In pancreatic β-cells, methyl pyruvate is a potent secretagogue and is widely used to study stimulus—secretion coupling. In contrast with pyruvate, which barely stimulates insulin secretion, methyl pyruvate was suggested to act as an effective mitochondrial substrate. We show that methyl pyruvate elicited electrical activity in the presence of 0.5mM glucose, in contrast with pyruvate. Accordingly, methyl pyruvate increased the cytosolic free Ca2+ concentration after an initial decrease, similar to glucose. The initial decrease was inhibited by thapsigargin, suggesting that methyl pyruvate stimulates ATP production. This assumption is supported by the observation that methyl pyruvate hyperpolarized the mitochondrial membrane potential, similar to glucose. However, in contrast with glucose, methyl pyruvate even slightly decreased NAD(P)H autofluorescence and did not influence ATP production or the ATP/ADP ratio. This observation questions the suggestion that methyl pyruvate acts as a powerful mitochondrial substrate. The finding that methyl pyruvate directly inhibited a cation current across the inner membrane of Jurkat T-lymphocyte mitochondria suggests that this metabolite may increase ATP production in β-cells by activating the respiratory chains without providing reduction equivalents. We conclude that this mechanism may account for a slight and transient increase in ATP production. We further show that methyl pyruvate inhibited the KATP current measured in the standard whole-cell configuration, an effect that was at least partly antagonized by diazoxide. Accordingly, single-channel currents in inside-out patches were blocked by methyl pyruvate. We conclude that inhibition of KATP channels, and not activation of metabolism, mediates the induction of electrical activity in pancreatic β-cells by methyl pyruvate.
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December 2002
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Research Article|
December 15 2002
Methyl pyruvate stimulates pancreatic β-cells by a direct effect on KATP channels, and not as a mitochondrial substrate
Martina DÜFER;
Martina DÜFER
∗Institute of Pharmacy, Department of Pharmacology, University of Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Germany,
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Peter KRIPPEIT-DREWS;
Peter KRIPPEIT-DREWS
∗Institute of Pharmacy, Department of Pharmacology, University of Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Germany,
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Linas BUNTINAS;
Linas BUNTINAS
†Department for Neurology, University of Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany
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Detlef SIEMEN;
Detlef SIEMEN
†Department for Neurology, University of Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany
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Gisela DREWS
Gisela DREWS
1
∗Institute of Pharmacy, Department of Pharmacology, University of Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Germany,
1To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
April 24 2002
Revision Received:
September 12 2002
Accepted:
September 27 2002
Accepted Manuscript online:
September 27 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2002
2002
Biochem J (2002) 368 (3): 817–825.
Article history
Received:
April 24 2002
Revision Received:
September 12 2002
Accepted:
September 27 2002
Accepted Manuscript online:
September 27 2002
Citation
Martina DÜFER, Peter KRIPPEIT-DREWS, Linas BUNTINAS, Detlef SIEMEN, Gisela DREWS; Methyl pyruvate stimulates pancreatic β-cells by a direct effect on KATP channels, and not as a mitochondrial substrate. Biochem J 15 December 2002; 368 (3): 817–825. doi: https://doi.org/10.1042/bj20020657
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