CONICET | Buscador de Institutos y Recursos Humanos

Diabetes is the most common metabolic disorder associated with significant morbidity and mortality. Infection is an important complication in diabetic patients and abnormalities in the immune system would be the major factor involved. Multiple low-doses of streptozotocin were administered to induce a murine model of type I diabetes and immune responses during disease progression were studied. The humoral response to a T-cell dependent antigen showed a decreased production of specific IgG but not IgM antibodies, one month after diabetes induction, thus indicating an impairment of isotype switching. Also, diminished proliferative responses to T and B selective mitogens were observed after 6-month of streptozotocin treatment. As high glucose levels have been demonstrated to be mainly involved in the initiation and progression of diabetic complications, the effect of high glucose concentrations on immune responses was studied. Mitogen-induced T and B lymphocyte proliferation was decreased when preincubating cells for 24 hrs with high glucose concentrations. Osmotic stress is not responsible of high glucose actions as manitol failed to induce this effect. Lymphocyte response to high glucose was concentration and time dependent and reverted after cell wash. Treatment of freshly obtained lymphocytes with supernatants from cells incubated with high glucose mimicked the preincubation effect. High glucose induced a decrease in nitric oxide synthase activity and an increase in the presence of necrotic and apoptotic lymphocytes. Moreover, high glucose rapidly generated reactive oxygen species and lipid peroxidation in T and B-lymphocytes. It is established that glucose reacts spontaneously with the amino groups of proteins to form reversible Schiff bases, which are then transformed into irreversible advanced glycosylation end proteins (AGE). Using [14C]-glucose, glycosylated products were obtained in supernatants of lymphocytes incubated with high glucose concentrations. In conclusion, in diabetes, hyperglycemia may interact with immune system leading to an impaired function. This interaction initially leads to reversible effects that, depending on time and concentration, conducted to the irreversible inhibition of the immune response. Glycosylated products and oxidative stress resulting from hyperglycemia would play key roles in the pathogenesis of immunosuppression in diabetic patients.