Role of the glucose‐sensing receptor in insulin secretion

Abstract

Glucose is a primary stimulator of insulin secretion. It has been thought that glucose exerts its effect by a mechanism solely dependent on glucose metabolism. We show here that glucose induces rapid Ca 2+ and cyclic AMP signals in β-cells. These rapid signals are independent of glucose-metabolism and are reproduced by non-metabolizable glucose analogues. These results led us to postulate that glucose activates a cell-surface receptor, namely the glucose-sensing receptor. Rapid signals induced by glucose are blocked by inhibition of a sweet taste receptor subunit T1R3 and a calcium-sensing receptor subunit CaSR. In accordance with these observations, T1R3 and CaSR form a heterodimer. In addition, a heterodimer of T1R3 and CaSR is activated by glucose. These results suggest that a heterodimer of T1R3 and CaSR is a major component of the glucose-sensing receptor. When the glucose-sensing receptor is blocked, glucose-induced insulin secretion is inhibited. Also, ATP production is significantly attenuated by the inhibition of the receptor. Conversely, stimulation of the glucose-sensing receptor by either artificial sweeteners or non-metabolizable glucose analogue increases ATP. Hence, the glucose-sensing receptor signals promote glucose metabolism. Collectively, glucose activates the cell-surface glucose-sensing receptor and promotes its own metabolism. Glucose then enters the cells and is metabolized through already activated metabolic pathways. The glucosesensing receptor is a key molecule regulating the action of glucose in β-cells.glucose, glucose-sensing receptor, sweet taste receptorGlucose is a primary fuel in the body, and in some organs, for example, in neurons in the central nervous system, glucose is the only fuel utilized in the cells. Accordingly, the plasma concentration of glucose is regulated tightly by the actions of various glucose-regulating hormones and the autonomic nervous system. Among these glucoseregulating hormones, insulin is a principal hormone regulating glucose metabolism in the body. 1 Insulin not only regulates the plasma concentration of glucose but it also modulates metabolism of glucose in many organs including the liver, skeletal muscle and adipose tissue.This important hormone, insulin, is produced and secreted solely in pancreatic β-cells. In these cells, various types of fuels, hormones and neurotransmitters regulate insulin secretion. Among them, the most important regulator of insulin secretion is glucose. Thus, glucose is a primary stimulator of insulin secretion and, unlike other modulators of secretion, it is able to stimulate insulin secretion by itself. 1The action of glucose in pancreatic β-cells has been investigated for several decades, and in particular, the mechanism by which glucose stimulates insulin secretion has been a matter of extensive research. According to the current understanding, glucose stimulates insulin secretion by a mechanism totally dependent on glucose metabolism. 2,3 Thus, glucose enters β-cell and is metabolized through the glycolytic pathway a...

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