YM201636, an inhibitor of retroviral budding and PIKfyve-catalyzed PtdIns(3,5)P2 synthesis, halts glucose entry by insulin in adipocytes.
YM201636, an inhibitor of retroviral budding and PIKfyve-catalyzed PtdIns(3,5)P2 synthesis, halts glucose entry by insulin in adipocytes.
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DOI：
10.1016/j.bbrc.2009.03.063
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发表时间：
2009-05-08
影响因子：
3.1
通讯作者：
Shisheva, Assia
中科院分区：
文献类型：
--
作者：
Ikonomov, Ognian C.;Sbrissa, Diego;Shisheva, Assia
关键词：
PIKfyve是PtdIns（3，5）P2生物合成的唯一酶，其控制适当的内体动力学，PIKfyve的沉默抑制逆转录病毒复制。一种新的PIKfyve特异性抑制剂YM 201636在800 nM时破坏逆转录病毒出芽，表明其可能用作抗逆转录病毒治疗。由于PIKfyve也是GLUT 4表面易位和葡萄糖内流的最佳胰岛素活化所需的，因此我们测试了YM 201636应用对3 T3 L1脂肪细胞中胰岛素响应性的结果。YM 201636在低至160 nM的剂量下几乎完全抑制基础和胰岛素活化的2-脱氧葡萄糖摄取，净胰岛素反应的IC 50 = 54 ± 4 nM。胰岛素诱导的GLUT 4易位在相当高的剂量下被部分抑制，与抑制胰岛素诱导的Akt/PKB磷酸化所需的剂量相当。除PIKfyve外，YM 201636还完全抑制IA类PI 3-激酶的胰岛素依赖性活化。我们认为，除了PIKfyve，在胰岛素信号传导至GLUT 4和葡萄糖摄取的背景下，YM 201636至少还有两个额外的靶标：胰岛素激活的IA类PI 3-激酶和一个在此未鉴定的高亲和力靶标，该靶标负责葡萄糖进入相对于GLUT 4易位的更大抑制。在显著低于有效逆转录病毒出芽破坏所需剂量的YM 201636剂量下，对葡萄糖内流的净胰岛素效应的深刻抑制警告了与抗逆转录病毒治疗中潜在的YM 201636使用相关的葡萄糖稳态的严重扰动。
Silencing of PIKfyve, the sole enzyme for PtdIns(3,5)P2 biosynthesis that controls proper endosome dynamics, inhibits retroviral replication. A novel PIKfyve-specific inhibitor YM201636 disrupts retroviral budding at 800 nM, suggesting its potential use as an antiretroviral therapeutic. Because PIKfyve is also required for optimal insulin activation of GLUT4 surface translocation and glucose influx, we tested the outcome of YM201636 application on insulin responsiveness in 3T3L1 adipocytes. YM201636 almost completely inhibited basal and insulin-activated 2-deoxyglucose uptake at doses as low as 160 nM, with IC50 = 54 ± 4 nM for the net insulin response. Insulin-induced GLUT4 translocation was partially inhibited at substantially higher doses, comparable to those required for inhibition of insulin-induced phosphorylation of Akt/PKB. In addition to PIKfyve, YM201636 also completely inhibited insulin-dependent activation of class IA PI 3-kinase. We suggest that apart from PIKfyve, there are at least two additional targets for YM201636 in the context of insulin signaling to GLUT4 and glucose uptake: the insulin-activated class IA PI 3-kinase and a here-unidentified high-affinity target responsible for the greater inhibition of glucose entry vs. GLUT4 translocation. The profound inhibition of the net insulin effect on glucose influx at YM201636 doses markedly lower than those required for efficient retroviral budding disruption warns of severe perturbations in glucose homeostasis associated with potential YM201636 use in antiretroviral therapy.
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DOI：
10.1073/pnas.0602941103
发表时间：
2006-10-03
影响因子：
11.1
作者：
Lopez-Verges, Sandra;Camus, Gregory;Berlioz-Torrent, Clarisse
通讯作者：
Berlioz-Torrent, Clarisse
影响因子：
4.8
作者：
Whitley, P;Reaves, BJ;Holman, GD
通讯作者：
Holman, GD
影响因子：
5.8
作者：
PILCH, PF;WILKINSON, W;OLEFSKY, JM
通讯作者：
OLEFSKY, JM
影响因子：
4.8
作者：
Sbrissa, D;Ikonomov, OC;Shisheva, A
通讯作者：
Shisheva, A
影响因子：
4.8
作者：
Hausdorff, SF;Fingar, DC;Birnbaum, MJ
通讯作者：
Birnbaum, MJ