Pancreatic alpha cell glucagon-liver FGF21 axis regulates beta cell regeneration in a mouse model of type 2 diabetes.
Pancreatic alpha cell glucagon-liver FGF21 axis regulates beta cell regeneration in a mouse model of type 2 diabetes.
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胰腺α细胞胰高血糖素-肝脏FGF21轴调节2型糖尿病小鼠模型中的β细胞再生
DOI：
10.1007/s00125-022-05822-2
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发表时间：
2023-03
期刊：
影响因子：
8.2
通讯作者：
Hong, Tianpei
中科院分区：
文献类型：
--
作者：
Cui, Xiaona;Feng, Jin;Wei, Tianjiao;Zhang, Linxi;Lang, Shan;Yang, Kun;Yang, Jin;Liu, Junling;Sterr, Michael;Lickert, Heiko;Wei, Rui;Hong, Tianpei
胰高血糖素受体 (GCGR) 拮抗作用可改善 2 型糖尿病小鼠模型中的高血糖并促进 β 细胞再生。然而，其根本机制仍不清楚。本研究旨在探讨GCGR拮抗剂诱导小鼠β细胞再生的机制。用拮抗性GCGR单克隆抗体(mAb)治疗db/db小鼠和高脂饮食(HFD)+链脲佐菌素(STZ)诱导的2型糖尿病小鼠，并评估代谢变量和胰岛细胞定量。血浆细胞因子阵列和肝脏 RNA 测序数据用于筛选可能的介质，包括成纤维细胞生长因子 21 (FGF21)。应用ELISA、定量RT-PCR和蛋白质印迹来验证FGF21的变化。利用 FGF21 中和抗体 (nAb) 阻断 FGF21 信号传导来阐明 FGF21 是否参与 GCGR mAb 在血浆条件培养和肝细胞共培养条件下对 β 细胞身份相关基因表达的影响。使用 FGF21 nAb 处理的 db/db 小鼠、全身性 Fgf21 敲除 (Fgf21−/−) 糖尿病小鼠和肝细胞特异性 Fgf21 敲除 (Fgf21Hep−/−) 糖尿病小鼠来揭示 FGF21 在 β 细胞再生中的参与。 BrdU 追踪研究用于分析接受 GCGR mAb 治疗的糖尿病小鼠的 β 细胞增殖情况。 GCGR mAb 治疗改善了血糖控制，并增加了胰岛数量（db/db 1.6±0.1 vs 0.8±0.1/mm2，p<0.001；HFD+STZ 1.2±0.1 vs 0.5±0.1/mm2，p<0.01）和面积（db/db 2.5±0.2 vs 1.2±0.2%，p<0.001；糖尿病小鼠中，HFD+STZ 1.0±0.1 vs 0.3±0.1%，p<0.01）。血浆细胞因子阵列和肝脏RNA测序数据显示血浆和肝脏中的FGF21水平因GCGR拮抗作用而上调。 GCGR mAb 诱导血浆 FGF21 水平上调（db/db 661.5±40.0 vs 466.2±55.7 pg/ml，p<0.05；HFD+STZ 877.0±106.8 vs 445.5±54.0 pg/ml，p<0.05）和肝脏 Fgf21 mRNA 水平（db/db） 3.2±0.5 vs 1.8±0.1，p<0.05；HFD+STZ 2.0±0.3 vs 1.0±0.2，p<0.05）和蛋白质（db/db 2.0±0.2 vs 1.4±0.1，p<0.05；HFD+STZ 1.6±0.1 vs 1.0±0.1，p<0.01）。暴露于 GCGR mAb 处理小鼠的血浆或肝细胞中，与培养的小鼠胰岛和 β 细胞系中 β 细胞身份相关的特征基因的 mRNA 水平上调，而 FGF21 nAb 阻断 FGF21 活性则减弱了这种上调。值得注意的是，GCGR mAb 诱导的 β 细胞数量增加的效应在 FGF21 nAb 处理的 db/db 小鼠、Fgf21−/− 糖尿病小鼠和 Fgf21Hep−/− 糖尿病小鼠中减弱。此外，GCGR mAb 治疗增强了两组糖尿病小鼠的 β 细胞增殖，而这种作用在 Fgf21−/− 和 Fgf21Hep−/− 小鼠中减弱。我们的研究结果表明，肝源性 FGF21 参与 2 型糖尿病小鼠模型中 GCGR 拮抗诱导的 β 细胞再生。在线版本包含可在 10.1007/s00125-022-05822-2 获取的补充材料。
Glucagon receptor (GCGR) antagonism ameliorates hyperglycaemia and promotes beta cell regeneration in mouse models of type 2 diabetes. However, the underlying mechanisms remain unclear. The present study aimed to investigate the mechanism of beta cell regeneration induced by GCGR antagonism in mice. The db/db mice and high-fat diet (HFD)+streptozotocin (STZ)-induced mice with type 2 diabetes were treated with antagonistic GCGR monoclonal antibody (mAb), and the metabolic variables and islet cell quantification were evaluated. Plasma cytokine array and liver RNA sequencing data were used to screen possible mediators, including fibroblast growth factor 21 (FGF21). ELISA, quantitative RT-PCR and western blot were applied to verify FGF21 change. Blockage of FGF21 