System-L amino acid transporters play a key role in pancreatic beta-cell signalling and function

The branched-chain amino acids (BCAA) leucine, isoleucine and valine, are essential amino acids that play a critical role in cellular signalling and metabolism. They acutely stimulate insulin secretion and activate the regulatory serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1), a kinase that promotes increased beta-cell mass and function. The effects of BCAA on cellular function are dependent on their active transport into mammalian cells via amino acid transporters and thus the expression and activity of these transporters likely influences beta-cell signalling and function. In this report we show that the System-L transporters are required for BCAA uptake into clonal beta-cell lines and pancreatic islets and that these are essential for signalling to mTORC1. Further investigation revealed that the System-L transporter LAT1 is abundantly expressed in islets and that knock-down of LAT1 using siRNA inhibits mTORC1 signalling, leucine-stimulated insulin secretion and islet cell proliferation. In summary, we show that the System-L transporter LAT1 is required for regulating β-cell signaling and function in islets and thus may be a novel pharmacological/nutritional target for the treatment and prevention of type-2 diabetes.