Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells?

• Published in: Journal of endocrinology Vol. 211; no. 1; pp. 99 - 106
• Main Authors: Whalley, N M, Pritchard, L E, Smith, D M, White, A
• Format: Journal Article
• Language: English
• Published: Bristol BioScientifica 01.10.2011
• Subjects: Animals; Biological and medical sciences; Cell Line; Cells, Cultured; Fundamental and applied biological sciences. Psychology; Glucagon - metabolism; Glucagon-Like Peptide 1 - metabolism; Glucagon-Secreting Cells - cytology; Glucagon-Secreting Cells - drug effects; Glucagon-Secreting Cells - metabolism; Glucose - pharmacology; Humans; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Male; Mice; Models, Animal; Paracrine Communication - physiology; Proglucagon - metabolism; Proprotein Convertase 1 - metabolism; Rats; Rats, Wistar; Regular papers; Vertebrates: endocrinology; Gastrointestinal hormone; β Cell; Langerhans islet; Endocrine pancreas; Glucagon like peptide 1
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1530/JOE-11-0094

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 , 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.