2-2--(hydroxynitrosohydrazono)bis-ethanamine and Diabetes-Mellitus--Type-1

It was recently reported that tyrosine kinase inhibitor imatinib mesylate (Gleevec) improves Type 2 diabetes, possibly by decreasing insulin resistance. However, as both Type 2 and Type 1 diabetes are characterized by beta-cell dysfunction and death, we investigated whether imatinib counteracts diabetes by maintaining beta-cell function. We observed that imatinib counteracted diabetes in two animal models, the streptozotocin-injected mouse and the nonobese diabetes mouse, and that this was paralleled by a partial preservation of the beta-cell mass. In addition, imatinib decreased the death of human beta-cells in vitro when exposed to NO, cytokines, and streptozotocin. The imatinib effect was mimicked by siRNA-mediated knockdown of c-Abl mRNA. Imatinib enhanced beta-cell survival by promoting a state similar to ischemic preconditioning, as evidenced by NF-kappaB activation, increased NO and reactive oxygen species production, and depolarization of the inner mitochondrial membrane. Imatinib did not suppress islet cell death in the presence of an NF-kappaB inhibitor, suggesting that NF-kappaB activation is a necessary step in the antiapoptotic action of imatinib. We conclude that imatinib mediates beta-cell survival and that this could contribute to the beneficial effects observed in diabetes.

Topics: Animals; Apoptosis; Benzamides; Cell Line, Tumor; Cytokines; Diabetes Mellitus, Type 1; Humans; Imatinib Mesylate; Islets of Langerhans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred NOD; Mice, Inbred Strains; NF-kappa B; Nitric Oxide; Nitric Oxide Donors; Nitroso Compounds; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Proto-Oncogene Proteins c-kit; Pyrimidines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA Interference; Streptozocin