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Volume 271, Number 28, Issue of July 12, 1996 pp. 16544-16552
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Suppression of Adenylate Kinase Catalyzed Phosphotransfer Precedes and Is Associated with Glucose-induced Insulin Secretion in Intact HIT-T15 Cells

(Received for publication, June 23, 1995, and in revised form, April 2, 1996)

L. Karl Olson , William Schroeder , R. Paul Robertson , Nelson D. Goldberg ^'' and Timothy F. Walseth

From the  Department of Pharmacology,  Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, and ^'' Department of Biochemistry, University of Minnesota, Minneapolis, Minnesota 55455

Adenine nucleotide metabolism was characterized in intact insulin secreting HIT-T15 cells during the transition from non-stimulated (i.e. 0.2 mM glucose) to the glucose-stimulated secretory state. Metabolic dynamics were monitored by assessing rates of appearance of ¹⁸O-labeled phosphoryls of endogenous nucleotides in cells incubated in medium enriched in [¹⁸O]water. Most prominent of the metabolic alterations associated with stimulated insulin secretion was the suppression in the rate of adenylate kinase (AK)-catalyzed phosphorylation of AMP by ATP. This was manifest as a graded decrease of up to 50% in the rate of appearance of -¹⁸O-labeled species of ADP and ATP and corresponded to the magnitude of the secretory response elicited over a range of stimulatory glucose concentrations. The only nucleotide exhibiting a significant concentration change associated with suppression of AK activity was AMP, which decreased by about 50%, irrespective of the glucose concentration. Leucine-stimulated secretion also decreased the rate of AK-catalyzed phosphotransfer. This secretory stimulus-related suppression of AK-catalyzed phosphotransfer occurs within 45 s of glucose addition, precedes insulin secretion, depends on the internalization and metabolism of glucose, and is independent of membrane depolarization and the influx of extracellular calcium. The secretory stimulus-induced decrease in AK-catalyzed phosphotransfer, therefore occurs prior to or at the time of K⁺_ATP channel closure but it is not associated with or a consequence of events occurring subsequent to K⁺_ATP channel closure. These results indicate that AK-catalyzed phosphotransfer may be a determinant of ATP to ADP conversion rates in the K⁺_ATP channel microenvironment; secretory stimuli-linked decreased rates of AK-catalyzed ADP generation from ATP (and AMP) would translate into an increased probability of ATP-liganded and, therefore, closed state of the channel.

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