Overexpression of monocarboxylate transporter-1 (Slc16a1) in mouse pancreatic ß-cells leads to relative hyperinsulinism during exercise

TY - JOUR

T1 - Overexpression of monocarboxylate transporter-1 (Slc16a1) in mouse pancreatic ß-cells leads to relative hyperinsulinism during exercise

AU - Pullen, Timothy J

AU - Sylow, Lykke

AU - Sun, Gao

AU - Halestrap, Andrew P

AU - Richter, Erik

AU - Rutter, Guy A

N1 - CURIS 2012 5200 072

PY - 2012/7

Y1 - 2012/7

N2 - 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.

AB - 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.

U2 - 10.2337/db11-1531

DO - 10.2337/db11-1531

M3 - Journal article

C2 - 22522610

SN - 0012-1797

VL - 61

SP - 1719

EP - 1725

JO - Diabetes

JF - Diabetes

IS - 7

ER -