States of hyperinsulinemia with resistance to insulin action on glucose disposal are frequently associated with proliferative tissue abnormalities of the skin (acanthosis nigricans), ovary, and heart. That insulin may be involved in the pathogenesis of these growth-related abnormalities despite resistance to its metabolic effects mediated through the insulin receptor issuggested by the known ability of high concentrations of insulin to stimulate DNA synthesis and cell proliferation in vitro through the insulin-like growth factor I (IGF-I) receptor. IGF-I receptors are present in skin keratinocytes, some ovarian tissue compartments, and in the heart. Furthermore, ovarian tissue from hyperinsulinemic insulin-resistant women responds to supraphysiologic insulin concentrations in vitro by enhanced steroidogenesis. Cultured, transformed T-lymphocytes from an infant with leprechaunism fail to augment basalcolony formation in response to physiologic insulin concentrations in vitro (compared to a doubling seen in normal subjects), but respond normally to supraphysiologic insulin concentrations, the effect of which is competitively inhibited by a monoclonal antibody to the IGF-I receptor. Thus, insulin action mediated through the IGF-I receptor may initiate growth-promoting tissue effects in the face of limited insulin effect on glucose metabolism. Such spillover actions may add to the morbidity associated with states of clinical insulin resistance.

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