uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Imatinib mesylate (Gleevec) protects against streptozotocin-induced diabetes and islet cell death in vitro
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.
2006 (English)In: Cell Biology International, ISSN 1065-6995, E-ISSN 1095-8355, Vol. 30, no 12, 1013-1017 p.Article in journal (Refereed) Published
Abstract [en]

The tyrosine kinase inhibitor imatinib mesylate (Gleevec) has been demonstrated to protect various cell types from death by inhibition of Abelson tyrosine kinase (c-Abl). The aim of the present study was to establish whether imatinib protects the insulin producing β-cell from the different apoptosis promoting agents in vitro and whether imatinib counteracts streptozotocin-induced diabetes in NMRI mice. We observe that imatinib attenuated the actions of several different death promoting substances. In addition, mice injected with streptozotocin did not develop diabetes when given imatinib. The beneficial effects of imatinib may be related to inhibition of the pro-apoptotic MAP kinase JNK. We conclude that imatinib protects against β-cell death and that this may contribute to the previously reported anti-diabetic actions of imatinib.

Place, publisher, year, edition, pages
2006. Vol. 30, no 12, 1013-1017 p.
Keyword [en]
Apoptosis, Diabetes, Imatinib, JNK, Pancreatic islet
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94676DOI: 10.1016/j.cellbi.2006.08.006ISI: 000242714100009PubMedID: 17020808OAI: oai:DiVA.org:uu-94676DiVA: diva2:168621
Available from: 2006-09-05 Created: 2006-09-05 Last updated: 2011-02-23Bibliographically approved
In thesis
1. Anti-Diabetic and Beta-Cell Protective Actions of Imatinib Mesylate
Open this publication in new window or tab >>Anti-Diabetic and Beta-Cell Protective Actions of Imatinib Mesylate
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes is a disease resulting from the progressive immune-mediated destruction of insulin producing β-cells. In order to understand more about diabetes we need to understand the mechanisms governing β-cell death.

The leukemia drug Gleevec is a tyrosine kinase inhibitor that targets c-Abl. Surprisingly, Gleevec also counteracts Type 2 diabetes and acts as a cell death inhibiting agent, via inhibition c-Abl. Since both Type 1 and Type 2 diabetes are characterized by an increased β-cell death, and the role of c-Abl is unknown in β-cells, we wanted to investigate the following:

1.Does Gleevec act via inhibition of c-Abl in β-cells?

2.Can Gleevec treatment prevent beta-cell death and diabetes?

3.Which downstream signaling pathways are affected by Gleevec?

In paper I, in order to determine whether Gleevec acts by inhibiting c-Abl, we used RNA-interference. Interestingly, siRNA against c-Abl produced by recombinant Dicer mediate almost complete and non-toxic silencing of c-Abl mRNA in dispersed islet cells and conferred protection from streptozotocin and cytokines.

In paper II we show that Gleevec protects β-cells from nitric oxide, pro-inflammatory cytokines and streptozotocin in vitro and that Gleevec can prevent diabetes development in the NOD mouse and the streptozotocin-injected mouse. We also present the hypothesis that Gleevec induces a state resembling ischemic preconditioning.

Paper III presents an additional mechanism by which Gleevec might improve β-cell survival, i.e. via the inhibition of the downstream stress-activated protein kinase c-Jun N-terminal kinase (JNK), the activity of which has been implicated in β-cell death signaling pathways.

In paper IV we explore the interactions between the adaptor protein Shb and c-Abl. We presently show an association between Shb-c-Abl and that Shb is a substrate for the c-Abl kinase that might regulate stress-induced c-Abl activity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 58 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 160
Cell biology, Cellbiologi, Diabetes
urn:nbn:se:uu:diva-7078 (URN)91-554-6615-X (ISBN)
Public defence
2006-09-26, B21, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2006-09-05 Created: 2006-09-05Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed
By organisation
Department of Medical Cell Biology
In the same journal
Cell Biology International
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 208 hits
ReferencesLink to record
Permanent link

Direct link