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Activation of sweet taste receptors may enhance glucose uptake several fold in rat intestine. AIM: To explore mechanisms of sweet taste receptor activation in glucose uptake in 3 intestinal cell lines. HYPOTHESIS: The artificial sweetener, acesulfame potassium (AceK), increases glucose uptake via activating sweet taste receptors to induce translocation GLUT2 to the apical membrane through the PLC βII pathway. METHODS: Caco-2, RIE-1, and IEC-6 cells (human, rat, and rat intestinal cell lines) were seeded on a 24-well plate at a density of 4x10⁴ cells/cm² in growth culture media and left to differentiate for 15 days after confluence. Caco-2 and RIE-1 cells express GLUT2, while IEC-6 cells do not. Cells were starved from glucose for 1 h and pre-incubated with and without 10 mM AceK for 30 min. Glucose uptake was measured by incubating the cells for 1 to 10 min with 0.5-50 mM glucose with and without 10 mM AceK. ¹⁴C-D-glucose was used to measure stereospecific, transporter-mediated uptake and ³H-L-glucose to measure passive uptake with or without the inhibitors 10 µM U-73122, a PLC βII inhibitor, 10 µM chelerythrine, a PKC inhibitor, and 2 µM cytochalasin B, a microtubular system disrupter. Glucose uptake was stopped by adding ice-cold PBS; cells were washed with PBS 2 times and solubilized with 0.1 N NaOH. All experiments were done on at least 3 separate occasions in triplicate. RESULTS: In Caco-2 and RIE-1 cells, 10 mM AceK increased carrier-mediated glucose uptake by 20-30% at apical glucose concentrations >25 mM (p<0.05), but not in the lesser glucose concentrations (<10 mM) nor at 1-min or 10-min incubations. U-73122, a PLC βII inhibitor, inhibited glucose uptake at the greater (>25 mM) glucose concentrations during the 5-min incubation; chelerythrine and cytochalasin B had similar effects. No effect was seen in IEC-6 cells. CONCLUSION: The artificial sweetener AceK, a known sweet taste receptor agonist, has no effect on glucose uptake in low (<25 mM) glucose concentrations, but increased glucose uptake at greater concentrations (> 25 mM) in our cell culture models when GLUT2 translocation occurs. The role of artificial sweeteners on glucose uptake appears to act in part by effects on the enterocyte itself. (Support: NIH DK39337-MGS)