Augmentation of Insulin Release by Glucose in the Absence of Extracellular Ca²⁺: New Insights Into Stimulus-Secretion Coupling

Glucose stimulates insulin secretion in the pancreatic β-cell by means of a synergistic interaction between at least two signaling pathways. One, the K_ATP channel-dependent pathway, increases the entry of Ca²⁺ through voltage-gated channels by closure of the K_ATP channels and depolarization of the β-cell membrane. The resulting increase in [Ca²⁺]_i stimulates insulin exocytosis. The other, a K_ATP 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.