Amelioration of diabetes by imatinib mesylate (Gleevec®):: role of β-cell NF-κB activation and anti-apoptotic preconditioning

It was recently reported that tyrosine kinase inhibitor imatinib mesylate (Gleevec (R)) improves Type 2 diabetes, possibly by decreasing insulin resistance. However, as both Type 2 and Type I 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 P-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-Ab1 mRNA. Imatinib enhanced beta-cell survival by promoting a state similar to ischemic preconditioning, as evidenced by NF-kappa B 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-kappa B inhibitor, suggesting that NF-kappa B activation is a necessary step in the antiapoptotic action of imatinib. We conclude that imatinib mediates P-cell survival and that this could contribute to the beneficial effects observed in diabetes.