Tyrosine Kinase Inhibitors and Diabetes: A Novel Treatment Paradigm?

Deregulation of protein tyrosine kinase (PTK) activity is implicated in various proliferative conditions. Multi-target tyrosine kinase inhibitors (TKIs) are increasingly used for the treatment of different malignancies. Recently, several clinical cases of the reversal of both type 1 and 2 diabetes mellitus (T1DM, T2DM) during TKI administration have been reported. Experimental in vivo and in vitro studies have elucidated some of the mechanisms behind this effect. For example, inhibition of Abelson tyrosine kinase (c-Abl) results in β cell survival and enhanced insulin secretion, while platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) inhibition leads to improvement in insulin sensitivity. In addition, inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) reduces the degree of islet cell inflammation (insulitis). Therefore, targeting several PTKs may provide a novel approach for correcting the pathophysiologic disturbances of diabetes.

TrendsTyrosine kinase inhibitors (TKIs) exert antihyperglycemic effects that can reverse or prevent type 1 and 2 diabetes mellitus by correcting insulin resistance and β cell dysfunction.C-Abl inhibition results in reduced β cell apoptosis, increased β cell survival, and enhanced insulin production.Inhibition of PDGFR improves insulin sensitivity by promoting adipogenesis and adiponectin secretion, and suppresses inflammatory responses in islets.EGFR inhibition indirectly improves insulin sensitivity by decreasing the expression of TNFα and IL6 and reducing M1 macrophage infiltration in adipose tissue.Inhibition of VEGFR2 increases islet vascularity, impairs T cell migration into the islet cells, and reduces the severity of insulitis.