title: Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells?
abstract: Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic α-cells, but is cleaved to glucagon-like peptide-1 (GLP-1) by PC1 in intestinal L-cells. The aim of this study was to identify mechanisms which switch processing of proglucagon to generate GLP-1 in the pancreas, given that GLP-1 can increase insulin secretion and β-cell mass. The α-cell line, αTC1-6, expressed PC1 at low levels and GLP-1 was detected in cells and in culture media. GLP-1 was also found in isolated human islets and in rat islets cultured for 7 days. High glucose concentrations increased Pc1 gene expression and PC1 protein in rat islets. High glucose (25  mM) also increased GLP-1 but decreased glucagon secretion from αTC1-6 cells suggesting a switch in processing to favour GLP-1. Three G protein-coupled receptors, GPR120, TGR5 and GPR119, implicated in the release of GLP-1 from L-cells are expressed in αTC1-6 cells. Incubation of these cells with an agonist of TGR5 increased PC1 promoter activity and GLP-1 secretion suggesting that this is a mechanism for switching processing to GLP-1 in the pancreas. Treatment of isolated rat islets with streptozotocin caused β-cell toxicity as evidenced by decreased glucose-stimulated insulin secretion. This increased GLP-1 but not glucagon in the islets. In summary, proglucagon can be processed to GLP-1 in pancreatic cells. This process is upregulated by elevated glucose, activation of TGR5 and β-cell destruction. Understanding this phenomenon may lead to advances in therapies to protect β-cell mass, and thereby slow progression from insulin resistance to type 2 diabetes.
authors.affiliation: Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, 3.016 AV Hill Building, Manchester M13 9PT, UK.
authors.forename: N M
authors.initials: NM
authors.lastname: Whalley
authors.forename: L E
authors.initials: LE
authors.lastname: Pritchard
authors.forename: D M
authors.initials: DM
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: White
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D023421:Models, Animal; D019899:Paracrine Communication / Q000502:physiology*; D052336:Proglucagon / Q000378:metabolism*; D045664:Proprotein Convertase 1 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007328:Insulin; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D045664:Proprotein Convertase 1; D005947:Glucose