Antibody against the insulin receptor causes disappearance of insulin receptors in 3T3-L1 cells: a possible explanation of antibody-induced insulin resistance.

The effect of a rabbit antibody induced against the rat insulin receptor (RAR) was tested using cultured 3T3-L1 fat cells. As previously seen with antibodies against the insulin receptor from patients with the type B syndrome of insulin resistance and acanthosis nigricans, RAR acutely mimicked the action of insulin by stimulating deoxyglucose uptake. After prolonged exposure of 3T3-L1 cells to RAR, insulinomimetic activity was lost and the cells became resistant to the action of insulin. This state of insulin resistance is similar to that seen with the human autoantibodies. However, unlike antibody from the patients, RAR did not acutely inhibit the binding of insulin to its receptor; rather, RAR increased the binding of insulin to its receptor by a mechanism consistent with an increase in the affinity of the receptor for insulin. With prolonged exposure to RAR there was a dramatic decrease in insulin-receptor binding on the treated 3T3-L1 fat cells. These results suggest that antibody against the insulin receptor induces insulin resistance by a mechanism that involves loss of cell-surface insulin receptors.