Sucralose, an activator of the glucose-sensing receptor, increases ATP by calcium-dependent and -independent mechanisms

Sucralose is an artificial sweetener and activates the glucose-sensing receptor expressed in pancreatic beta-cells. Although sucralose does not enter beta-cells nor acts as a substrate for glucokinase, it induces a marked elevation of intracellular ATP ([ATP](c)). The present study was conducted to identify the signaling pathway responsible for the elevation of [ATP](c) induced by sucralose. Previous studies have shown that sucralose elevates cyclic AMP (cAMP), activates phospholipase C (PLC) and stimulates Ca2+ entry by a Na+ dependent mechanism in MIN6 cells. The addition of forskolin induced a marked elevation of cAMP, whereas it did not affect [ATP](c). Carbachol, an activator of PLC, did not increase [ATP](c). In addition, activation of protein kinase C by dioctanoylglycerol did not affect [ATP](c). In contrast, nifedipine, an inhibitor of the voltage-dependent Ca2+ channel, significantly reduced [ATP](c) response to sucralose. Removal of extracellular Na+ nearly completely blocked sucralose-induced elevation of [ATP](c). Stimulation of Na+ entry by adding a Na+ ionophore monensin elevated [ATP](c). The monensin-induced elevation of [ATP](c) was only partially inhibited by nifedipine and loading of BAPTA, both of which completely abolished elevation of [Ca2+](c). These results suggest that Na+ entry is critical for the sucralose-induced elevation of [ATP](c). Both calcium-dependent and -independent mechanisms are involved in the action of sucralose.