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Regulation of GLUTag Cell Secretory Activity by Other Signals

Despite the predominant role of nutrients in the regulation of GLP-1 release, a number of other signals have been identified that exert stimulatory effects on the primary L-cell as well as on GLUTag cells. As many of these signaling mediators are induced by nutrient ingestion, this constitutes an indirect pathway that links food components to the release of GLP-1. Such indirect actions are particularly important to GLP-1 release, since L-cells are mainly concentrated in the distal ileum and colon (Dong and Brubaker 2012), and nutrients have not reached this area of the gastrointestinal tract when the initial phase of prandial GLP-1 secretion is triggered. Initially, a neurohormonal mechanism, involving the vagus nerve, was shown to mediate the very rapid rise in GLP-1 levels after nutrient ingestion (Dong and Brubaker 2012). Consistent with this hypothesis, a stimulatory effect of two muscarinic agonists, bethanechol and carbachol, has been found in GLUTag cells (Brubaker et al. 1998), although expression of muscarinic receptors by this cell line has not been reported to date. Notwithstanding, direct activation of downstream protein kinase C signaling does stimulate GLP-1 release from the GLUTag cells (Brubaker et al. 1998). Similarly, the incretin hormone, glucose-dependent insulinotrophic peptide (GIP), secreted by the enteroendocrine K cells in response to carbohydrates and fats, has been reported to trigger GLP-1 secretion at a concentration range of 30–100 nM (Brubaker et al. 1998). The effects of GIP on GLUTag cells are mediated through activation of the protein kinase A signaling pathway (Simpson et al. 2007). Other agents capable of raising the intracellular levels of cAMP, such as forskolin plus the cAMP phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, have also been found to stimulate both GLP-1 secretion and production in GLUTag cells (Drucker et al. 1994) and are commonly used as positive controls when the secretory activity of this cell line is examined. Supporting the prominent role of intracellular cAMP levels in GLP-1 secretion, it has been reported that phosphodiesterase inhibition enhances the GLP-1 response to physiological secretagogues such as GIP (Simpson et al. 2007). Finally, other nutrient-dependent bioactive peptides, including leptin and insulin, have also been shown to stimulate GLP-1 secretion from GLUTag cells. The effects of leptin are believed to be produced via activation of the Janus-activated kinase/signal transducers and activators of transcription signaling pathway (Anini and Brubaker 2003), whereas the effects of insulin are mediated through the activation of the extracellular signal-regulated kinases and are dependent upon the presence of glucose (Lim et al. 2009).

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