title: System-L amino acid transporters play a key role in pancreatic β-cell signalling and function.
abstract: 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 β-cell mass and function. The effects of BCAA on cellular function are dependent on their active transport into the mammalian cells via amino acid transporters and thus the expression and activity of these transporters likely influence β-cell signalling and function. In this report, we show that the System-L transporters are required for BCAA uptake into clonal β-cell lines and pancreatic islets, and that these are essential for signalling to mTORC1. Further investigation revealed that the System-L amino acid transporter 1 (LAT1) is abundantly expressed in the islets, and that knockdown of LAT1 using siRNA inhibits mTORC1 signalling, leucine-stimulated insulin secretion and islet cell proliferation. In summary, we show that the LAT1 is required for regulating β-cell signalling and function in islets and thus may be a novel pharmacological/nutritional target for the treatment and prevention of type 2 diabetes.
authors.affiliation: Research School of BiologyAustralian National University, Acton, Australia.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of InfectionImmunity and Inflammation, University of Leicester, UK.
authors.forename: Violeta D
authors.initials: VD
authors.lastname: Beltran
authors.affiliation: Health Innovations Research Institute (HIRI)School of Medical Sciences, RMIT University, Bundoora, Australia.
authors.forename: Stanley M H
authors.initials: SM
authors.lastname: Chan
authors.affiliation: Department of InfectionImmunity and Inflammation, University of Leicester, UK.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of InfectionImmunity and Inflammation, University of Leicester, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Bevington
authors.affiliation: Health Innovations Research Institute (HIRI)School of Medical Sciences, RMIT University, Bundoora, Australia terence.herbert@rmit.edu.au.
authors.forename: Terence P
authors.initials: TP
authors.lastname: Herbert
mesh_terms: D027062:Amino Acid Transport System L / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D027062:Amino Acid Transport System L; D007328:Insulin; D027283:Large Neutral Amino Acid-Transporter 1; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007930:Leucine
keywords: amino acid transporters; cellular signalling; diabetes; islets; mTORC1