Glucose stimulates insulin secretion in the pancreatic β-cell by means of a synergistic interaction between at least two signaling pathways. One, the KATP channel-dependent pathway, increases the entry of Ca2+ through voltage-gated channels by closure of the KATP channels and depolarization of the β-cell membrane. The resulting increase in [Ca2+]i stimulates insulin exocytosis. The other, a KATP channel-independent pathway, requires that [Ca2+]i be elevated and augments the Ca2+-stimulated release. These mechanisms are in accord with the belief that glucose-stimulated insulin secretion has an essential requirement for extracellular Ca2+ and increased [Ca2+]i. However, when protein kinases A and C are activated simultaneously, a large effect of glucose to augment insulin release can be seen in the absence of extracellular Ca2+, under conditions in which [Ca2+]i is not increased, and even when [Ca2+]i is decreased to low levels by intracellular chelation with BAPTA. In the presence or absence of Ca2+, there are similarities in the characteristics of augmentation of insulin release that suggest that only one augmentation mechanism may be involved. These similarities include time course, glucose dose-responses, augmentation by nutrients other than glucose such as α-ketoisocaproate (α-KIC), and augmentation by the fatty acids palmitate and myristate. However, augmentation in the presence and absence of Ca2+ is distinctly different in GTP dependency. Therefore, exocytosis under these two conditions appears to be triggered differently—one by Ca2+ and the other by GTP or a GTPdependent mechanism. The augmentation pathways are likely responsible for time-dependent potentiation of secretion and for the second phase of glucose-stimulated insulin release.
Augmentation of Insulin Release by Glucose in the Absence of Extracellular Ca2+: New Insights Into Stimulus-Secretion Coupling
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Mitsuhisa Komatsu, Thomas Schermerhorn, Mitsuhiko Noda, Susanne G Straub, Toru Aizawa, Geoffrey W G Sharp; Augmentation of Insulin Release by Glucose in the Absence of Extracellular Ca2+: New Insights Into Stimulus-Secretion Coupling. Diabetes 1 December 1997; 46 (12): 1928–1938. https://doi.org/10.2337/diab.46.12.1928
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