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J. Biol. Chem., Vol. 276, Issue 5, 2979-2985, February 2, 2001

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Hexamminecobalt(III) Chloride Inhibits Glucose-induced Insulin Secretion at the Exocytotic Process^*

Yoshiharu Tsubamoto, Kazuhiro Eto, Mitsuhiko Noda, Samira Daniel^§, Sechiko Suga^¶, Shigeo Yamashita, Haruo Kasai, Makoto Wakui^¶, Geoffrey W. G. Sharp^§, Satoshi Kimura, and Takashi Kadowaki^**

From the Departments of  Metabolic Diseases and  Physiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, the ^§ Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401, and the ^¶ Department of Physiology, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan

Hexamminecobalt(III) (HAC) chloride was found to have a potent inhibitory effect on glucose-induced insulin secretion from pancreatic islets. HAC at 2 mM inhibited the secretion in response to 22.2 mM glucose by 90% in mouse islets. Perifusion experiments revealed that the first phase of insulin secretion was severely suppressed and that the second phase of secretion was completely abrogated. Removal of HAC from the perifusate immediately restored insulin secretion with a transient overshooting above the normal level. However, HAC failed to affect glucose-induced changes in D-[6-¹⁴C]glucose oxidation, levels of reduced forms of NAD and NADP, mitochondrial membrane potential, ATP content, cytosolic calcium concentration, or calcium influx into mitochondria. Furthermore, HAC inhibited 50 mM potassium-stimulated insulin secretion by 77% and 10 µM mastoparan-stimulated insulin secretion in the absence of extracellular Ca²⁺ by 80%. The results of a co-immunoprecipitation study of lysates from insulin-secreting HC9 cells using anti-syntaxin and anti-vesicle-associated membrane protein antibodies for immunoprecipitation or Western blotting suggested that HAC inhibited disruption of the SNARE complex, which is normally observed upon glucose challenge. These results suggest that the inhibitory effect of HAC on glucose-induced insulin secretion is exerted at a site(s) distal to the elevation of cytosolic [Ca²⁺], possibly in the exocytotic machinery per se; and thus, HAC may serve as a useful tool for dissecting the molecular mechanism of insulin exocytotic processes.

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