title: Impact of glucagon-like peptide-1 (7-36) amide, isosteviol and 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside on leucine-mediated α-cell dysfunction.
abstract: OBJECTIVE
  To investigate the acute and chronic effects of l-leucine on pancreatic α-cell function in vitro. Furthermore, we wanted to explore if glucagon-like peptide-1 (GLP-1), isosteviol (ISV) and 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) counteract changes in α-cell function induced by chronic exposure to leucine.
  
  
  METHODS
  Isolated mice islets were incubated with 10 mM leucine for 2 or 72 h. We investigated glucagon and insulin secretion at 2 mM and 16.7 mM glucose. In addition, we cultured clonal α-TC1-6 cells with 5 mM leucine, 5 mM leucine plus GLP-1 (10(-6)  M), or ISV (10(-6)  M) or AICAR (10(-5)  M) at high glucose for 72 h. We measured the glucagon secretion, cholesterol (CHO) and triglyceride (TG) content, cell proliferation as well as gene expression.
  
  
  RESULTS
  Ten millimolar of leucine for 2 h significantly stimulated glucagon and insulin secretion both at 2 and 16.7 mM glucose in mice islets. After 72 h incubation with 10 mM leucine the glucagon secretion was enhanced at both 2 and 16.7 mM glucose, whereas the glucose-stimulated insulin secretion (16.7 mM glucose) was inhibited. Chronic exposure to 5 mM leucine increased glucagon secretion, CHO and TG content, cell proliferation and Pcsk2 (p < 0.001), MafB (p < 0.05), Gcg (p < 0.001), Prkaa1 (p < 0.01), Hmgcr (p < 0.001), Srebf2 (p < 0.001), Acaca (p < 0.001), Mtor (p < 0.05) mRNA expression in clonal α-TC1-6 cells. While GLP-1 was cable of reducing glucagon hypersecretion and Pcsk2 (p < 0.05) mRNA expression. ISV and AICAR had no effect on leucine-induced glucagon hypersecretion.
  
  
  CONCLUSIONS
  Long-term exposure to leucine induces hypersecretion of glucagon secretion, that is, aminoacidotoxicity and influences some key genes of pancreatic α-cells. Interestingly, GLP-1 counteracts the leucine-induced α-cell dysfunction.
authors: Department of Medicine and Endocrinology, Aarhus University Hospital, Aarhus C, Denmark.
authors: X
authors: X
authors: Chen
authors: K
authors: K
authors: Hermansen
authors: P B
authors: PB
authors: Jeppesen
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D050416:Glucagon-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*
chemical_list: D045786:Diterpenes, Kaurane; D010446:Peptide Fragments; D011498:Protein Precursors; D012263:Ribonucleosides; C515747:isosteviol; C055453:glucagon-like peptide 1 (7-36)amide; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D007930:Leucine