Abstract
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 Ca2+ concentration ([Ca2+]c); glucose evoked an immediate elevation of [Ca2+]c, which was followed by a decrease in [Ca2+]c, and after a certain lag period it induced large oscillatory elevations of [Ca2+]c. Initial rapid peak and subsequent reduction of [Ca2+]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 Ca2+, 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 Gs, and deletion of the T1R3 gene. These results indicate that glucose induces rapid changes in [Ca2+]c and [cAMP]c by activating the cell-surface glucose-sensing receptor. Hence, glucose generates rapid intracellular signals by activating the cell-surface receptor.
Highlights
Secretion of insulin is regulated by nutrients, neurotransmitters and hormones in pancreatic βcells [1]
It should be noted that, when we monitored [Ca2+]c by using a Ca2+ indicator with stronger fluorescence fluo-8, we could detect the rapid peak of [Ca2+]c in a fraction of the cells (Fig 1E). This elevation is due at least partly to release of Ca2+ from an intracellular pool(s) since the rapid elevation of [Ca2+]c was observed in the absence of extracellular Ca2+
Since the rapid elevation of [Ca2+]c was inhibited by an inhibitor of phospholipase C (PLC) and an inhibitor of Gq, it may be due to a release of calcium from endoplasmic reticulum (ER) caused by inositol trisphosphate
Summary
Secretion of insulin is regulated by nutrients, neurotransmitters and hormones in pancreatic βcells [1]. Glucose is a primary stimulator of insulin secretion and is able to induce secretion by itself. When ambient glucose concentration rises, insulin secretion is initiated after a certain lag period [1]. The mechanism by which glucose stimulates insulin secretion has been investigated extensively for several decades [1, 2]. It was shown some decades ago that glucose induces complex changes in ion fluxes and membrane potential [3,4,5,6].
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