THE DEVELOPMENT OF INSULIN-RESISTANCE WITH HIGH-FAT FEEDING IN RATS DOES NOT INVOLVE EITHER DECREASED INSULIN-RECEPTOR TYROSINE KINASE-ACTIVITY OR MEMBRANE GLYCOPROTEIN PC-1

Recent studies have suggested that the insulin receptor tyrosine kinas e inhibitor, membrane glycoprotein PC-1, may play a role in certain in sulin resistant states. In the present study, we examined whether eith er insulin receptor function or PC-1 activity was altered during the d evelopment of insulin resistance that occurs with high fat feeding in normal rats. Over the course of 14 days of high fat feeding, both maxi mal and submaximal (physiological) insulin-stimulated skeletal muscle glucose uptake decreased gradually; after 14 days of high fat feeding, submaximal and maximal insulin-stimulated glucose uptake decreased by similar to 40 and similar to 50%, respectively. In contrast, in the s ame muscles (tibialis anterior) of these animals, neither insulin rece ptor content nor insulin-stimulated insulin receptor autophosphorylati on was altered after 14 days of high fat feeding. PC-1 has both nucleo tide pyrophosphatase (EC 3.6.1.9) and alkaline phosphodiesterase I (EC 3.1.4.1) enzyme activities. These enzyme activities showed no changes during the course of 14 days of high fat feeding. Individual data rev ealed that there was no significant correlation between insulin-stimul ated glucose uptake and alkaline phosphodiesterase or nucleotide pyrop hosphatase activity (P > 0.05). Together, these data indicate that nei ther defects in insulin receptor function nor elevated PC-1 activities are involved in the development of insulin resistance in rats with hi gh fat feeding, and the insulin resistance induced with high fat feedi ng is likely due to postreceptor defects in Skeletal muscle. (C) 1996 Academic Press, Inc.