Tyrosine kinase inhibitors (TKi) hold promise as a treatment for a variety of disorders ranging from those in oncology to diseases thought as immune mediated.
Tyrphostin AG490 is a potent Jak-Stat TKi shown effective in the prevention of allograft transplant rejection, experimental
autoimmune disease, as well as the treatment of
cancer. However, given its ability to modulate this important but pleiotropic intracellular pathway, we thought that it is important to examine its effects on
glucose metabolism and expression of major
transcription factors and
adipokines associated with
insulin insensitivity and diabetes. We investigated the metabolic effects of
AG490 on
glucose levels in vivo using an animal model of diabetes, nonobese diabetic (NOD) mice, and
transcription factor expression through assessment of human adipocytes.
AG490 treatment of young nondiabetic NOD mice significantly reduced
blood glucose levels (p = 0.002). In vitro, treatment of adipocytes with
rosiglitazone, an
insulin sensitizer that binds to
peroxisome proliferator-activated receptor (
PPAR) receptors and increases the adipocyte response to
insulin, significantly increased the expression of the
antidiabetic adipokine adiponectin. Importantly, the combination of
rosiglitazone plus
Tyrphostin AG490 further increased this effect and was specifically associated with significant upregulation of C-enhanced
binding protein (C/EBP) (p < 0.0001). In terms of the mechanism underlying this action, regulatory regions of the PPARĪ³, ADIPOQ, and C/EBP contain the Stat5
DNA-binding sequences and were demonstrated, by gel shift experiments in vitro. These data suggest that blocking Jak-Stat signaling with
AG490 reduces
blood glucose levels and modulates the expression of
transcription factors previously associated with diabetes, thereby supporting its potential as a
therapy for this disease.