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 -cell dysfunction and death, we investigated whether imatinib counteracts diabetes by maintaining -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 -cell mass. In addition, imatinib decreased the death of human -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 -cell survival by promoting a state similar to ischemic preconditioning, as evidenced by NF-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-B inhibitor, suggesting that NF-B activation is a necessary step in the antiapoptotic action of imatinib. We conclude that imatinib mediates -cell survival and that this could contribute to the beneficial effects observed in diabetes.--Hägerkvist, R., Sandler, S., Mokhtari, D., Welsh, N. Amelioration of diabetes by imatinib mesylate (Gleevec): role of -cell NF-B activation and anti-apoptotic preconditioning.