In
type 1 diabetes, humoral and cell-mediated responses to
insulin and
proinsulin are detectable.
Autoantibodies to
insulin are associated with impending disease in young individuals and are used as predictive markers to determine disease risk. The aim of this study was to investigate whether different
cytokine patterns of cellular reactivity to
insulin might serve as additional specific markers of disease maturation and might improve disease prediction in individuals at risk. We correlated T and B cell responses to
insulin in subjects with increased genetic risk (
HLA-DRB1*04, DQB1*0302) for diabetes with or without islet
autoantibodies (Ab+ subjects and controls, respectively) and HLA-matched patients. Peripheral blood mononuclear cells were stimulated with 15 overlapping
proinsulin peptides (16-mer), and proinflammatory Th1 (IFNgamma) and anti-inflammatory Th2 (IL-4)
cytokines were analyzed. We observed a simultaneous increase in
IL-4 and IFNgamma secretion in early islet autoimmunity of Ab+ subjects, but not in
insulin-treated T1D patients. Furthermore, the increase in
IL-4 secretion in Ab+ subjects was associated with
insulin autoantibody responses. There was no correlation of either IFNgamma or
IL-4 secretion with
insulin antibody responses in patients already treated with exogenous
insulin. In conclusion, our findings reveal that quantification of
cytokine responses to
proinsulin in peripheral blood may prove to be a promising specific marker of diabetes progression and could, in addition to
insulin autoantibodies, be used in the prediction of
type 1 diabetes.