Many drugs can increase insulin secretion in vitro, but only few have a therapeutic potential. Stimulatory hormones and neurotransmitters modestly increase the triggering signal and strongly activate amplifying pathways biochemically distinct from that set into operation by nutrients. The increase in β-cell metabolism also generates amplifying signals that augment the efficacy of Ca 2+ on the exocytotic machinery. By closing ATP-sensitive K + channels (K ATP channels) in the plasma membrane, glucose and other metabolized nutrients depolarize β-cells, stimulate Ca 2+ influx, and increase the cytosolic concentration of free Ca 2+ ( i), which constitutes the indispensable triggering signal to induce exocytosis of insulin granules. Physiologically, insulin secretion is subject to a dual, hierarchal control by triggering and amplifying pathways.
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