REGULATION OF INSULIN-RECEPTOR AND RECEPT OR GENE-EXPRESSION

The insulin receptor is a membrane macromolecule whose expression on t he cell surface is essential for cell sensitivity to insulin. Current knowledge on the regulation of expression of the insulin receptor and its gene in human and animal cells is presented. Although ubiquitously distributed, the insulin receptor and its messenger RNA (mRNA) are ma inly expressed in metabolically active cells such as hepatocytes and a dipocytes. Two receptor isoforms, generated by alternative splicing of exon 11, have been identified. Isoform B (exon 11+) predominates in l iver and adipocytes, and isoform A (exon 11-) in brain, spleen and leu kocytes. In vivo and in several cell models, the expression of the ins ulin receptor and/or its mRNA is under positive regulation by glucocor ticoid hormones and negative regulation by insulin. Glucocorticoid hor mones stimulate receptor gene transcription and receptor protein synth esis. Insulin stimulates receptor protein degradation and, in certain cell types, decreases receptor mRNA level. Vanadate (an insulinomimeti c agent) corrects, in vivo, the hyperexpression of the liver receptor observed in experimental insulinopenic diabetes, but its effects on re ceptor expression in vitro are complex and vary with the cell type. In vivo the insulin receptor and/or its mRNA are expressed early in feta l development with a high level, in liver, of isoform A. Maximal expre ssion is reached at the end of gestation and then decreases after birt h. In several cell models, receptor protein and/or mRNA expression is affected by cell growth and/or differentiation. Several cis- and trans -acting factors regulating the expression of the human insulin recepto r gene and its response to glucocorticoid hormones have been identifie d.