A high-fructose diet induces changes in pp185 phosphorylation in muscle and liver of rats

Insulin stimulates the tyrosine kinase activity of its receptor resulting i n the tyrosine phosphorylation of pp185, which contains insulin receptor su bstrates IRS-I and IRS-2. These early steps in insulin action are essential for the metabolic effects of insulin. Feeding animals a high-fructose diet results in insulin resistance. However, the exact molecular mechanism unde rlying this effect is unknown. In the present study, we determined the leve ls and phosphorylation status of the insulin receptor and pp185 (IRS-IM) in liver and muscle of rats submitted to a high-fructose diet evaluated by im munoblotting with specific antibodies. Feeding fructose (28 days) induced a discrete insulin resistance, as demonstrated by the insulin tolerance test . Plasma glucose and serum insulin and cholesterol levels of the two groups of rats, fructose-fed and control, were similar, whereas plasma triacylgly cerol concentration was significantly increased in the rats submitted to th e fructose diet (P<0.05). There were no changes in insulin receptor concent ration in the liver or muscle of either group. However, insulin-stimulated receptor autophosphorylation was reduced to 72 +/- 4% (P<0.05) in the liver of high-fructose rats. The IRS-1 protein levels were similar in both liver and muscle of the two groups of rats. In contrast, there was a significant decrease in insulin-induced pp185 (IRS-IR) phosphorylation, to 83 +/- 5% ( P<0.05) in liver and to 77 +/- 4% (P<0.05) in muscle of the high-fructose r ats. These data suggest that changes in the early steps of insulin signal t ransduction may have an important role in the insulin resistance induced by hi,oh-fructose feeding.