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Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise

Exercise-induced hyperinsulinism (EIHI) is an autosomal dominant disorder characterized by inappropriate insulin secretion in response to vigorous physical exercise or pyruvate injection. Activating mutations in the monocarboxylate transporter-1 (MCT1, SLC16A1) promoter have been linked to EIHI. Exp...

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Autores principales: Pullen, Timothy J., Sylow, Lykke, Sun, Gao, Halestrap, Andrew P., Richter, Erik A., Rutter, Guy A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379650/
https://www.ncbi.nlm.nih.gov/pubmed/22522610
http://dx.doi.org/10.2337/db11-1531
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author Pullen, Timothy J.
Sylow, Lykke
Sun, Gao
Halestrap, Andrew P.
Richter, Erik A.
Rutter, Guy A.
author_facet Pullen, Timothy J.
Sylow, Lykke
Sun, Gao
Halestrap, Andrew P.
Richter, Erik A.
Rutter, Guy A.
author_sort Pullen, Timothy J.
collection PubMed
description Exercise-induced hyperinsulinism (EIHI) is an autosomal dominant disorder characterized by inappropriate insulin secretion in response to vigorous physical exercise or pyruvate injection. Activating mutations in the monocarboxylate transporter-1 (MCT1, SLC16A1) promoter have been linked to EIHI. Expression of this pyruvate transporter is specifically repressed (disallowed) in pancreatic β-cells, despite nearly universal expression across other tissues. It has been impossible to determine, however, whether EIHI mutations cause MCT1 expression in patient β-cells. The hypothesis that MCT1 expression in β-cells is sufficient to cause EIHI by allowing entry of pyruvate and triggering insulin secretion thus remains unproven. Therefore, we generated a transgenic mouse capable of doxycycline-induced, β-cell–specific overexpression of MCT1 to test this model directly. MCT1 expression caused isolated islets to secrete insulin in response to pyruvate, without affecting glucose-stimulated insulin secretion. In vivo, transgene induction lowered fasting blood glucose, mimicking EIHI. Pyruvate challenge stimulated increased plasma insulin and smaller excursions in blood glucose in transgenic mice. Finally, in response to exercise, transgene induction prevented the normal inhibition of insulin secretion. Forced overexpression of MCT1 in β-cells thus replicates the key features of EIHI and highlights the importance of this transporter’s absence from these cells for the normal control of insulin secretion.
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spelling pubmed-33796502013-07-01 Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise Pullen, Timothy J. Sylow, Lykke Sun, Gao Halestrap, Andrew P. Richter, Erik A. Rutter, Guy A. Diabetes Islet Studies Exercise-induced hyperinsulinism (EIHI) is an autosomal dominant disorder characterized by inappropriate insulin secretion in response to vigorous physical exercise or pyruvate injection. Activating mutations in the monocarboxylate transporter-1 (MCT1, SLC16A1) promoter have been linked to EIHI. Expression of this pyruvate transporter is specifically repressed (disallowed) in pancreatic β-cells, despite nearly universal expression across other tissues. It has been impossible to determine, however, whether EIHI mutations cause MCT1 expression in patient β-cells. The hypothesis that MCT1 expression in β-cells is sufficient to cause EIHI by allowing entry of pyruvate and triggering insulin secretion thus remains unproven. Therefore, we generated a transgenic mouse capable of doxycycline-induced, β-cell–specific overexpression of MCT1 to test this model directly. MCT1 expression caused isolated islets to secrete insulin in response to pyruvate, without affecting glucose-stimulated insulin secretion. In vivo, transgene induction lowered fasting blood glucose, mimicking EIHI. Pyruvate challenge stimulated increased plasma insulin and smaller excursions in blood glucose in transgenic mice. Finally, in response to exercise, transgene induction prevented the normal inhibition of insulin secretion. Forced overexpression of MCT1 in β-cells thus replicates the key features of EIHI and highlights the importance of this transporter’s absence from these cells for the normal control of insulin secretion. American Diabetes Association 2012-07 2012-06-15 /pmc/articles/PMC3379650/ /pubmed/22522610 http://dx.doi.org/10.2337/db11-1531 Text en © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Islet Studies
Pullen, Timothy J.
Sylow, Lykke
Sun, Gao
Halestrap, Andrew P.
Richter, Erik A.
Rutter, Guy A.
Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise
title Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise
title_full Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise
title_fullStr Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise
title_full_unstemmed Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise
title_short Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise
title_sort overexpression of monocarboxylate transporter-1 (slc16a1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise
topic Islet Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379650/
https://www.ncbi.nlm.nih.gov/pubmed/22522610
http://dx.doi.org/10.2337/db11-1531
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