REGULATION OF GENE-EXPRESSION BY INSULIN

The past 5 years have seen much progress in the field of insulin-regulated gene expression. The list of insulin -regulated genes has grown dramatically, though in many cases the physiological significance of this regulation remains to be established. There has also been much progress towards the identification of insulin response sequences. In some genes, such as PEPCK, GAPDH, c-fos and amylase the IRS has been mapped to a short DNA sequence (30 bp). In other genes only broad insulin response regions have been identified. The PEPCK and GAPDH IRSs have very different sequences so it will be interesting to see whether either of these IRSs will mediate an effect of insulin on the expression of other genes. If so, since insulin stimulates GAPDH expression but inhibits PEPCK expression, will the respective IRSs be confined to genes that are regulated in the same direction ? Alternatively, both of these elements may be specific for the gene in which they were identified, and one or more different IRSs may regulate other genes. This would not be unprecedented. Phorbol esters, like insulin, have been shown to regulate the expression of more than 40 genes. At least four distinct phorbol ester response sequences are known [178]. There is also considerable interest in the proteins that bind to these insulin response sequences, so the isolation and cloning of these proteins is a major goal. Purification of these proteins will be required for an understanding of how they communicate (directly or indirectly) through protein-protein interactions with the transcription complex and hence mediate their effect on transcription. Moreover, the potential involvement of such proteins in the pathogenesis of type II diabetes will need to be investigated. Finally, since these proteins represent the final step in a signal cascade, it is hoped that it will be possible to elucidate the successive steps required for insulin action by working back from these proteins to the insulin receptor.