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

Department of Medical Cell Biology, Uppsala University, Biomedicum, Uppsala, Sweden

¹Correspondence: Department of Medical Cell Biology, Uppsala University, Biomedicum, P.O. Box 571, SE-75123 Uppsala, Sweden. E-mail: Nils.Welsh{at}medcellbiol.uu.se06-6910com

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 ß-cell dysfunction and death, we investigated whether imatinib counteracts diabetes by maintaining ß-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 ß-cell mass. In addition, imatinib decreased the death of human ß-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 ß-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 ß-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 ß-cell NF-B activation and anti-apoptotic preconditioning.

Key Words: pancreatic islet • c-Abl • NO

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