Insulin resistance is a common clinical feature of obesity and non-insulin-dependent diabetes mellitus, and is characterized by elevated serum levels of glucose, insulin, and lipids. The mechanism by which insulin resistance is acquired is unknown. We have previously demonstrated that upon chronic treatment of fibroblasts with insulin, conditions that mimic the hyperinsulinemia associated with insulin resistance, the membrane-associated insulin receptor subunit is proteolytically cleaved, resulting in the generation of a cytosolic fragment of the subunit, `, and that the generation of ` is inhibited by the thiol protease inhibitor E64 (Knutson, V. P.(1991) J. Biol. Chem. 266, 15656-15662). In this report, we demonstrate that in 3T3-L1 adipocytes: 1) cytosolic ` is generated by chronic insulin administration to the cells, and that E64 inhibits the production of `; 2) chronic administration of insulin to the adipocytes leads to an insulin-resistant state, as measured by lipogenesis and glycogen synthesis, and E64 totally prevents the generation of this insulin-induced cellular insulin resistance; 3) E64 has no effect on the insulin-induced down-regulation of insulin receptor substrate-1, and therefore insulin resistance is not mediated by the down-regulation of insulin receptor substrate-1; 4) under in vitro conditions, partially purified ` stoichiometrically inhibits the insulin-induced autophosphorylation of the insulin receptor subunit; and 5) administration of E64 to obese Zucker fatty rats improves the insulin resistance of the rats compared to saline-treated animals. These data indicate that ` is a mediator of insulin resistance, and the mechanism of action of ` is the inhibition of the insulin-induced autophosphorylation of the subunit of the insulin receptor.

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