Augmentation of insulin release by glucose in the absence of extracellular Ca2+: new insights into stimulus-secretion coupling

• Published in: Diabetes (New York, N.Y.) Vol. 46; no. 12; pp. 1928 - 1938
• Main Authors: Komatsu, M., Schermerhorn, T., Noda, M., Straub, S. G., Aizawa, T., Sharp, G. W.
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01-12-1997
• ISSN: 0012-1797; 1939-327X; 0012-1797
• DOI: 10.2337/diabetes.46.12.1928

Augmentation of insulin release by glucose in the absence of extracellular Ca2+: new insights into stimulus-secretion coupling.
M Komatsu ,
T Schermerhorn ,
M Noda ,
S G Straub ,
T Aizawa and
G W Sharp
Department of Geriatrics, Endocrinology, and Metabolism, Shinshu University School of Medicine, Nagano-ken, Japan.
Abstract
Glucose stimulates insulin secretion in the pancreatic beta-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 beta-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 alpha-ketoisocaproate (alpha-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 GTP-dependent
mechanism. The augmentation pathways are likely responsible for time-dependent potentiation of secretion and for the second
phase of glucose-stimulated insulin release.