Amelioration of diabetes by imatinib mesylate (Gleevec): role of beta-cell NF-kappaB activation and anti-apoptotic preconditioning

Hägerkvist, RobertUppsala universitet,Institutionen för medicinsk cellbiologi (författare)

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.

Sandler, StellanUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)stelsand (författare)
Mokhtari, DariushUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)damok087 (författare)
Welsh, NilsUppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)nilswels (författare)
Uppsala universitetInstitutionen för medicinsk cellbiologi (creator_code:org_t)

Av författaren/redakt...: Hägerkvist, Robe ...; Sandler, Stellan; Mokhtari, Darius ...; Welsh, Nils

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