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Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2007 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 21, no 2, p. 618-628Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2007. Vol. 21, no 2, p. 618-628
Keywords [en]
pancreatic islet, c-Abl, NO
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-25284DOI: 10.1096/fj.06-6910comISI: 000244686300034PubMedID: 17135364OAI: oai:DiVA.org:uu-25284DiVA, id: diva2:53058
Available from: 2007-02-12 Created: 2007-02-12 Last updated: 2017-12-07Bibliographically approved

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Hägerkvist, RobertSandler, StellanMokhtari, DariushWelsh, Nils

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