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

Abstract

Sucralose is an artificial sweetener and activates the glucose-sensing receptor expressed in pancreatic β-cells. Although sucralose does not enter β-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.