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

Neville McClenaghan, Peter Flatt

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.
LanguageEnglish
Pages38-46
JournalPancreas
Volume20
Issue number1
Publication statusPublished - Jan 2000

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Keto Acids
Adenosine Triphosphate
Insulin
Mannoheptulose
Sodium Cyanide
Diazoxide
Glucose
Sodium Azide
Isoleucine
Valine
Verapamil
Leucine
Arginine
phenylpyruvic acid
Acids
3-methylvaleric acid

Cite this

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title = "Metabolic and K-ATP channel-independent actions of keto acid initiators of insulin secretion",
abstract = "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.",
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Metabolic and K-ATP channel-independent actions of keto acid initiators of insulin secretion. / McClenaghan, Neville; Flatt, Peter.

In: Pancreas, Vol. 20, No. 1, 01.2000, p. 38-46.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Metabolic and K-ATP channel-independent actions of keto acid initiators of insulin secretion

AU - McClenaghan, Neville

AU - Flatt, Peter

PY - 2000/1

Y1 - 2000/1

N2 - 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.

AB - 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.

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