EGFR Tyrosine Kinase Inhibitor (PD153035) Improves Glucose Tolerance and Insulin Action in High-Fat Diet–Fed Mice
Patricia O. Prada
Eduardo R. Ropelle
Rosa H. Mour ao
Claudio T. de Souza
Jose R. Pauli
Dennys E. Cintra
Andre Schenka
Silvana A. Rocco
Roberto Rittner
Kleber G. Franchini
Jose Vassallo
Lcio A. Velloso
Jose B. Carvalheira
Mario J.A. Saad
OBJECTIVE-In obesity, an increased macrophage infiltration in adipose tissue occurs, contributing to low-grade inflammation and insulin resistance. Epidermal growth factor receptor (EGFR) mediates both chemotaxis and proliferation in monocytes and macrophages. However, the role of EGFR inhibitors in this subclinical inflammation has not yet been investigated. We investigated, herein, in vivo efficacy and associated molecular mechanisms by which PD153035, an EGFR tyrosine kinase inhibitor, improved diabetes control and insulin action. RESEARCH DESIGN AND METHODS-The effect of PD153035 was investigated on insulin sensitivity, insulin signaling, and c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-B activity in tissues of high-fat diet (HFD)-fed mice and also on infiltration and the activation state of adipose tissue macrophages (ATMs) in these mice. RESULTS-PD153035 treatment for 1 day decreased the protein expression of inducible nitric oxide synthase, tumor necrosis factor (TNF)-, and interleukin (IL)-6 in the stroma vascular fraction, suggesting that this drug reduces the M1 proinflammatory state in ATMs, as an initial effect, in turn reducing the circulating levels of TNF- and IL-6, and initiating an improvement in insulin signaling and sensitivity. After 14 days of drug administration, there was a marked improvement in glucose tolerance; a reduction in insulin resistance; a reduction in macrophage infiltration in adipose tissue and in TNF-, IL-6, and free fatty acids; accompanied by an improvement in insulin signaling in liver, muscle, and adipose tissue; and also a decrease in insulin receptor substrate-1 Ser307 phosphorylation in JNK and inhibitor of NF-B kinase (IKK) activation in these tissues. CONCLUSIONS-Treatment with PD153035 improves glucose tolerance, insulin sensitivity, and signaling and reduces subclinical inflammation in HFD-fed mice. Diabetes 58:2910-2919, 2009
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Erosine kinase inhibitors are used in the clinic to
pidermal growth factor receptor (EGFR)
tytreat malignancies (1). It has recently been
observed that a modest number of patients,
suffering from both malignancies and type 2 diabetes, were
successfully treated not only for their malignancies but
also for diabetes when given some tyrosine kinase
inhibitors (25). However, the molecular mechanisms that
account for the effect of these drugs on insulin action and
glucose metabolism are unknown.
Insulin stimulates a signaling network composed of a
number of molecules, initiating the activation of insulin
receptor tyrosine kinase and phosphorylation of insulin
receptor substrates, including insulin receptor substrate
(IRS)-1 and IRS-2 (6 8). Following tyrosine
phosphorylation, IRS-1/IRS-2 bind and activate the enzyme
phosphatidylinositol 3-kinase (PI3-K). The activation of PI3-K
increases serine phosphorylation of Akt, which is
responsible for most of the metabolic actions of insulin, such as
glucose transport, lipogenesis, and glycogen synthesis
(7,8).
In the most prevalent forms of insulin resistance,
dietinduced obesity, and type 2 diabetes, there is a
downregulation in this signaling pathway in insulin-sensitive tissues,
parallel to a state of chronic low-grade inflammation (6).
Several serine/threonine kinases are activated by
inflammatory or stressful stimuli and contribute to inhibition of
insulin signaling, including c-Jun NH2-terminal kinase
(JNK) (9 13) and inhibitor of nuclear factor (NF)-B
kinase (IKK) (12,14). In obesity, an increased
macrophage infiltration in adipose tissue occurs, contributing to
this low-grade inflammation (1517), which has an
important role in the increased tissue production of
proinflammatory molecules and acute-phase proteins associated
with obesity (13,14). EGFR has been described in
monocytes and in macrophages and mediates both chemotaxis
and proliferation in macrophages (18 20). However, the
role of EGFR inhibitors on this subclinical inflammation of
obesity was not yet investigated.
PD153035 has been shown to possess highly potent and
selectively inhibitory activity against EGFR tyrosine
kinase and rapidly suppresses autophosphorylation of EGFR
at low nanomolar concentrations in fibroblasts and human
epidermoid carcinoma cells, as well as selectively
blocking EGF-mediated cellular processes, including
mitogenesis and early gene expression (2123). In addition,
PD153035 has been shown to reduce JNK and IKK/IB/
NF-B pathways (24,25). Moreover, EGFR and other
tyrosine kinase inhibitors have also been shown to inhibit
the growth of monocyte/macrophages, suggesting possible
mechanisms to improve insulin action (26 29).
Herein, we investigated the in vivo efficacy and
associated molecular mechanisms by which PD153035, an EGFR
tyrosine kinase inhibitor, imp (...truncated)