Roles of insulin-like growth factor-I and growth hormone in mediating insulin resistance in acromegaly.

Most patients with acromegaly have some degree of insulin resistance. The principal mediator of insulin resistance in acromegaly is hypersecretion of growth hormone. Growth hormone acts at several levels to block insulin actions including inhibiting phosphorylation of the insulin receptor and one of its principal signaling molecules IRS-1 in response to insulin administration. This leads to reduced sensitivity to insulin in the periphery in stimulating peripheral glucose uptake and to increased resistance to insulin's ability to suppress gluconeogenesis. Furthermore growth hormone excess leads to mobilization of free fatty acids which inhibit insulin stimulated glucose oxidation by acting as a competitive energy source thus leading to further worsening of insulin resistance. These abnormalities can be overcome by administering agents which either lower growth hormone secretion or block growth hormone action. The role of elevated IGF-I in acromegaly in mediating insulin resistance is more difficult to analyze. Indirect inferences from the data that are available suggest that IGF-I is acting to enhance insulin sensitivity and partially counteracting the insulin antagonistic effects of growth hormone. In a recent study administration of IGF-I to acromegalics was shown to improve insulin sensitivity over and above the level that could be achieved by simply blocking growth hormone action. Therefore it appears that the net effect of IGF-I is to counterbalance some of the effects of growth hormone hypersecretion on insulin resistance.