Alterations in Insulin Binding Induced by Changes in Vivo in the Levels of Glucocorticoids and Growth Hormone*

Abstract

Previous studies have shown that the sensitivity of tissues to insulin is diminished in states of glucocorticoid and GH [growth hormone] excess and is increased when these hormones are deficient. To evaluate the role of the insulin receptor in these states, [125I]insulin binding to purified rat liver plasma membranes with a variety of perturbations of both glucocorticoids and GH was studied. Glucocorticoid excess was produced in rats by administration of ACTH (40 U[units]/day for 4 days) or dexamethasone (1 mg/day for 4 days). This resulted in an insulin-resistant state. Associated with this insulin resistance, there was a 50-60% decrease in insulin binding to its specific receptors in liver. Conversely, adrenalectomy, which produces an increase in insulin sensitivity, was associated with an increase in insulin binding to liver. Computer-assisted Scatchard analysis using a negative cooperative model for the insulin-receptor interaction indicated that the changes in insulin binding in these states were most likely due entirely to changes in receptor affinity, with no change in receptor concentration. GH administration also produced mild insulin resistance and a decrease in receptor concentration. This was associated with a reciprocal increase in receptor affinity and thus, no major alteration in insulin binding occurred at low physiological insulin concentrations. Hypophysectomized rats showed an increase in receptor concentration and a decrease in affinity, and GH treatment only partially corrected these changes. Rats implanted with MtT [rat pituitary] tumor (which secretes ACTH, GH and PRL [prolactin]) have the combined effects of excess glucocortiocoids and GH and are very insulin resistant. Liver membranes prepared from these rats showed a decrease in insulin binding and receptor affinity similar to that observed in other states of glucocorticoid excess. Adrenalectomy of the tumor-bearing rats resulted in an increase in insulin binding despite the persistence of the elevated levels of GH, ACTH and PRL. Alterations in insulin receptor affinity and number may play a major role in the states of altered insulin sensitivity which accompany glucocorticoid excess and deficiency, and follow hypophysectomy. The insulin resistance associated with GH excess is mediated at either a site on the receptor distal to the insulin-binding site (transduction) or at 1 or more of the intracellular reactions important in insulin action.