could induce pathological damage in diabetics have not been totally clarified, we have obtained sufficient evidence to prove that antigen-antibody complexes exist in diabetics, are associated with higher frequencies of complications, and have the capacity to interact with cells in a potentially pathogenic fashion.