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Amelioration of dia...
Amelioration of diabetes by imatinib mesylate (Gleevec) : role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning
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- Hägerkvist, Robert (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Sandler, Stellan (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Mokhtari, Dariush (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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- Welsh, Nils (author)
- Uppsala universitet,Institutionen för medicinsk cellbiologi
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(creator_code:org_t)
- 2006-11-29
- 2007
- English.
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In: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 21:2, s. 618-628
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Keyword
- pancreatic islet
- c-Abl
- NO
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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