Glucagon-Like Peptide 1 Increases β-Cell Regeneration by Promoting α- to β-Cell Transdifferentiation
Glucagon-Like Peptide 1 Increases β-Cell Regeneration by Promoting α- to β-Cell Transdifferentiation
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DOI：
10.2337/db18-0155
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发表时间：
2018-12-01
期刊：
影响因子：
7.7
通讯作者：
Jun, Hee-Sook
中科院分区：
文献类型：
--
作者：
Lee, Young-Sun;Lee, Changmi;Jun, Hee-Sook
胰升糖素样肽-1(GLP-1)可促进胰腺细胞的增殖，-细胞可能是新细胞生成的来源。我们研究了GLP-1是否通过细胞转分化增加细胞数量。表达GLP-1的重组腺病毒(Rad-GLP-1)处理的RIP-Creer、R26-YFP小鼠的非细胞来源的新细胞显著增加。GLP-1受体激动剂exendin-4可使rad-GLP-1处理的小鼠胰岛和Tc1克隆9(TC1-9)细胞的增殖细胞增加。Rad-GLP-1或exendin-4在体内外均能显著增加胰岛素(+)、胰升糖素(+)细胞的数量。标记胰升糖素细胞的谱系追踪显示，rad-GLP-1处理的rad-GLP-1-rtA、Tet-O-CRE、R26-yfp小鼠的细胞再生细胞比例高于rad产生半乳糖苷酶处理的小鼠。此外，exendin-4还可增加TC1-9细胞和去细胞胰岛成纤维细胞生长因子21(FGF21)的表达和分泌。经FGF21处理后，胰腺和十二指肠同源盒-1和神经原蛋白-3的表达增加，胰岛素(+)、胰升糖素(+)细胞明显增加。在FGF21小干扰RNA或FGF21基因敲除小鼠的胰岛中，由exendin-4产生的胰岛素(+)胰高血糖素(+)细胞显著减少。与野生型小鼠相比，FGF21基因敲除小鼠通过rad-GLP-1治疗产生的胰岛素(+)细胞显著减少。我们认为GLP-1在细胞转分化过程中具有重要作用，可能部分通过FGF21的诱导而产生新的细胞。
Glucagon-like peptide 1 (GLP-1) can increase pancreatic -cells, and -cells could be a source for new -cell generation. We investigated whether GLP-1 increases -cells through -cell transdifferentiation. New -cells originating from non--cells were significantly increased in recombinant adenovirus expressing GLP-1 (rAd-GLP-1)-treated RIP-CreER;R26-YFP mice. Proliferating -cells were increased in islets of rAd-GLP-1-treated mice and TC1 clone 9 (TC1-9) cells treated with exendin-4, a GLP-1 receptor agonist. Insulin(+)glucagon(+) cells were significantly increased by rAd-GLP-1 or exendin-4 treatment in vivo and in vitro. Lineage tracing to label the glucagon-producing -cells showed a higher proportion of regenerated -cells from -cells in rAd-GLP-1-treated Glucagon-rtTA;Tet-O-Cre;R26-YFP mice than rAd producing -galactosidase-treated mice. In addition, exendin-4 increased the expression and secretion of fibroblast growth factor 21 (FGF21) in TC1-9 cells and -cell-ablated islets. FGF21 treatment of -cell-ablated islets increased the expression of pancreatic and duodenal homeobox-1 and neurogenin-3 and significantly increased insulin(+)glucagon(+) cells. Generation of insulin(+)glucagon(+) cells by exendin-4 was significantly reduced in islets transfected with FGF21 small interfering RNA or islets of FGF21 knockout mice. Generation of insulin(+) cells by rAd-GLP-1 treatment was significantly reduced in FGF21 knockout mice compared with wild-type mice. We suggest that GLP-1 has an important role in -cell transdifferentiation to generate new -cells, which might be mediated, in part, by FGF21 induction.