Glucagon receptor blockage inhibits ?-cell dedifferentiation through FoxO1
Glucagon receptor blockage inhibits ?-cell dedifferentiation through FoxO1
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胰高血糖素受体阻断通过 FoxO1 抑制 β 细胞去分化
DOI：
10.1152/ajpendo.00101.2022
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发表时间：
2022-01-01
影响因子：
5.1
通讯作者：
Wei，Rui
中科院分区：
文献类型：
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作者：
Wang，Kangli;Cui，Xiaona;Wei，Rui
胰高血糖素分泌的胰腺α细胞在糖尿病的发展中起着关键作用。胰高血糖素促进β细胞分泌胰岛素。然而，胰高血糖素对β细胞功能和表型的长期影响仍然是难以捉摸的。在这项研究中，我们发现长期胰高血糖素干预或胰高血糖素干预与棕榈酸的存在下调β细胞特异性标志物，并抑制培养的β细胞中的胰岛素分泌。这些结果表明，胰高血糖素在病理条件下诱导β细胞去分化。胰高血糖素受体（GCGR）单克隆抗体（mAb）阻断胰高血糖素可减弱胰高血糖素诱导的β细胞去分化。在原代胰岛中，GCGR mAb处理上调β细胞特异性标志物并增加胰岛素含量，表明内源性胰高血糖素-GCGR信号传导的阻断抑制了β细胞去分化。为了研究可能的机制，我们发现胰高血糖素降低FoxO 1的表达。FoxO 1抑制剂模拟胰高血糖素的作用，而FoxO 1过表达逆转胰高血糖素诱导的β细胞去分化。GCGR单抗可降低糖尿病小鼠血糖水平，上调胰岛素水平，增加胰岛β细胞面积，抑制胰岛β细胞去分化。在老年β细胞特异性FoxO 1基因敲除小鼠（血糖水平升高作为糖尿病模型）中，GCGR mAb的降糖作用减弱，血浆胰岛素水平、β细胞面积和β细胞去分化不受GCGR mAb影响。我们的研究结果证明胰高血糖素在病理条件下诱导β细胞去分化，并且该作用部分由FoxO 1介导。我们的研究揭示了α-和β-细胞之间的一种新的串扰，有助于理解糖尿病的病理生理学，并发现糖尿病治疗的新靶点。新&值得注意的是分泌胰高血糖素的胰腺α-细胞可以与β-细胞相互作用。然而，胰高血糖素对β细胞功能和表型的长期影响仍然难以捉摸。我们的新发现表明，长期胰高血糖素诱导培养的β细胞中的β细胞去分化。FoxO 1抑制剂模拟胰高血糖素信号传导，而GCGR mAb的胰高血糖素信号传导阻断逆转胰高血糖素的作用。在2型糖尿病小鼠中，GCGR mAb增加β细胞面积，改善β细胞功能，抑制β细胞去分化，其作用部分由FoxO 1介导。
Glucagon-secreting pancreatic α-cells play pivotal roles in the development of diabetes. Glucagon promotes insulin secretion from β-cells. However, the long-term effect of glucagon on the function and phenotype of β-cells had remained elusive. In this study, we found that long-term glucagon intervention or glucagon intervention with the presence of palmitic acid downregulated β-cell-specific markers and inhibited insulin secretion in cultured β-cells. These results suggested that glucagon induced β-cell dedifferentiation under pathological conditions. Glucagon blockage by a glucagon receptor (GCGR) monoclonal antibody (mAb) attenuated glucagon-induced β-cell dedifferentiation. In primary islets, GCGR mAb treatment upregulated β-cell-specific markers and increased insulin content, suggesting that blockage of endogenous glucagon-GCGR signaling inhibited β-cell dedifferentiation. To investigate the possible mechanism, we found that glucagon decreased FoxO1 expression. FoxO1 inhibitor mimicked the effect of glucagon, whereas FoxO1 overexpression reversed the glucagon-induced β-cell dedifferentiation. Indb/dbmice and β-cell lineage-tracing diabetic mice, GCGR mAb lowered glucose level, upregulated plasma insulin level, increased β-cell area, and inhibited β-cell dedifferentiation. In aged β-cell-specific FoxO1 knockout mice (with the blood glucose level elevated as a diabetic model), the glucose-lowering effect of GCGR mAb was attenuated and the plasma insulin level, β-cell area, and β-cell dedifferentiation were not affected by GCGR mAb. Our results proved that glucagon induced β-cell dedifferentiation under pathological conditions, and the effect was partially mediated by FoxO1. Our study reveals a novel cross talk between α- and β-cells and is helpful to understand the pathophysiology of diabetes and discover new targets for diabetes treatment.NEW & NOTEWORTHYGlucagon-secreting pancreatic α-cells can interact with β-cells. However, the long-term effect of glucagon on the function and phenotype of β-cells has remained elusive. Our new finding shows that long-term glucagon induces β-cell dedifferentiation in cultured β-cells. FoxO1 inhibitor mimicks whereas glucagon signaling blockage by GCGR mAb reverses the effect of glucagon. In type 2 diabetic mice, GCGR mAb increases β-cell area, improves β-cell function, and inhibits β-cell dedifferentiation, and the effect is partially mediated by FoxO1.