Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in β cells
Hisamitsu Ishihara, … , Lester R. Drewes, Claes B. Wollheim
Hisamitsu Ishihara, … , Lester R. Drewes, Claes B. Wollheim
Published December 1, 1999
Citation Information: J Clin Invest. 1999;104(11):1621-1629. https://doi.org/10.1172/JCI7515.
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Article

Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in β cells

Abstract

Previous investigations revealed low activities of lactate dehydrogenase (LDH) and plasma membrane monocarboxylate transporters (MCT) in the pancreatic β cell. In this study the significance of these characteristics was explored by overexpressing type A LDH (LDH-A) and/or type 1 MCT (MCT-1) in the clonal INS-1 β cells and isolated rat islets. Inducible overexpression of LDH-A resulted in an 87-fold increase in LDH activity in INS-1 cells. Adenovirus-mediated overexpression of MCT-1 increased lactate transport activity 3.7-fold in INS-1 cells. Although overexpression of LDH-A, and/or MCT-1 did not affect glucose-stimulated insulin secretion, LDH-A overexpression resulted in stimulation of insulin secretion even at a low lactate concentration with a concomitant increase in its oxidation in INS-1 cells regardless of MCT-1 co-overexpression. Adenovirus-mediated overexpression of MCT-1 caused an increase in pyruvate oxidation and conferred pyruvate-stimulated insulin release to isolated rat islets. Although lactate did not stimulate insulin secretion from control or MCT-1–overexpressing islets, co-overexpression of LDH-A and MCT-1 evoked lactate-stimulated insulin secretion with a concomitant increase in lactate oxidation in rat islets. These results suggest that low expression of MCT and LDH is requisite to the specificity of glucose in insulin secretion, protecting the organism from undesired hypoglycemic actions of pyruvate and lactate during exercise and other catabolic states.

Authors

Hisamitsu Ishihara, Haiyan Wang, Lester R. Drewes, Claes B. Wollheim

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Overexpression of MCT-1 through a recombinant adenovirus and its effects...
Overexpression of MCT-1 through a recombinant adenovirus and its effects on isolated islets. (a) One hundred twenty islets infected with either AdCAlacZ or AdCAMCT-1 were used for immunoblot analyses. The result is representative of 3 independent experiments. (b) Ten islets infected with recombinant adenoviruses in each tube were incubated in KRBH with indicated stimuli for 60 minutes. Data show the mean ± SEM of 5 independent experiments. Statistical significance between MCT-1–overexpressing islets and control islets was obtained at 10 mM pyruvate (P < 0.05). (c) 14CO2 formation during 2-hour incubation with 15 mM [U-14C]glucose or 10 mM [1-14C]pyruvate was measured. Data show the mean ± SEM of 5 independent experiments. *Difference from control islets at P < 0.05. Open bars, islets infected with AdCAlacZ; shaded bars, islets infected with AdCAMCT-1.