MEMBRANE GLYCOPROTEIN PC-1 AND INSULIN-RESISTANCE

Peripheral resistance to insulin is a major component of non-insulin d ependent diabetes mellitus. Defects in insulin receptor tyrosine kinas e activity have been demonstrated in several tissues from insulin resi stant subjects, but mutations in the insulin receptor gene occur in on ly a small fraction of cases. Therefore, other molecules that are capa ble of modulating the function of the insulin receptor are likely cand idates in the search for the cellular mechanisms of insulin resistance . We have isolated an inhibitor of insulin receptor tyrosine kinase ac tivity from cultured fibroblasts of an insulin resistant NIDDM patient and identified it as membrane glycoprotein PC-1. Subsequently we have demonstrated that expression of PC-1 is elevated in fibroblasts from other insulin resistant subjects, both with and without NIDDM. Studies in muscle, the primary site for insulin-mediated glucose disposal, ha ve shown that the levels of PC-1 in this tissue are inversely correlat ed to insulin action both in vivo and in vitro. Transfection of PC-1 i nto cultured cells has confirmed that overexpression of PC-1 can produ ce impairments in insulin receptor tyrosine kinase activity and the su bsequent cellular responses to insulin. Preliminary data suggests a di rect interaction between PC-1 and the insulin receptor. However, the m echanisms whereby PC-1 inhibits insulin receptor signaling remain to b e determined.