Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, University of Manchester, 3.016 AV Hill Building, Manchester M13 9PT, UK.
J Endocrinol. 2011 Oct;211(1):99-106. doi: 10.1530/JOE-11-0094. Epub 2011 Jul 27.
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.
胰高血糖素原在胰腺的α细胞中被前激素转化酶 2（PC2）切割为胰高血糖素，但在肠 L 细胞中被 PC1 切割为胰高血糖素样肽-1（GLP-1）。本研究的目的是鉴定在胰腺中将胰高血糖素原加工为 GLP-1 的机制，因为 GLP-1 可以增加胰岛素分泌和β细胞量。αTC1-6 细胞系低水平表达 PC1，细胞和培养基中均检测到 GLP-1。还在分离的人胰岛和培养 7 天的大鼠胰岛中发现了 GLP-1。高葡萄糖浓度增加了大鼠胰岛中的 Pc1 基因表达和 PC1 蛋白。高葡萄糖（25mM）也增加了 GLP-1，但减少了 αTC1-6 细胞中胰高血糖素的分泌，表明加工过程发生转变有利于 GLP-1。三种 G 蛋白偶联受体，GPR120、TGR5 和 GPR119，与 L 细胞中 GLP-1 的释放有关，在 αTC1-6 细胞中表达。用 TGR5 的激动剂孵育这些细胞可增加 PC1 启动子活性和 GLP-1 分泌，表明这是一种在胰腺中将加工过程转换为 GLP-1 的机制。用链脲佐菌素处理分离的大鼠胰岛会导致β细胞毒性，这表现为葡萄糖刺激的胰岛素分泌减少。这增加了胰岛中的 GLP-1，但不是胰高血糖素。总之，胰高血糖素原可在胰腺细胞中加工为 GLP-1。该过程受葡萄糖升高、TGR5 激活和β细胞破坏的上调。了解这种现象可能会导致保护β细胞量的治疗方法的进步，从而减缓从胰岛素抵抗到 2 型糖尿病的进展。
