An important observation in this study is that IRS-1 overexpression in the mice results in an undesirable effect on
Imatinib Mesylate tolerance. Since the insulinogenic index in IRS-1-Tg mice was comparable to that in WT mice, insulin secretion seems to be maintained in IRS-1-Tg mice. This suggests that glucose intolerance in IRS-1-Tg mice would be caused by impaired insulin action. Interestingly, a significant attenuation in Akt phosphorylation is observed in the liver of the IRS-1-Tg mice. Tyrosine phosphorylation of the insulin receptor and YXXM motif on IRS is also significantly impaired in the liver, suggesting that impairment of
insulin signal in the liver is, at least in part, caused at the insulin receptor level. In the current study, we find that serum TNF-α concentration is significantly higher in IRS-1-Tg mice than WT mice. It has been shown that TNF-α plays a crucial role in obesity-associated insulin resistance [18]. More importantly, TNF-α attenuates tyrosine phosphorylation of insulin receptor and inhibits insulin signaling [19]. Elevation of TNF-α in IRS-1-Tg mice would have indispensable role in insulin resistance in our model.
