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The secretion of insulin is closely regulated in vivo in order to maintain the plasma glucose concentration in a narrow range despite long periods of fasting and intermittent food intake. The regulation of insulin secretion has been studied extensively and involves a complex interaction of glucose and other nutrients, and endocrine, paracrine, and neurohumoral factors. The effects of these factors on insulin secretion are transduced by their interaction with specific receptor molecules on the surface of the β-cell. The physiologic role of many of these ligand-receptor interactions in altering insulin secretion has been clarified recently and their distal signaling mechanisms characterized.