美国威斯康星大学麦迪逊分校Matthew J. Merrins和耶鲁大学Richard G. Kibbey课题组合作发现丙酮酸激酶调控胰岛素分泌通路的信号强度。这一研究成果于2020年11月3号发表在国际学术期刊《细胞-代谢》上。

在本研究中，研究人员发现丙酮酸激酶（PK）将ADP和磷酸烯醇丙酮酸（PEP）转换为ATP和丙酮酸，这是β细胞感知糖酵解和线粒体氧化底物的基础。定位于线粒体膜的PK足以关闭KATP通道并引发钙离子内流。小分子PK激活剂增加了ATP/ADP和钙离子浮动的频率，并有效地增强了胰岛素的分泌。PK通过周期性降低线粒体ADP来限制呼吸，从而加速PEP循环，直到线粒体膜去极化恢复ADP和氧化磷酸化为止。

该发现支持β细胞代谢的分区模型，其中PK局部产生胰岛素分泌所需的ATP/ADP。周期性PK活性使线粒体执行合成和氧化功能，而对葡萄糖氧化没有任何影响。这些发现表明基于PK激活的糖尿病潜在治疗方法是目前β细胞功能共认单状态模型所无法预测的。

据悉，胰腺β细胞将营养物代谢与适当的胰岛素分泌结合在一起。

附：英文原文

Title: Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway

Author: Sophie L. Lewandowski, Rebecca L. Cardone, Hannah R. Foster, Thuong Ho, Evgeniy Potapenko, Chetan Poudel, Halena R. VanDeusen, Sophia M. Sdao, Tiago C. Alves, Xiaojian Zhao, Megan E. Capozzi, Arnaldo H. de Souza, Ishrat Jahan, Craig J. Thomas, Craig S. Nunemaker, Dawn Belt Davis, Jonathan E. Campbell, Richard G. Kibbey, Matthew J. Merrins

Issue&Volume: 2020/11/03

Abstract: Pancreatic β cells couple nutrient metabolism with appropriate insulin secretion.Here, we show that pyruvate kinase (PK), which converts ADP and phosphoenolpyruvate(PEP) into ATP and pyruvate, underlies β cell sensing of both glycolytic and mitochondrialfuels. Plasma membrane-localized PK is sufficient to close KATP channels and initiate calcium influx. Small-molecule PK activators increase the frequencyof ATP/ADP and calcium oscillations and potently amplify insulin secretion. PK restrictsrespiration by cyclically depriving mitochondria of ADP, which accelerates PEP cyclinguntil membrane depolarization restores ADP and oxidative phosphorylation. Our findingssupport a compartmentalized model of β cell metabolism in which PK locally generatesthe ATP/ADP required for insulin secretion. Oscillatory PK activity allows mitochondriato perform synthetic and oxidative functions without any net impact on glucose oxidation.These findings suggest a potential therapeutic route for diabetes based on PK activationthat would not be predicted by the current consensus single-state model of β cell function.

DOI: 10.1016/j.cmet.2020.10.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30540-4