Abstract

Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic alpha-cells, but is cleaved to 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 beta 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 7d. 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 αTC1-6 cells suggesting a switch in processing to favour GLP-1. Three GPCRs, 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 PC-1 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 beta 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 beta cell destruction. Understanding this phenomenon may lead to advances in therapies to protect beta cell mass, and thereby slow progression from insulin resistance to type 2 diabetes.