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Mice immunized to bovine insulin were observed to develop anti-idiotypic antibodies which behaved in in vitro assays as antibodies to the insulin receptor. The studies described here were undertaken to investigate the effects of these antibodies in vivo on the physiology of glucose homeostasis and the state of insulin receptors. Mice developing anti-idiotypic receptor antibodies manifested abnormal fasting blood glucose concentrations: a period of hypoglycemia followed by a period of hyperglycemia. Moreover, the mice were deficient in their ability to respond to a glucose load. Changes in the number and activity of insulin receptors were associated with these physiological aberrations. In an insulin binding assay, adipocytes obtained from immunized mice had only 40% of the number of insulin receptors demonstrable on the adipocytes of control mice. The lipogenic response of the affected adipocytes was also relatively insensitive to insulin, and in addition, they manifested only 70% of the maximal response to high concentrations of insulin. Thus, development of anti-idiotypic receptor antibodies appeared to be associated with insulin resistance of adipocytes and abnormal glucose homeostasis.