The role of immunity and inflammation in the development of diabetic complications

Our group has carried out pivotal clinical studies on large cohorts of type 1 and type 2 diabetes to determine the impact of modified LDL-IC as well as inflammatory cytokines/adipokines and acute-phase reactant proteins in the development of diabetic complications. We have demonstrated that high levels of specific LDL modifications in circulating ICs correlate with increased risk for the development and progression of macrovascular disease, nephropathy, and retinopathy, frequently exceeding conventional risk factors in their predictive power. In cardiovascular disease, differences in the type of LDL modification and the stage of disease seem to lead to/predict different outcomes. The differences observed with ICs containing different types of modified LDL raises interesting questions about the role of the predominant LDL modification in the ICs and the cellular patterns of macrophage activation, survival, and apoptosis that result from LDL-IC ingestion. The differences observed in the predictive power of modified LDL-ICs at different stages of CVD development strongly suggest that modified LDL-ICs are causally related with the development of atherosclerosis and/or plaque instability. The association of cytokines/adipokines and acute-phase reactant proteins with the development of complications in type 1 diabetes is less strong than that observed with modified LDL-ICs and occurs at a later phase of the development of complications. In conclusion, the human humoral autoimmune response to modified forms of LDL is a typical adaptive response, with a switch to IgG synthesis and increasing antibody affinity that leads to the release of proinflammatory mediators, and it has unquestionable pathogenic characteristics. © 2013 The Japan Diabetes Society (outside the USA).