Expression of the putative inhibitor of the insulin receptor tyrosine kinase PC-1 in dermal fibroblasts from patients with syndromes of severe insulin resistance

OBJECTIVE To date, mutations in the insulin receptor gene are the only clearly defined cause of extreme insulin resistance in man, Recently, however, some patients with severe insulin resistance have been reported to have marked over-expression of the transmembrane glycoprotein PC-1 in their cultured fibroblasts. This protein appears to act as an endogenous inhibitor of the insulin receptor tyrosine kinase which suggests that primary over-expression of PC-1 may play an aetiological role in some forms of insulin resistance, One sub-type of extreme insulin resistance in which the insulin receptor gene has been reported to be normal is pseudo-acromegalic insulin resistance, The main aim of this study was to determine whether overexpression of PC-1 might contribute to the severe insulin resistance exhibited by some patients with pseudo-acromegaly. DESIGN AND PATIENTS PC-1 phosphodiesterase activity and PC-1 protein and mRNA content were measured in cultured dermal fibroblasts from three severely insulin resistant pseudo-acromegalic patients, These were compared with fibroblasts from normoinsulinaemic normoglycaemic controls and from subjects with known genetic defects in the insulin receptor or IRS-1. RESULTS In the fibroblasts from pseudo-acromegalic insulin resistant subjects PC-1 activity and PC-1 protein and mRNA levels were indistinguishable from the normoinsulinaemic controls, Consistent with this observation, insulin receptor tyrosine kinase activity was similar in extracts from fibroblasts of pseudoacromegalic subjects and normal controls, Surprisingly, subjects with insulin receptor or IRS-1 mutations had a profound reduction in PC-1 activity (p less than or equal to 0.005), protein (p less than or equal to 0.05) and mRNA levels (p less than or equal to 0.005). CONCLUSIONS The results indicate that PC-1 overexpression does not appear to contribute to the insulin resistant state of pseudo-acromegalic patients, The finding of normal insulin receptor tyrosine kinase activity in these subjects suggests that the site of defective insulin signalling is likely to be distal to the receptor. The unexpected finding that PC-1 activity, protein and mRNA were all dramatically reduced in patients with lesions early in the insulin signalling cascade provides further evidence for a link, albeit as yet poorly understood, between cellular insulin action and the expression of PC-1.