Lactate activation of α-cell K ATP channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca 2+ entry.

Autor: Zaborska KE; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Dadi PK; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Dickerson MT; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Nakhe AY; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Thorson AS; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Schaub CM; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Graff SM; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Stanley JE; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Kondapavuluru RS; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Denton JS; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA., Jacobson DA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: david.a.jacobson@vanderbilt.edu.
Jazyk: angličtina
Zdroj: Molecular metabolism [Mol Metab] 2020 Dec; Vol. 42, pp. 101056. Date of Electronic Publication: 2020 Jul 28.
DOI: 10.1016/j.molmet.2020.101056
Abstrakt: Objective: Elevations in pancreatic α-cell intracellular Ca 2+ ([Ca 2+ ] i ) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control α-cell Ca 2+ handling is unknown. Lactate enters cells through monocarboxylate transporters (MCTs) and is also produced during glycolysis by lactate dehydrogenase A (LDHA), an enzyme expressed in α-cells. As lactate activates ATP-sensitive K + (K ATP ) channels in cardiomyocytes, lactate may also modulate α-cell K ATP . Therefore, this study investigated how lactate signaling controls α-cell Ca 2+ handling and GCG secretion.
Methods: Mouse and human islets were used in combination with confocal microscopy, electrophysiology, GCG immunoassays, and fluorescent thallium flux assays to assess α-cell Ca 2+ handling, V m , K ATP currents, and GCG secretion.
Results: Lactate-inhibited mouse (75 ± 25%) and human (47 ± 9%) α-cell [Ca 2+ ] i fluctuations only under low-glucose conditions (1 mM) but had no effect on β- or δ-cells [Ca 2+ ] i . Glyburide inhibition of K ATP channels restored α-cell [Ca 2+ ] i fluctuations in the presence of lactate. Lactate transport into α-cells via MCTs hyperpolarized mouse (14 ± 1 mV) and human (12 ± 1 mV) α-cell V m and activated K ATP channels. Interestingly, pyruvate showed a similar K ATP activation profile and α-cell [Ca 2+ ] i inhibition as lactate. Lactate-induced inhibition of α-cell [Ca 2+ ] i influx resulted in reduced GCG secretion in mouse (62 ± 6%) and human (43 ± 13%) islets.
Conclusions: These data demonstrate for the first time that lactate entry into α-cells through MCTs results in K ATP activation, V m hyperpolarization, reduced [Ca 2+ ] i , and inhibition of GCG secretion. Thus, taken together, these data indicate that lactate either within α-cells and/or elevated in serum could serve as important modulators of α-cell function.
(Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze: MEDLINE
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