β-cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1
β-cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1
复制标题
DOI：
10.2337/diabetes.54.2.482
复制
发表时间：
2005-02-01
期刊：
影响因子：
7.7
通讯作者：
Drucker, DJ
中科院分区：
文献类型：
--
作者：
Li, YH;Cao, XM;Drucker, DJ
胰高血糖素样肽-1 (GLP-1) 调节能量摄入、胃肠蠕动和营养物质处理。胰岛 β 细胞对于 GLP-1 作用的相对重要性仍不清楚。我们通过分析 Pdx1 基因 β 细胞特异性失活的小鼠（β 细胞 (Pdx1-/-) 小鼠），确定了胰岛 R 细胞和胰腺十二指肠同源盒-1 (Pdx1) 转录因子对 GLP-1 受体 (GLP-1R) 依赖性作用的作用。 GLP-1R 激动剂 exendin-4 (Ex-4) 降低了对照同窝小鼠（β-Cell(Pdx1+/+) 小鼠）腹膜内 (i.p.) 葡萄糖激发后的血糖波动，但不降低 beta-Cell(Pdx1-/-) 小鼠的血糖波动。同样，Ex-4 未能增加 β 细胞 (Pdx1-/-) 小鼠的血浆胰岛素、胰腺胰岛素含量和胰腺胰岛素 mRNA 转录物的水平。此外，Ex-4 显着增加 β 细胞增殖并减少 β 细胞凋亡（Pdx1+/+）小鼠，但不影响 β 细胞（Pdx1-/-）小鼠。此外，Ex-4 增加了 β 细胞 (Pdx1+/+) 小鼠胰岛中胰岛素和胰淀素 mRNA 转录物的水平，并增强了葡萄糖刺激的胰岛素分泌，但在 β 细胞 (Pdx1-/-) 小鼠胰岛中则不然。令人惊讶的是，Ex-4 未能降低 β 细胞 (Pdx1-/-) 小鼠的血浆胰高血糖素水平。这些发现表明，Pdx1 表达对于整合调节 α 细胞胰高血糖素分泌的 GLP-1R 依赖性信号以及胰岛 β 细胞的生长、分化功能和存活至关重要。
Glucagon-like peptide-1 (GLP-1) regulates energy intake, gastrointestinal motility, and nutrient disposal. The relative importance of the islet beta-cell for GLP-1 actions remains unclear. We determined the role of the islet R-cell and the pancreatic duodenal homeobox-1 (Pdx1) transcription factor for GLP-1 receptor (GLP-1R)-dependent actions through analysis of mice with beta-cell-specific inactivation of the Pdx1 gene (beta-cell(Pdx1-/-) mice). The GLP-1R agonist exendin-4 (Ex-4) reduced glycemic excursion following intraperitoneal (i.p.) glucose challenge in control littermates (beta-Cell(Pdx1+/+) mice) but not in beta-Cell(Pdx1-/-) mice. Similarly, Ex-4 failed to increase levels of plasma insulin, pancreatic insulin content, and pancreatic insulin mRNA transcripts in beta-cell(Pdx1-/-) mice. Furthermore, Ex-4 significantly increased beta-cell proliferation and reduced beta-cell apoptosis in beta-call(Pdx1+/+) mice but not in beta-cell(Pdx1-/-) mice. Moreover, Ex-4 increased the levels of insulin and amylin mRNA transcripts and augmented glucose-stimulated insulin secretion in islets from beta-cell(Pdx1+/+) mice but not in beta-cell(Pdx1-/-) islets. Surprisingly, Ex-4 failed to reduce levels of plasma glucagon in beta-cell(Pdx1-/-) mice. These findings demonstrate that Pdx1 expression is essential for integrating GLP-1R-dependent signals regulating alpha-cell glucagon secretion and for the growth, differentiated function, and survival of islet beta-cells.