Investigations of Strategies to Counteract Proinflammatory Cytokines in Experimental Type 1 Diabetes

Sammanfattning: Type 1 diabetes (T1D) is a chronic autoimmune disease targeted against the pancreatic ?-cells. Proinflammatory cytokines are considered to play a major role in the destruction of the insulin-producing ?-cells. This thesis studied strategies to counteract proinflammatory cytokines in experimental T1D. Both animal models for T1D as well as ?-cell preparations exposed in vitro to putative noxious conditions were examined.In the first study we observed that cytokine treatment of mouse pancreatic islets lacking inducible nitric oxide synthase (iNOS) induced a prolongation of the early stimulatory phase of glucose stimulated insulin secretion. Various experiments led to the conclusion that this prolonged stimulatory effect may involve the DAG/PLD/PKC pathway.Next, we transplanted mouse islets deficient in iNOS to spontaneously diabetic NOD mice. We observed a normalization of hyperglycemia but not a delayed allograft rejection compared to transplanted wild type islets. Thus, absence of iNOS in the graft was not sufficient to prolong allograft survival.In paper III we found that sustained glucose stimulation of rat pancreatic islets was coupled to a decreased conversion of proinsulin to insulin. Islet treatment with IL-1? was also coupled to a decreased proinsulin conversion. Islet proconvertase activity may be a target in islet damage.In paper IV prolactin (PRL) was administered to mice in the multiple low dose streptozotocin model and we observed that PRL enhanced a Th2 response. This may contribute to the protective action by PRL in this model of autoimmune T1D.Finally, by examining ?-cells overexpressing Suppressor of cytokine signalling 3 (SOCS-3) it was found that this could inhibit IL-1? induced signalling through the NF-?B and MAPK pathways. SOCS-3 overexpression also inhibited apoptosis induced by cytokines in primary ?-cells. Lastly, we demonstrated that SOCS-3 transgenic islets were protected in an allogeneic transplantation model.