Increased accumulation of
methylglyoxal (MG) has been linked to different
insulin resistance states including diabetes and
hypertension. In this study, the effects of MG on
insulin signaling pathway were investigated. Following 9 weeks of
fructose treatment, an
insulin resistance state was developed in Sprague-Dawley (SD) rats, demonstrated as increased
triglyceride and
insulin levels,
high blood pressure, and decreased
insulin-stimulated
glucose uptake by adipose tissue. More importantly, we observed a close correlation between the development of
insulin resistance and elevated MG level in serum and adipose tissue. Both
insulin resistance state and the elevated MG level were reversed by the MG scavenger, N-acetyl
cysteine (NAC). When 3T3-L1 adipocytes were treated directly with MG, the impaired
insulin signaling was also observed, indicated by decreased
insulin-induced
insulin-receptor substrate-1 (IRS-1)
tyrosine phosphorylation and the decreased
kinase activity of
phosphatidylinositol (
PI) 3-kinase (PI3K). The ability of NAC to block MG-impairment of PI3K activity and IRS-1 phosphorylation further confirmed the role of MG in the development of
insulin resistance. In conclusion, the increase in endogenous MG accumulation impairs
insulin-signaling pathway and decreases
insulin-stimulated
glucose uptake in adipose tissue, which may contribute to the development of
insulin resistance.