Nutrient-dependent regulation of β-cell proinsulin content.
Nutrient-dependent regulation of β-cell proinsulin content.
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DOI：
10.1016/j.jbc.2023.104836
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发表时间：
2023-07
影响因子：
4.8
通讯作者：
Arvan, Peter
中科院分区：
文献类型：
--
作者：
Xu, Xiaoxi;Arunagiri, Anoop;Alam, Maroof;Haataja, Leena;Evans, Charles R.;Zhao, Ivy;Castro-Gutierrez, Roberto;Russ, Holger A.;Demangel, Caroline;Qi, Ling;Tsai, Billy;Liu, Ming;Arvan, Peter
胰岛素由胰岛素原制成，但禁食/进食控制胰腺β细胞中稳态调节的胰岛素原池的程度在很大程度上仍然未知。在这里，我们首先检查了β细胞系（INS 1 E和Min 6，它们增殖缓慢，每2-3天常规饲喂一次新鲜培养基），发现胰岛素原池大小在1 - 2小时内对每次饲喂作出反应，受到新鲜营养物的量和提供频率的影响。我们没有观察到营养喂养对环己酰亚胺追踪实验中胰岛素原总周转率的影响。我们发现，营养喂养主要与翻译起始因子eIF 2 α的快速去磷酸化有关，这预示着胰岛素原水平升高（此后，胰岛素水平升高），随后在随后的几个小时内，其再磷酸化对应于胰岛素原水平的下降。整合应激反应抑制剂ISRIB或一般对照非去阻遏2（非PERK）激酶抑制剂抑制eIF 2 α再磷酸化可减弱胰岛素原水平的下降。此外，我们证明了氨基酸对胰岛素原池的重要贡献;质谱显示β细胞贪婪地消耗细胞外谷氨酰胺，丝氨酸和半胱氨酸。最后，我们表明，在啮齿动物和人类胰岛，新鲜的营养供应动态增加前胰岛素原，这可以量化没有脉冲标记。因此，可用于胰岛素生物合成的胰岛素原受禁食/进食周期的节律性控制。
Insulin is made from proinsulin, but the extent to which fasting/feeding controls the homeostatically regulated proinsulin pool in pancreatic β-cells remains largely unknown. Here, we first examined β-cell lines (INS1E and Min6, which proliferate slowly and are routinely fed fresh medium every 2–3 days) and found that the proinsulin pool size responds to each feeding within 1 to 2 h, affected both by the quantity of fresh nutrients and the frequency with which they are provided. We observed no effect of nutrient feeding on the overall rate of proinsulin turnover as quantified from cycloheximide-chase experiments. We show that nutrient feeding is primarily linked to rapid dephosphorylation of translation initiation factor eIF2α, presaging increased proinsulin levels (and thereafter, insulin levels), followed by its rephosphorylation during the ensuing hours that correspond to a fall in proinsulin levels. The decline of proinsulin levels is blunted by the integrated stress response inhibitor, ISRIB, or by inhibition of eIF2α rephosphorylation with a general control nonderepressible 2 (not PERK) kinase inhibitor. In addition, we demonstrate that amino acids contribute importantly to the proinsulin pool; mass spectrometry shows that β-cells avidly consume extracellular glutamine, serine, and cysteine. Finally, we show that in both rodent and human pancreatic islets, fresh nutrient availability dynamically increases preproinsulin, which can be quantified without pulse-labeling. Thus, the proinsulin available for insulin biosynthesis is rhythmically controlled by fasting/feeding cycles.
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影响因子：
7.7
作者：
Israeli, Tal;Riahi, Yael;Leibowitz, Gil
通讯作者：
Leibowitz, Gil
DOI：
10.1016/j.jchromb.2019.05.039
发表时间：
2019-08-15
影响因子：
3
作者：
Liu, Zhenzhen;Tu, Mei-Juan;Yu, Ai-Ming
通讯作者：
Yu, Ai-Ming
影响因子：
4.8
作者：
Guo, Huan;Xiong, Yi;Liu, Ming
通讯作者：
Liu, Ming
影响因子：
4.8
作者：
Haataja, Leena;Snapp, Erik;Arvan, Peter
通讯作者：
Arvan, Peter
影响因子：
56.9
作者：
Jang, Wonyul;Puchkov, Dmytro;Haucke, Volker
通讯作者：
Haucke, Volker