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J Biol Chem, Vol. 274, Issue 36, 25386-25392, September 3, 1999

NADH Shuttle System Regulates K_ATP 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 (K_ATP) channel and depolarization of the plasma membrane in response to glucose in  cells, although properties of the K_ATP 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 K_ATP 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 K_ATP channel-dependent pathway and steps distal to an elevation of cytosolic Ca²⁺ concentration in glucose-induced insulin secretion.

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