Mechanisms of action of nonglucose insulin secretagogues.

Insulin release induced by nonglucose secretagogues is initiated from beta-cell by a wide variety of stimuli through specific receptors or binding sites. Activation of receptors in turn generates or enhances the cytosol levels of cAMP, cADPR, IP3, DAG, and AA. These second messengers then activate protein kinases, change the ion currents cross the cell membrane, and mobilize intracellular Ca2+, thereby increasing phosphorylated proteins in the cytosol and augmenting [Ca2+]i. These events trigger exocytotic discharge of insulin. The crucial steps in receptor-mediated stimulation-secretion coupling and their relationship to glucose-stimulated insulin release is summarized in Figure 1. At the present stage of research, the general processes of secretagogue binding to receptors, of generating second messengers, of activating several types of protein kinase, and of altering the membrane potential as well as cytosol calcium levels has been intensively studied and qualitatively clarified. However, we know little about the exact nature of substrates of different protein kinases and their function in the insulin secretion process. With the help of molecular biology and protein chemistry, we expect that this gap will be filled in the near future.