Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning.
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.
Hägerkvist
Robert
R
Department of Medical Cell Biology, Uppsala University, Biomedicum, P.O. Box 571, SE-75123 Uppsala, Sweden.
Sandler
Stellan
S
Mokhtari
Dariush
D
Welsh
Nils
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D000068877:Imatinib Mesylate; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology
D001549:Benzamides; D016207:Cytokines; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D013311:Streptozocin; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016315:Proto-Oncogene Proteins c-abl