胞吐
细胞内
内科学
分泌物
内分泌学
生物
氧化应激
细胞生物学
基础(医学)
胞浆
蛋白酶
氧化还原
生物化学
化学
胰岛素
酶
医学
有机化学
作者
Haopeng Lin,Kunimasa Suzuki,Nancy Smith,Xi Li,Lisa Nalbach,Sónia Fuentes,Aliya F Spigelman,Xiao-Qing Dai,Austin Bautista,Mourad Ferdaoussi,Saloni Aggarwal,Andrew R. Pepper,Letícia Prates Roma,Emmanuel Ampofo,Wenhong Li,Patrick E. MacDonald
标识
DOI:10.1038/s41467-023-44589-x
摘要
Pancreatic β-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. Here we show, in β-cells from overweight humans without diabetes and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca2+ influx. RNA-seq of sorted β-cells suggests altered metabolic pathways early following high fat diet, where we find increased basal oxygen consumption and proton leak, but a more reduced cytosolic redox state. Increased β-cell exocytosis after 2-day high fat diet is dependent on this reduced intracellular redox state and requires the sentrin-specific SUMO-protease-1. Mice with either pancreas- or β-cell-specific deletion of this fail to up-regulate exocytosis and become rapidly glucose intolerant after 2-day high fat diet. Mechanistically, redox-sensing by the SUMO-protease requires a thiol group at C535 which together with Zn+-binding suppresses basal protease activity and unrestrained β-cell exocytosis, and increases enzyme sensitivity to regulation by redox signals.
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