Review
Tyrosine Kinase Inhibitors and Diabetes: A Novel Treatment Paradigm?

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Tyrosine 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.

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.

Section snippets

Tyrosine Kinase Inhibitors and Diabetes: The Basics

PTKs phosphorylate tyrosine residues on target proteins, thereby changing their function. Deregulation of PTK activity, by genetic or epigenetic alterations, is implicated in various proliferative conditions, especially neoplastic diseases [1]. Activated forms of these enzymes can cause increase in tumor cell growth, induce antiapoptotic effects, and promote angiogenesis [2] (Box 1). This basic understanding has paved the way for the development of selective TKIs that attenuate these activities.

Antidiabetic Effects of TKIs

Over the past few years, several reports in the literature from clinical observations, animal models, and in vitro studies have documented the effect of TKIs in glucose metabolism in both T1DM and T2DM (Table 1, Table 2).

The Antidiabetic Effect of TKIs: Potential Mechanisms

The potential mechanisms underlying the antidiabetic action of TKI may differ depending on the type of the tyrosine kinase that is inhibited (Figure 1). However, in some of the antidiabetic effects of imatinib, there is still uncertainty regarding the molecular mechanisms involved.

Concluding Remarks and Future Perspectives

Clinical reports, as well as experimental animal and in vitro studies, have provided sufficient evidence that TKIs not only reverse, but also prevent the clinical manifestation of both T1DM and T2DM. By inhibiting several tyrosine kinases, this new class of agents exerts multiple effects that target the two main defects of diabetes: insulin resistance and β cell dysfunction.

In contrast to conventional therapy, TKIs appear to preserve β cell function, which has been regarded as the Holy Grail

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