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Abstract
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 beta subunit is proteolytically cleaved, resulting in the generation of a cytosolic fragment of the beta subunit, beta', and that the generation of beta' 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 beta' is generated by chronic insulin administration to the cells, and that E64 inhibits the production of beta'; 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 beta' stoichiometrically inhibits the insulin-induced autophosphorylation of the insulin receptor beta 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 beta' is a mediator of insulin resistance, and the mechanism of action of beta' is the inhibition of the insulin-induced autophosphorylation of the beta subunit of the insulin receptor.
Highlights
The protein; a decrease in the binding of insulin; a decrease in the number of insulin receptor molecules expressed on the plasma membrane of the target cell; or a so-called “post-receptor defect” in which there is a decreased interaction between the insulin receptor and downstream effector molecules
This insulin-induced loss of immunodetectable  subunit is consistent with the insulin-induced loss of insulin binding activity we have previously reported in 3T3-L1 adipocytes [28]
The studies reported here in 3T3-L1 adipocytes are consistent with our earlier findings in fibroblasts; the 61-kDa fragment of the insulin receptor is released from the cell membranes by chronic treatment with insulin into the cytosol of the cells
Summary
The protein; a decrease in the binding of insulin; a decrease in the number of insulin receptor molecules expressed on the plasma membrane of the target cell; or a so-called “post-receptor defect” in which there is a decreased interaction between the insulin receptor and downstream effector molecules. We have previously demonstrated that upon chronic treatment of cultured fibroblasts with insulin, the cellular level of the intact insulin receptor protein decreases, and a fragment of the insulin receptor  subunit is produced and released from the cellular membranes into the cytosol of the cell [38].
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