Resolving Discrepant Findings on ANGPTL8 in β-Cell Proliferation: A Collaborative Approach to Resolving the Betatrophin Controversy.
Resolving Discrepant Findings on ANGPTL8 in β-Cell Proliferation: A Collaborative Approach to Resolving the Betatrophin Controversy.
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DOI：
10.1371/journal.pone.0159276
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kushner JA
中科院分区：
文献类型：
--
作者：
Cox AR;Barrandon O;Cai EP;Rios JS;Chavez J;Bonnyman CW;Lam CJ;Yi P;Melton DA;Kushner JA
ANGPTL 8的β-细胞促有丝分裂作用已经受到实质性辩论。最初的发现表明，小鼠中ANGPTL 8过表达诱导β细胞增殖增加17倍。随后的小鼠研究反驳了这一说法，但最近的一份关于大鼠的报告支持了最初的观察结果。这些相互矛盾的结果可以通过ANGPTL 8表达的变化和β细胞定量的不同方法来解释。为了解决这一争议，三个独立的实验室合作进行了一项盲法研究，以测试ANGPTL 8对β细胞增殖的影响。通过静脉注射将与麦芽糖结合蛋白（MBP）融合的重组人betatrophin（hBT）递送至小鼠。结果表明ANGPTL 8不刺激显著的β细胞增殖。每个实验室采用不同的方法进行β细胞鉴定，导致β细胞增殖的定量可变，并表明需要标准化β细胞定量实践。我们还观察到ANGPTL 8在刺激CD 45+造血衍生细胞增殖中的新作用，这可以部分解释已发表的差异。总体而言，ANGPTL 8诱导显著和特异性β细胞增殖的假设不再得到支持。然而，虽然ANGPTL 8不刺激稳健的β细胞增殖，但使用药物诱导的（S961）胰岛素抵抗的原始实验模型在随后的研究中得到验证，因此仍然代表了用于研究β细胞扩增所必需或足够的信号的稳健系统。作为补充说明，我们要赞扬协作小组的努力，在多个实验室重复结果和程序，作为解决文献差异的有效方法。
The β-cell mitogenic effects of ANGPTL8 have been subjected to substantial debate. The original findings suggested that ANGPTL8 overexpression in mice induced a 17-fold increase in β-cell proliferation. Subsequent studies in mice contested this claim, but a more recent report in rats supported the original observations. These conflicting results might be explained by variable ANGPTL8 expression and differing methods of β-cell quantification. To resolve the controversy, three independent labs collaborated on a blinded study to test the effects of ANGPTL8 upon β-cell proliferation. Recombinant human betatrophin (hBT) fused to maltose binding protein (MBP) was delivered to mice by intravenous injection. The results demonstrate that ANGPTL8 does not stimulate significant β-cell proliferation. Each lab employed different methods for β-cell identification, resulting in variable quantification of β-cell proliferation and suggests a need for standardizing practices for β-cell quantification. We also observed a new action of ANGPTL8 in stimulating CD45+ hematopoietic-derived cell proliferation which may explain, in part, published discrepancies. Overall, the hypothesis that ANGPTL8 induces dramatic and specific β-cell proliferation can no longer be supported. However, while ANGPTL8 does not stimulate robust β-cell proliferation, the original experimental model using drug-induced (S961) insulin resistance was validated in subsequent studies, and thus still represents a robust system for studying signals that are either necessary or sufficient for β-cell expansion. As an added note, we would like to commend collaborative group efforts, with repetition of results and procedures in multiple laboratories, as an effective method to resolve discrepancies in the literature.