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

• Published in: ENDOCRINE JOURNAL Vol. 63; no. 8; pp. 715 - 725
• Main Authors: Li, Longfei, Ohtsu, Yoshiaki, Nakagawa, Yuko, Masuda, Katsuyoshi, Kojima, Itaru
• Format: Journal Article
• Language: English
• Published: Japan The Japan Endocrine Society 2016
• Subjects: Adenosine Triphosphate - metabolism; Animals; ATP; Calcium; Calcium - metabolism; Calcium - pharmacology; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cells, Cultured; Cyclic AMP - metabolism; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Glucose metabolism; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Mice; Nifedipine - pharmacology; Sucrose - analogs & derivatives; Sucrose - pharmacology; Sweet taste receptor; Sweetening Agents - pharmacology; β-cell
• ISSN: 0918-8959; 1348-4540
• DOI: 10.1507/endocrj.EJ16-0217

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.