Artemether Does Not Turn α Cells into β Cells.
Artemether Does Not Turn α Cells into β Cells.
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DOI：
10.1016/j.cmet.2017.10.002
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发表时间：
2018-01-09
期刊：
影响因子：
29
通讯作者：
Huising MO
中科院分区：
文献类型：
--
作者：
van der Meulen T;Lee S;Noordeloos E;Donaldson CJ;Adams MW;Noguchi GM;Mawla AM;Huising MO
胰腺α细胞保留了相当大的可塑性，并且在适当的情况下可以转分化为功能成熟的β细胞。在寻找可靶向的机制基础时，最近的一篇论文表明，广泛使用的抗疟药物蒿甲醚抑制α细胞转录因子Arx，以促进向β细胞的转分化。然而，本文中的关键初始实验是在胰岛细胞系中进行的，并且大多数随后的验证实验暗示转分化，而没有直接证明α细胞转化为β细胞。事实上，我们没有发现蒿甲醚促进原代α细胞转分化为β细胞的证据。此外，蒿甲醚使原代β细胞中的Ins2表达降低>100倍，抑制葡萄糖摄取，并消除β细胞响应于葡萄糖的钙应答和胰岛素分泌。我们的观察结果表明，蒿甲醚诱导一般胰岛内分泌细胞去分化，并质疑青蒿素在治疗糖尿病中促进α细胞向β细胞转分化的效用。抗疟疾药物蒿甲醚最近被证明可以促进α细胞向β细胞的转分化。货车der Meulen等现在报道了在用高剂量蒿甲醚处理的完整胰岛中刺激后β细胞基因表达、葡萄糖摄取、钙反应和胰岛素分泌的丧失。
Pancreatic alpha cells retain considerable plasticity and can – under the right circumstances – transdifferentiate into functionally mature beta cells. In search of a targetable mechanistic basis, a recent paper suggested that the widely used antimalarial drug artemether suppresses the alpha cell transcription factor Arx to promote transdifferentiation into beta cells. However, key initial experiments in this paper were carried out in islet cell lines and most subsequent validation experiments implied transdifferentiation without direct demonstration of alpha to beta cell conversion. Indeed, we find no evidence that artemether promotes transdifferentiation of primary alpha cells into beta cells. Moreover, artemether reduces Ins2 expression in primary beta cells >100-fold, suppresses glucose uptake, and abrogates beta cell calcium responses and insulin secretion in response to glucose. Our observations suggest that artemether induces general islet endocrine cell dedifferentiation and call into question the utility of artemisinins to promote alpha to beta cell transdifferentiation in treating diabetes. The antimalaria drug artemether has been recently shown to promote transdifferentiation of alpha cells into beta cells. Van der Meulen et al. now report loss of beta cell gene expression, glucose uptake, calcium responses and insulin secretion following stimulation in intact islets treated with a high dose of artemether.
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