Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice

Abstract

The recent development of small-molecule tyrosine kinase (TK) inhibitors offers increasing opportunities for the treatment of autoimmune diseases. In this study, we investigated the potential of this new class of drugs to treat and cure type 1 diabetes (T1D) in the NOD mouse. Treatment of prediabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed T1D. Similar results were observed with sunitinib (Sutent), an additional approved multikinase inhibitor, suggesting that the primary target of imatinib, c-Abl, was not essential in blocking disease in this model. Additional studies with another TK inhibitor, PLX647 (targeting c-Kit and c-Fms) or an anti-c-Kit mAb showed only marginal efficacy whereas a soluble form of platelet-derived growth factor receptor (PDGFR), PDGFR␤Ig, rapidly reversed diabetes. These findings strongly suggest that inhibition of PDGFR is critical to reverse diabetes and highlight a crucial role of inflammation in the development of T1D. These conclusions were supported by the finding that the adaptive immune system was not significantly affected by imatinib treatment. Finally, and most significantly, imatinib treatment led to durable remission after discontinuation of therapy at 10 weeks in a majority of mice. Thus, long-term efficacy and tolerance is likely to depend on inhibiting a combination of tyrosine kinases supporting the use of selective kinase inhibitors as a new, potentially very attractive approach for the treatment of T1D.autoimmunity ͉ diabetes ͉ tyrosine kinase inhibitor ͉ imatinib ͉ PDGFR

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

“…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). More recently, we have demonstrated that plasma levels of an adipokine, adiponectin, are elevated two-to three-fold in CML patients after 3 months of imatinib therapy .…”

AMP-dependent Kinase Inhibits Oxidative Stress-induced Caveolin-1 Phosphorylation and Endocytosis by Suppressing the Dissociation between c-Abl and Prdx1 Proteins in Endothelial Cells

“…The complex of c-Abl⅐Prdx1 is thought to be a major target of oxidative stress and has been shown to play an important role in the pathogenesis of vascular disease, such as atherosclerosis and diabetes mellitus (43)(44)(45)(46) as well as cancer and other agingrelated diseases such as osteoporosis (47). Further study using disease-model animal is required to elucidate the significance of protective role of AMPK on c-Abl⅐Prdx1 complex in these diseases.…”

The use of targeted therapies in pancreatic neuroendocrine tumours: patient assessment, treatment administration, and management of adverse events

“…Given that the inhibition of plateletderived growth factor receptor by sunitinib can promote pancreatic β-cell survival [Mokhtari and Welsh, 2010], sunitinib treatment may be suitable for patients with glucagonoma but may have detrimental effects on patients with insulinoma. Preclinical studies have shown sunitinib to, in fact, reverse type 1 diabetes [Louvet et al 2008]. In a patient with metastatic renal cell carcinoma, however, sunitinib treatment induced long-term remission from recent-onset type 1 diabetes mellitus [Templeton et al 2008].…”