Amelioration of diabetes by imatinib mesylate (Gleevec®): role of ‐cell NF‐KB activation and anti‐apoptotic preconditioning

Abstract

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.

Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice

“…In this regard, we note that Hagerkvist et al recently showed that imatinib ameliorates type 2 diabetes in rats by lowering insulin resistance (45). However, in a related study (22), the authors concluded that imatinib treatment preserved ␤ cell viability through an Abl-dependent inhibition of NFB. Our studies suggest that an Abl-independent mechanism of action is a key to the affects of imatinib in the T1D setting.…”

“…Furthermore, imatinib can be administered for as short as 10 weeks with long-lasting effects working through the inhibition of PDGFR. These results, coupled with recent studies demonstrating a direct protective effect of imatinib on type 2 diabetes in rodents (22) suggests that this molecule and other kinase inhibitors such as sunitinib have potential as a therapeutic to treat patients with this disease.…”

Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib

“…Although a decrease was observed at week 4, this was not significant (data not shown, P ¼ 0.06). Third, amelioration of diabetes by imatinib (Gleevec s ) has been reported in animal models (Hagerkvist et al, 2007) and in human (Veneri et al, 2005). This unexpected effect was related to the protective effect of imatinib on b cells by an antiapoptotic action through NF-kB activation.…”

Suppression of PDGF-induced PI3 kinase activity by imatinib promotes adipogenesis and adiponectin secretion

“…In support of this, improved glycaemic control has also been observed following imatinib treatment in animal models of diabetes. In streptozotocin-induced and spontaneous (non-obese diabetic and db/db) mouse models of diabetes, imatinib has been shown to preserve islet b-cell function, in part through the suppression of c-abl-mediated islet cell apoptosis (Hagerkvist et al 2007, Han et al 2009). Imatinib and other inhibitors of PDGFR have also been shown to prevent and even reverse diabetes in nonobese diabetic mice through a mechanism that may involve suppression of a PDGF-induced inflammatory response (Louvet et al 2008).…”