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J Biol Chem, Vol. 274, Issue 36, 25386-25392, September 3, 1999
NADH Shuttle System Regulates KATP
Channel-dependent Pathway and Steps Distal to Cytosolic
Ca2+ Concentration Elevation in Glucose-induced Insulin
Secretion
Kazuhiro
Eto ,
Sechiko
Suga§,
Makoto
Wakui§,
Yoshiharu
Tsubamoto ,
Yasuo
Terauchi ,
Junko
Taka ,
Shinichi
Aizawa¶,
Mitsuhiko
Noda ,
Satoshi
Kimura ,
Haruo
Kasai , and
Takashi
Kadowaki
From the Department of Metabolic Diseases and
Department of Physiology, Graduate School of Medicine,
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan,
§ Department of Physiology, Hirosaki University School of
Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan, and ¶ Department
of Morphogenesis, Institute of Molecular Embryology and Genetics,
Kumamoto University School of Medicine, 4-24-1 Kuhonji, Kumamoto 862, Japan
The NADH shuttle system is composed of the
glycerol phosphate and malate-aspartate shuttles. We generated mice
that lack mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), a
rate-limiting enzyme of the glycerol phosphate shuttle. Application of
aminooxyacetate, an inhibitor of the malate-aspartate shuttle, to
mGPDH-deficient islets demonstrated that the NADH shuttle system was
essential for coupling glycolysis with activation of mitochondrial ATP
generation to trigger glucose-induced insulin secretion.
The present study revealed that blocking the NADH shuttle system
severely suppressed closure of the ATP-sensitive potassium (KATP) channel and depolarization of the plasma
membrane in response to glucose in cells, although properties of
the KATP channel on the excised cell membrane were
unaffected. In mGPDH-deficient islets treated with aminooxyacetate,
Ca2+ influx through the plasma membrane induced by a
depolarizing concentration of KCl in the presence of the
KATP channel opener diazoxide restored insulin secretion.
However, the level of the secretion was only ~40% of wild-type
controls. Thus, glucose metabolism through the NADH shuttle system
leading to efficient ATP generation is pivotal to activation of both
the KATP channel-dependent pathway and steps
distal to an elevation of cytosolic Ca2+ concentration in
glucose-induced insulin secretion.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1999 by the American Society for Biochemistry and Molecular Biology.
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