Expression kinetics reveal the self-adaptive role of ß cells during the progression of diabetes.

OBJECTIVE: To determine the histopathological and molecular changes in ß-cells at different time intervals following streptozotocin (STZ)-induced diabetes. METHODS: STZ (65 mg/kg body weight) was given to overnight fasted rats that were sacrificed after 1, 3, and 10 days of injection. Changes in islet morphology and in the expression of various factors involved in ß-cell proliferation, inflammation and apoptosis were analyzed. RESULTS: Superoxide dismutase (Sod) expression was completely reduced and that of NF-kB and iNOS were significantly increased, along with lymphocytic infiltration in the islets within 24 h of STZ injection. In addition, the ß-cell protective markers Bcl-2, IL-6, Ki67, Hif-1α, VEGF and insulin were also enhanced, indicating a compensatory response of the ß-cells to the initial damaging effects. Lymphocytic infiltration decreased after 3 days of injection, accompanied by enhanced expression of both GLP-1R and GIP R. The unresponsiveness of the incretin ligands after STZ administration further suggested a compensatory approach by the incretin receptors independent of glucose regulation. After 10 days, lymphocytic infiltration and inflammatory markers again increased, along with a concomitant reduction in the expression of incretin receptors, and upregulation of the protective markers. Furthermore, the saturation peak of blood glucose indicated progressive diabetes. CONCLUSIONS: The ß-cells follow a biphasic pattern of expression of certain factors in order to achieve a balance between apoptosis, autophagy, neo-genesis, hypoxia and proliferation, and achieve homeostatic protection before the onset of diabetes. The drug interventions at an early stage, which are specific to these pathways, could be beneficial in preventing the progression of diabetes pathogenesis.