The Insulin Resistance of Acromegaly: Evidence for Two Alterations in the Insulin Receptor on Circulating Monocytes

Abstract

[¹²⁵I]Insulin binding to insulin receptors on circulating monocytes was studied in 11 patients with acromegaly (human GH, 7–240 ng/ml) and 22 normal volunteers. The acromegalic patients had normal or nearly normal glucose tolerance but represented a full range of insulin resistance. Insulin binding to its receptors showed two characteristic abnormalities. Total receptor concentration per cell was decreased in proportion to the hyperinsulinemia, such that the receptor concentration was inversely related to the basal level of the plasma insulin, similar to our findings in patients with obesity, diabetes, and insulinsecreting tumors. In addition, the affinity of the empty receptor (limiting high affinity state) was increased. Since the affinity of the filled receptor (limiting low affinity state) was unaltered, the negative cooperativity was increased. In most cases, the reciprocal changes in receptor concentration and limiting high affinity state resulted in normal amounts of insulin bound at basal insulin concentrations but a decrease in insulin binding at high (stimulated) insulin concentrations. The decrease in receptor concentration, the increase in receptor affinity, and the severity of insulin resistance correlated well with the magnitude of elevation of plasma GH. In vitro incubation of normal monocytes with plasma of acromegalic patients or GH itself for periods of up to 3 h had no effect on insulin binding. In summary, we have detected two abnormalities in insulin binding to its receptors in patients with acromegaly which correlate very closely with the severity of the GH excess and the hyperinsulinemia. The molecular sequence of events that produce these changes remain to be determined.