title: Mice lacking neutral amino acid transporter B(0)AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control.
abstract: OBJECTIVE
  Type 2 diabetes arises from insulin resistance of peripheral tissues followed by dysfunction of β-cells in the pancreas due to metabolic stress. Both depletion and supplementation of neutral amino acids have been discussed as strategies to improve insulin sensitivity. Here we characterise mice lacking the intestinal and renal neutral amino acid transporter B(0)AT1 (Slc6a19) as a model to study the consequences of selective depletion of neutral amino acids.
  
  
  METHODS
  Metabolic tests, analysis of metabolite levels and signalling pathways were used to characterise mice lacking the intestinal and renal neutral amino acid transporter B(0)AT1 (Slc6a19).
  
  
  RESULTS
  Reduced uptake of neutral amino acids in the intestine and loss of neutral amino acids in the urine causes an overload of amino acids in the lumen of the intestine and reduced systemic amino acid availability. As a result, higher levels of glucagon-like peptide 1 (GLP-1) are produced by the intestine after a meal, while the liver releases the starvation hormone fibroblast growth factor 21 (FGF21). The combination of these hormones generates a metabolic phenotype that is characterised by efficient removal of glucose, particularly by the heart, reduced adipose tissue mass, browning of subcutaneous white adipose tissue, enhanced production of ketone bodies and reduced hepatic glucose output.
  
  
  CONCLUSIONS
  Reduced neutral amino acid availability improves glycaemic control. The epithelial neutral amino acid transporter B(0)AT1 could be a suitable target to treat type 2 diabetes.
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Rose
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
authors.forename: Tjeerd P
authors.initials: TP
authors.lastname: Sijmonsma
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Angelika
authors.initials: A
authors.lastname: Bröer
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main 65926, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Pfenninger
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, 69120 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main 65926, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Schmoll
authors.affiliation: Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bröer
keywords: Amino acid metabolism; BAT, brown adipose tissue; BM, body mass; Epithelial transport; IPGTT, intraperitoneal glucose tolerance test; IPITT, intraperitoneal insulin tolerance test; NEFA, non-esterified fatty acids; RER, respiratory exchange ratio; Type 2 diabetes; WAT, white adipose tissue; aWAT, abdominal white adipose tissue; iWAT, inguinal white adipose tissue