Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China.
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
EBioMedicine. 2019 Mar;41:73-84. doi: 10.1016/j.ebiom.2019.02.037. Epub 2019 Mar 1.
Glucagon-like peptide-1 (GLP-1) and its based agents improve glycemic control. Although their attenuating effect on hepatic glucose output has drawn our attention for decades, the potential mechanisms remain unclear.
Cytokine array kit was used to assess cytokine profiles in db/db mice and mouse primary hepatocytes treated with exenatide (exendin-4). Two diabetic mouse models (db/db and Pax6) were treated with a GLP-1 analog exenatide or liraglutide. The expression and secretion of fibroblast growth factor 21 (FGF21) in the livers of diabetic mice, primary mouse and human hepatocytes, and the human hepatic cell line HepG2 treated with or without GLP-1 analog were measured. Blockage of FGF21 with neutralizing antibody or siRNA, or hepatocytes isolated from Fgf21 knockout mice were used, and the expression and activity of key enzymes in gluconeogenesis were analyzed. Serum FGF21 level was evaluated in patients with type 2 diabetes (T2D) receiving exenatide treatment.
Utilizing the cytokine array, we identified that FGF21 secretion was upregulated by exenatide (exendin-4). Similarly, FGF21 production in hepatocytes was stimulated by exenatide or liraglutide. FGF21 blockage attenuated the inhibitory effects of the GLP-1 analogs on hepatic glucose output. Similar results were also observed in primary hepatocytes from Fgf21 knockout mice. Furthermore, exenatide treatment increased serum FGF21 level in patients with T2D, particularly in those with better glucose control.
We identify that function of GLP-1 in inhibiting hepatic glucose output is mediated via the liver hormone FGF21. Thus, we provide a new extra-pancreatic mechanism by which GLP-1 regulates glucose homeostasis. FUND: National Key Research and Development Program of China, the National Natural Science Foundation of China, the Natural Science Foundation of Beijing and Peking University Medicine Seed Fund for Interdisciplinary Research.
胰高血糖素样肽-1（GLP-1）及其衍生药物可改善血糖控制。尽管其抑制肝葡萄糖输出的作用已引起我们数十年的关注，但潜在机制仍不清楚。
采用细胞因子阵列试剂盒评估 db/db 小鼠和外泌肽（exendin-4）处理的原代鼠肝细胞中的细胞因子谱。用 GLP-1 类似物 exenatide 或 liraglutide 治疗两种糖尿病小鼠模型（db/db 和 Pax6）。检测糖尿病小鼠、原代鼠和人肝细胞以及经 GLP-1 类似物处理或未处理的 HepG2 人肝细胞系中肝脏内成纤维细胞生长因子 21（FGF21）的表达和分泌。使用中和抗体或 siRNA 阻断 FGF21，或使用 Fgf21 基因敲除小鼠的肝细胞，分析糖异生关键酶的表达和活性。评估接受 exenatide 治疗的 2 型糖尿病（T2D）患者的血清 FGF21 水平。
利用细胞因子阵列，我们发现 exenatide（exendin-4）可上调 FGF21 的分泌。同样，exenatide 或 liraglutide 也可刺激肝细胞中 FGF21 的产生。FGF21 阻断可减弱 GLP-1 类似物对肝葡萄糖输出的抑制作用。在 Fgf21 基因敲除小鼠的原代肝细胞中也观察到了类似的结果。此外，exenatide 治疗可增加 T2D 患者的血清 FGF21 水平，尤其在血糖控制较好的患者中。
我们发现 GLP-1 抑制肝葡萄糖输出的功能是通过肝脏激素 FGF21 介导的。因此，我们提供了 GLP-1 调节葡萄糖稳态的一种新的胰腺外机制。
国家重点研发计划、国家自然科学基金、北京市自然科学基金和北京大学医学部交叉学科研究种子基金。
