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Diabetes 51:S29-S32, 2002
© 2002 by the American Diabetes Association, Inc.

Section 1: Insulin Release: Some Molecular Requisites

Triggering of Insulin Release by a Combination of cAMP Signal and Nutrients

An ATP-Sensitive K+ Channel–Independent Phenomenon

Mitsuhisa Komatsu, Yoshihiko Sato, Satoko Yamada, Keishi Yamauchi, Kiyoshi Hashizume, and Toru Aizawa

From the Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, Matsumoto, Japan

Nutrient augmentation of Ca2+-triggered insulin release occurs in an ATP-sensitive K+ (KATP) channel–independent manner. Here, using rat islets, we explored the possibility of the KATP channel-independent nutrient triggering of insulin release. In the presence of 250 µmol/l diazoxide, simultaneous application of forskolin and 16.7 mmol/l glucose strongly stimulated insulin release: fourfold and eightfold increases with 1 and 30 µmol/l forskolin, respectively. {alpha}-Ketoisocaproate (KIC) and 3-isobutylmethylxanthine (IBMX) could be used in place of glucose and forskolin, respectively, to trigger insulin release in the presence of diazoxide. Triggering of insulin release by a combination of nutrients and forskolin was not attenuated by 10 µmol/l nifedipine (a blocker of voltage-dependent Ca2+ channels) and 2 µmol/l thapsigargin (an inhibitor of intracellular Ca2+-ATPase), ascertaining independence of this phenomenon from Ca2+ entry and from intracellular Ca2+ liberation. As anticipated, the action of glucose and KIC was greatly (>80%) suppressed by inhibition of mitochondrial metabolism by 2 mmol/l sodium azide (NaN3). A combination of palmitate and dimethyl glutamate (a cell-permeable glutamate donor), but not either one alone, weakly but unequivocally triggered insulin release when applied simultaneously with forskolin. In this case, however, mitochondrial poisoning by azide was without effect. The finding suggests that a combination of induced palmitoylation and cytosolic glutamate accumulation partially reconstituted signaling beyond mitochondrial metabolism in the ß-cell upon glucose stimulation. In conclusion, a combination of cAMP signal and nutrients potently triggers insulin release under full activation of the KATP channel, indicating the multiplicity of driving force for insulin exocytosis.


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A. Szollosi, M. Nenquin, L. Aguilar-Bryan, J. Bryan, and J.-C. Henquin
Glucose Stimulates Ca2+ Influx and Insulin Secretion in 2-Week-old beta-Cells Lacking ATP-sensitive K+ Channels
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[Abstract] [Full Text] [PDF]


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Copyright © 2002 by the American Diabetes Association.