Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells

Glucose activates the glucose-sensing receptor T1R3 and facilitates its own metabolism in pancreatic β-cells. An inhibitor of this receptor would be helpful in elucidating the physiological function of the glucose-sensing receptor. The present study was conducted to examine whether or not lactisole can be used as an inhibitor of the glucose-sensing receptor. In MIN6 cells, in a dose-dependent manner, lactisole inhibited insulin secretion induced by sweeteners, acesulfame-K, sucralose and glycyrrhizin. The IC 50 was ∼4 mmol/l. Lactisole attenuated the elevation of cytoplasmic Ca 2 + concentration ([Ca 2 + ] c ) evoked by sucralose and acesulfame-K but did not affect the elevation of intracellular cAMP concentration ([cAMP] c ) induced by these sweeteners. Lactisole also inhibited the action of glucose in MIN6 cells. Thus, lactisole significantly reduced elevations of intracellular [NADH] and intracellular [ATP] induced by glucose, and also inhibited glucose-induced insulin secretion. To further examine the effect of lactisole on T1R3, we prepared HEK293 cells stably expressing mouse T1R3. In these cells, sucralose elevated both [Ca 2 + ] c and [cAMP] c . Lactisole attenuated the sucralose-induced increase in [Ca 2 + ] c but did not affect the elevation of [cAMP] c . Finally, lactisole inhibited insulin secretion induced by a high concentration of glucose in mouse islets. These results indicate that the mouse glucose-sensing receptor was inhibited by lactisole. Lactisole may be useful in assessing the role of the glucose-sensing receptor in mouse pancreatic β-cells.