Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells.
Bottom Line: These effects were attributed to the ability of indole to affect two key molecular mechanisms in L cells.On the one hand, indole inhibited voltage-gated K(+) channels, increased the temporal width of action potentials fired by L cells, and led to enhanced Ca(2+) entry, thereby acutely stimulating GLP-1 secretion.On the other hand, indole slowed ATP production by blocking NADH dehydrogenase, thus leading to a prolonged reduction of GLP-1 secretion.
Affiliation: Institute of Metabolic Science and MRC Metabolic Diseases Unit, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK; Cavendish Laboratory, Department of Physics, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, UK. Electronic address: email@example.com.Show MeSH
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Mentions: Cumulative GLP-1 secretion from GLUTag cells was measured in the presence of saline buffer containing 1 mM glucose and 0.1% (wt/vol) BSA over 240 min (Figure 1A). The GLP-1 concentration in the medium increased approximately linearly with time under these conditions, reflecting a relatively constant GLP-1 secretory rate (Figure 1B). In the additional presence of 1 mM indole, GLP-1 secretion was modified over both short and long time periods. Very high GLP-1 concentrations were measured in the medium of indole-treated cells after only 5 min, indicating a rapid initial stimulation of secretion (Figures 1A and 1B). Thereafter, GLP-1 concentrations continued to rise, but the rate of release was slower than that observed in the absence of indole (Figure 1B). At the end of the 240 min incubation period, cumulative released GLP-1 was ~35% less in the presence of 1 mM indole than in its absence. These data indicate that although indole acutely stimulates GLP-1 secretion, it exerts a suppressive effect on the rate of hormone release over prolonged time periods. We examined the dose dependence of indole on both the short- and long-term actions by measuring cumulative GLP-1 release after 6 and 240 min incubations (Figures 1C and 1D). After 6 min, the acute stimulatory effect of indole was evident at concentrations above 1 mM. After 240 min, by contrast, the suppressive effect was evident at indole concentrations as low as 0.3 mM. To clarify the interaction between indole and GLUTag cells, we investigated the molecular mechanisms that determine the modulation of GLP-1 secretion by indole.
Affiliation: Institute of Metabolic Science and MRC Metabolic Diseases Unit, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK; Cavendish Laboratory, Department of Physics, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, UK. Electronic address: firstname.lastname@example.org.