Glucose Evokes Rapid Ca(2+) and Cyclic AMP Signals by Activating the Cell-Surface Glucose-Sensing Receptor in Pancreatic β-Cells

Glucose is a primary stimulator of insulin secretion in pancreatic β-cells. High concentration of glucose has been thought to exert its action solely through its metabolism. In this regard, we have recently reported that glucose also activates a cell-surface glucose-sensing receptor and facilitates its own metabolism. In the present study, we investigated whether glucose activates the glucose-sensing receptor and elicits receptor-mediated rapid actions. In MIN6 cells and isolated mouse β-cells, glucose induced triphasic changes in cytoplasmic Ca(2+) concentration ([Ca(2+)](c)); glucose evoked an immediate elevation of [Ca(2+)](c), which was followed by a decrease in [Ca(2+)](c), and after a certain lag period it induced large oscillatory elevations of [Ca(2+)](c). Initial rapid peak and subsequent reduction of [Ca(2+)](c) were independent of glucose metabolism and reproduced by a nonmetabolizable glucose analogue. These signals were also blocked by an inhibitor of T1R3, a subunit of the glucose-sensing receptor, and by deletion of the T1R3 gene. Besides Ca(2+), glucose also induced an immediate and sustained elevation of intracellular cAMP ([cAMP](c)). The elevation of [cAMP](c) was blocked by transduction of the dominant-negative G(s), and deletion of the T1R3 gene. These results indicate that glucose induces rapid changes in [Ca(2+)](c) and [cAMP](c) by activating the cell-surface glucose-sensing receptor. Hence, glucose generates rapid intracellular signals by activating the cell-surface receptor.