MULTIPLE SIGNALING PATHWAYS INVOLVED IN THE METABOLIC EFFECTS OF INSULIN

The metabolic effects of insulin are initiated by the binding of insul in to the extracellular domain of the insulin receptor within the plas ma membrane of muscle and adipose and liver cells. The subsequent acti vation of the intracellular tyrosine protein kinase activity of the re ceptor leeds to autophosphorylation of the receptor as well: as phosph orylation of a number of intracellular proteins. This gives rise to th e activation of Ras and phosphatidylinositol 3-kinase and hence to the activation of a number of serine/threonine protein kinases. Many of t hese kinases appear to be arranged in cascades, including a cascade th at results in the activation of mitogen-activated protein kinase and a nother that may result in the activation of protein kinase B, leading to the inhibition of glycogen synthase kinase-3 and the activation of the 70 kiloDalton ribosomal S6 protein kinase (p70 S6 kinase). We have explored the role of these! early events in the the stimulation of gl ycogen, fatty acid, and protein synthesis by insulin in rat epididymal fat cells. Comparisons have been made between the metabolic effects o f insulin and those of epidermal growth factor, since these 2 agents h ave contrasting effects on p70 S6 kinase and mitogen-activated protein kinase. The effects of wortmannin (which inhibits phosphatidylinosito l 3-kinase), and rapamycin (which blocks the activation of p70 S6 kina se) have also been studied. These and other studies indicate that the mitogen-activated protein kinase cascade is probably not important in the acute metabolic effects of insulin, but may have a role in the reg ulation of gene transcription and hence the more long-term effects of insulin. The short-term metabolic effects of insulin appear to involve at least 3 distinct signaling pathways: (1) those leading to increase s in glucose transport and the activation of glycogen synthase, acetyl -CoA carboxylase, eukaryotic initiation factor-2B, and phosphodiestera se, which may involve phosphatidylinositol 3-kinase and protein kinase B; (2) those leading to some of the effects of insulin on protein syn thesis (formation of eukaryotic initiation factor-4F complex, S6 phosp horylation, and activation of eukaryotic elongation factor-2), which m ay involve phosphatidylinositol 3-kinase and p70 S6 kinase; and finall y, (3) that leading to the activation of pyruvate dehydrogenase, which is unique in apparently not requiring activation of phosphatidylinosi tol 3-kinase. (C) 1997 by Excerpta Medico, Inc.