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Metabolic and K-ATP channel-independent actions of keto acid initiators of insulin secretion

McClenaghan, Neville and Flatt, Peter (2000) Metabolic and K-ATP channel-independent actions of keto acid initiators of insulin secretion. PANCREAS, 20 (1). pp. 38-46. [Journal article]

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Insulin-releasing effects of 2-ketobutyric acid (KB), 2-ketoisocaproic acid (KIC), 2-keto-3-methylvaleric acid (KMV), and 3-phenylpyruvic acid (PP) were examined by using clonal beta cells. Whereas KIC, KMV, and PP dose-dependently initiated insulin secretion and potentiated the effects of 4.2-16.7 mM glucose, equimolar KB was without effect. Transport inhibition by using 10 mM valine, isoleucine, 2-cyano-3 hydroxycinnamate or 2-cyano-4 hydroxycinnamate, or metabolic inhibition by 15 mM mannoheptulose, 5 mM sodium azide, 5 mM sodium cyanide, or removal of HCO3 reduced the secretory effects of KIC, KMV, and PP. Whereas K+ depletion reduced keto acid-induced insulin output, depolarizing concentrations of L-leucine and L-arginine potentiated the keto acid-induced effects. Under depolarizing conditions (25 mM KCl and 16.7 mM glucose), 10 mM KIC, KMV, or PP induced insulin secretion, suggesting K-ATP channel-independent actions. Furthermore, the K-ATP channel opener diazoxide reduced, but did not abolish, the keto acid-induced effects. However, voltage-dependent Ca2+ channel blockade with verapamil or removal of extracellular Ca2+ abolished keto acid-induced insulin release. Collectively, these results indicate that KIC, KMV, and PP initiate insulin secretion at least partially independently of K-ATP channel activity, through both mitochondrial metabolism and regulation of Ca2+ influx.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:3104
Deposited By: Professor Peter Flatt
Deposited On:13 Jan 2010 16:19
Last Modified:15 Jun 2011 10:10

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