Signaling System Activated by the Glucose-Sensing Receptor

Abstract

Glucose is a primary stimulator of insulin secretion in pancreatic β-cells. It has long been thought that glucose augments insulin secretion solely by a mechanism dependent on glucose metabolism. Consequently, it takes a certain period of time for glucose to initiate cellular responses. With regard to the membrane potential, for example, it takes at least half a minute to observe glucose-induced depolarization of the plasma membrane. This lag period is thought to be a time required for glucose metabolism. To address the possibility that glucose activates a cell-surface receptor, we developed sensitive methods to monitor changes in cytoplasmic free calcium ([Ca2+]c), cyclic AMP ([cAMP]c), and activation of protein kinase C (PKC). Using sensitive methods, we investigated whether or not glucose induces immediate signals in β-cells. Indeed, glucose evoked immediate changes in [Ca2+]c, [cAMP]c and PKC activity. Importantly, these rapid signals were independent of glucose metabolism and were reproduced by addition of nonmetabolizable glucose analogs. Since these signals were inhibited by inhibition of Gq or Gs, it is quite likely that glucose activates a cell-surface receptor and generates immediate intracellular signals in pancreatic β-cells.