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

NM Whalley, LE Pritchard, DM Smith, A White - J Endocrinol, 2011 - joe.bioscientifica.com
NM Whalley, LE Pritchard, DM Smith, A White
J Endocrinol, 2011joe.bioscientifica.com
Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic a-
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 b-cell
mass. The a-cell line, aTC1-6, 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 …
Abstract
Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic a-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 b-cell mass. The a-cell line, aTC1-6, 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 (25mM) also increased GLP-1 but decreased glucagon secretion from aTC1-6 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 aTC1-6 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 b-cell toxicity as evidenced by decreased glucosestimulated 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 b-cell destruction. Understanding this phenomenon may lead to advances in therapies to protect b-cell mass, and thereby slow progression from insulin resistance to type 2 diabetes.
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