signalling by FGF21-neutralising antibody (nAb) was used to clarify whether FGF21 was involved in the effects of GCGR mAb on the expression of beta cell identity-related genes under plasma-conditional culture and hepatocyte co-culture conditions. FGF21 nAb-treated db/db mice, systemic Fgf21-knockout (Fgf21−/−) diabetic mice and hepatocyte-specific Fgf21-knockout (Fgf21Hep−/−) diabetic mice were used to reveal the involvement of FGF21 in beta cell regeneration. A BrdU tracing study was used to analyse beta cell proliferation in diabetic mice treated with GCGR mAb. GCGR mAb treatment improved blood glucose control, and increased islet number (db/db 1.6±0.1 vs 0.8±0.1 per mm2, p<0.001; HFD+STZ 1.2±0.1 vs 0.5±0.1 per mm2, p<0.01) and area (db/db 2.5±0.2 vs 1.2±0.2%, p<0.001; HFD+STZ 1.0±0.1 vs 0.3±0.1%, p<0.01) in diabetic mice. The plasma cytokine array and liver RNA sequencing data showed that FGF21 levels in plasma and liver were upregulated by GCGR antagonism. The GCGR mAb induced upregulation of plasma FGF21 levels (db/db 661.5±40.0 vs 466.2±55.7 pg/ml, p<0.05; HFD+STZ 877.0±106.8 vs 445.5±54.0 pg/ml, p<0.05) and the liver levels of Fgf21 mRNA (db/db 3.2±0.5 vs 1.8±0.1, p<0.05; HFD+STZ 2.0±0.3 vs 1.0±0.2, p<0.05) and protein (db/db 2.0±0.2 vs 1.4±0.1, p<0.05; HFD+STZ 1.6±0.1 vs 1.0±0.1, p<0.01). Exposure to plasma or hepatocytes from the GCGR mAb-treated mice upregulated the mRNA levels of characteristic genes associated with beta cell identity in cultured mouse islets and a beta cell line, and blockage of FGF21 activity by an FGF21 nAb diminished this upregulation. Notably, the effects of increased beta cell number induced by GCGR mAb were attenuated in FGF21 nAb-treated db/db mice, Fgf21−/− diabetic mice and Fgf21Hep−/− diabetic mice. Moreover, GCGR mAb treatment enhanced beta cell proliferation in the two groups of diabetic mice, and this effect was weakened in Fgf21−/− and Fgf21Hep−/− mice. Our findings demonstrate that liver-derived FGF21 is involved in the GCGR antagonism-induced beta cell regeneration in a mouse model of type 2 diabetes. The online version contains supplementary material available at 10.1007/s00125-022-05822-2.
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DOI：
10.1073/pnas.0701600104
发表时间：
2007-05-01
影响因子：
11.1
作者：
Ogawa, Yasushi;Kurosu, Hiroshi;Kuro-o, Makoto
通讯作者：
Kuro-o, Makoto
前α细胞衍生的β细胞有助于2型糖尿病小鼠拮抗性胰高血糖素受体抗体诱导的β细胞新生
影响因子：
5.8
作者：
Cui, Xiaona;Feng, Jin;Wei, Tianjiao;Gu, Liangbiao;Wang, Dandan;Lang, Shan;Yang, Kun;Yang, Jin;Yan, Hai;Wei, Rui;Hong, Tianpei
通讯作者：
Hong, Tianpei
影响因子：
64.8
作者：
Dor, Y;Brown, J;Melton, DA
通讯作者：
Melton, DA
影响因子：
105.7
作者：
Li, Yongze;Teng, Di;Shan, Zhongyan
通讯作者：
Shan, Zhongyan
影响因子：
7.7
作者：
Lee, Young-Sun;Lee, Changmi;Jun, Hee-Sook
通讯作者：
Jun, Hee-Sook