Abstract
Treatment of primary cultured adipocytes with 20 mM glucose resulted in a progressive increase in specific 125I-insulin binding that began almost immediately (no lag period) and culminated in a 60% increase by 24 h. This effect was dose-dependent (glucose ED50 of 4.6 mM) and mediated by an increase in insulin receptor affinity. Moreover, it appears that glucose modulates insulin receptor affinity through de novo protein synthesis rather than through covalent modification of receptors, since cycloheximide selectively inhibited the glucose-induced increase in insulin binding capacity (ED50 of 360 ng/ml) and restored receptor affinity to control values. Importantly, insulin sensitivity of the glucose transport system was increased by glucose treatment (63%) to an extent comparable with the enhancement in receptor affinity, thus indicating a functional coupling between insulin binding and insulin action. When the long term effects of insulin were assessed (24 h), we found that insulin treatment reduced 125I-insulin binding by greater than 60% by down-regulating the number of cell surface receptors in a dose-dependent manner (insulin ED50 of 7.4 ng/ml). On the basis of these studies, we conclude that 1) insulin binding is subject to dual regulation (glucose controls insulin action by enhancing receptor affinity, whereas insulin controls the number of cell surface receptors); and 2) glucose appears to modulate insulin receptor affinity through the rapid biosynthesis of an affinity regulatory protein.
Highlights
On the basis of these studies, we conclude that 1) insulin binding is subject to dual regulation; and 2) glucose appears to modulate insulin receptor affinity through the rapid biosynthesis of an affinity regulatory protein
Since all three of these components were present in the medium when we conducted our earlier studies on receptor downregulation (l), we felt it necessary to examine whether glucose or amino acids are required for the expression of insulininduced receptor down-regulation and whether either of these two components could influence ““I-insulin binding to isolated adipocytes
When cells were exposed to 20 mM glucose, a progressive increase in specific ‘251-insulin binding was observed that began almost immediately and culminated in a 60% increase by 24 h
Summary
MM glucose resulted in a progressive increase in specific “‘I-insulin binding that began almost immediately (no lag period) and culminated in a 60% increase by 24 h This effect was dose-dependent (glucose ED6,, of 4.6 mM) and mediated by an increase in insulin receptor affinity. In an earlier study [1] we found that a lag time of 4-6 h precedes insulininduced loss of cell surface receptors and that insulin triggers receptor down-regulation such that receptor loss continues after removal of insulin. When cells were exposed to insulin for 12 h, washed, and resuspended in insulin-free medium, a progressive loss of surface receptors was observed for up to 36 h We interpreted both the triggering effect of insulin and the lag time preceding insulin-induced receptor loss as indicative that a signal is generated by the initial binding event that, in turn, mediates insulin receptor. Since all three of these components were present in the medium when we conducted our earlier studies on receptor downregulation (l), we felt it necessary to examine whether glucose or amino acids are required for the expression of insulininduced receptor down-regulation and whether either of these two components could influence ““I-insulin binding to isolated adipocytes
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