Hui H, Wright C, Perfetti R
Division of Diabetes, Endocrinology and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Diabetes. 2001 Apr;50(4):785-96. doi: 10.2337/diabetes.50.4.785.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone capable of restoring normal glucose tolerance in aging glucose-intolerant Wistar rats. Whether the antidiabetic properties of GLP-1 are exclusively due to its insulin secretory activity remains to be determined. A GLP-1-dependent differentiation of pancreatic precursor cells into mature beta-cells has recently been proposed. The aim of this study was to investigate whether pancreatic ductal epithelial cells could be differentiated into insulin-secreting cells by exposing them to GLP-1. Rat (ARIP) and human (PANC-1) cell lines, both derived from the pancreatic ductal epithelium, were used to test this hypothesis. A major difference distinguishes these two cell lines: whereas ARIP cells spontaneously express the beta-cell differentiation factor islet duodenal homeobox-1 (IDX-1), PANC-1 cells are characteristically IDX-1 negative. GLP-1 induced the differentiation of ARIP cells into insulin-synthesizing cells, although it did not affect the phenotype of PANC-1 cells, as determined by fluorescence-activated cell sorting (FACS) analysis. Differentiation of ARIP cells by exposure to human GLP-1 occurs in a time- and dose-dependent manner, and this is associated with an increase in IDX-1 and insulin mRNA levels. Secretion of insulin was also induced in a parallel manner, and it was regulated by the concentration of glucose in the culture medium. Interestingly, PANC-1 cells, when stably transfected with human IDX-1, gained responsiveness to GLP-1 and were able to differentiate into beta-cells, as determined by FACS analysis, insulin gene expression, intracellular insulin content, and insulin accumulation in the culture medium. Finally, we demonstrated that the receptor for GLP-1 is constitutively expressed by ARIP and PANC-1 cells and that the mRNA level for this transcript was increased by cellular transfection with human IDX-1. In summary, our study provides evidence that GLP-1 is a differentiation factor for pancreatic ductal cells and that its effect requires the expression of IDX-1.
胰高血糖素样肽-1（GLP-1）是一种肠促胰岛素激素，能够使衰老的糖耐量异常Wistar大鼠恢复正常糖耐量。GLP-1的抗糖尿病特性是否完全归因于其胰岛素分泌活性仍有待确定。最近有人提出胰腺前体细胞可依赖GLP-1分化为成熟的β细胞。本研究的目的是调查胰腺导管上皮细胞暴露于GLP-1后是否可分化为胰岛素分泌细胞。源自胰腺导管上皮的大鼠细胞系（ARIP）和人细胞系（PANC-1）用于验证这一假设。这两种细胞系有一个主要区别：ARIP细胞自发表达β细胞分化因子胰岛十二指肠同源盒-1（IDX-1），而PANC-1细胞的特征是IDX-1阴性。通过荧光激活细胞分选（FACS）分析确定，GLP-1可诱导ARIP细胞分化为胰岛素合成细胞，尽管它不影响PANC-1细胞的表型。通过暴露于人类GLP-1使ARIP细胞分化呈时间和剂量依赖性，这与IDX-1和胰岛素mRNA水平升高有关。胰岛素分泌也以类似方式被诱导，且受培养基中葡萄糖浓度调节。有趣的是，通过FACS分析、胰岛素基因表达、细胞内胰岛素含量以及培养基中胰岛素积累确定，当PANC-1细胞稳定转染人IDX-1后，获得了对GLP-1的反应能力，并能够分化为β细胞。最后，我们证明ARIP和PANC-1细胞组成性表达GLP-1受体，并且通过用人IDX-1进行细胞转染可使该转录本的mRNA水平升高。总之，我们的研究提供了证据表明GLP-1是胰腺导管细胞的分化因子，其作用需要IDX-1的表达。
