Anti-Diabetic and Beta-Cell Protective Actions of Imatinib Mesylate

Sammanfattning: Type 1 diabetes is a disease resulting from the progressive immune-mediated destruction of insulin producing ?-cells. In order to understand more about diabetes we need to understand the mechanisms governing ?-cell death.The leukemia drug Gleevec is a tyrosine kinase inhibitor that targets c-Abl. Surprisingly, Gleevec also counteracts Type 2 diabetes and acts as a cell death inhibiting agent, via inhibition c-Abl. Since both Type 1 and Type 2 diabetes are characterized by an increased ?-cell death, and the role of c-Abl is unknown in ?-cells, we wanted to investigate the following:1.Does Gleevec act via inhibition of c-Abl in ?-cells?2.Can Gleevec treatment prevent beta-cell death and diabetes? 3.Which downstream signaling pathways are affected by Gleevec?In paper I, in order to determine whether Gleevec acts by inhibiting c-Abl, we used RNA-interference. Interestingly, siRNA against c-Abl produced by recombinant Dicer mediate almost complete and non-toxic silencing of c-Abl mRNA in dispersed islet cells and conferred protection from streptozotocin and cytokines.In paper II we show that Gleevec protects ?-cells from nitric oxide, pro-inflammatory cytokines and streptozotocin in vitro and that Gleevec can prevent diabetes development in the NOD mouse and the streptozotocin-injected mouse. We also present the hypothesis that Gleevec induces a state resembling ischemic preconditioning.Paper III presents an additional mechanism by which Gleevec might improve ?-cell survival, i.e. via the inhibition of the downstream stress-activated protein kinase c-Jun N-terminal kinase (JNK), the activity of which has been implicated in ?-cell death signaling pathways. In paper IV we explore the interactions between the adaptor protein Shb and c-Abl. We presently show an association between Shb-c-Abl and that Shb is a substrate for the c-Abl kinase that might regulate stress-induced c-Abl activity.