Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise
- Timothy J. Pullen1,
- Lykke Sylow2,
- Gao Sun1,
- Andrew P. Halestrap3,
- Erik A. Richter2 and
- Guy A. Rutter1⇓
- 1Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Faculty of Medicine, Imperial College London, London, U.K.
- 2Molecular Physiology Group, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
- 3Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, U.K.
- Corresponding author: Guy A. Rutter, .
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.
- Received October 31, 2011.
- Accepted February 24, 2012.
- © 2012 by the American Diabetes Association.
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