美国杜克大学医学中心Christopher B. Newgard研究组取得最新进展。他们提出还原性TCA循环代谢促进了谷氨酰胺和葡萄糖刺激的胰岛素分泌。该研究于2020年12月14日发表于《细胞-代谢》。

他们证明了用葡萄糖或谷氨酰胺+ 2-氨基双环-（2,2,1）-庚烷-2-羧酸（Gln + BCH）刺激大鼠胰岛素瘤细胞或原代胰岛可诱导还原性的“逆时针”三羧酸（TCA）循环，使谷氨酰胺转化为柠檬酸盐。异柠檬酸脱氢酶2（IDH2）的分子或药理抑制作用，催化2-酮戊二酸还原为异柠檬酸的羧基化反应，导致葡萄糖和Gln + BCH刺激的还原TCA循环通量受损，NADPH水平降低和胰岛素抑制分泌。IDH2的药理抑制作用还可以抑制活体小鼠的胰岛素分泌。

此前研究已经提出了癌细胞中产生的还原性TCA循环通量机制，该研究中，他们证明了还原性TCA循环通量还产生调节胰岛素分泌的刺激-分泌偶联因子，即使在非分裂细胞中也是如此。

据了解，代谢燃料通过产生第二种使胰岛素颗粒胞吐作用的信使来调节胰岛素的分泌，但是所涉及的生化途径尚不完全清楚。

附：英文原文

Title: Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion

Author: Guo-Fang Zhang, Mette V. Jensen, Sarah M. Gray, Kimberley El, You Wang, Danhong Lu, Thomas C. Becker, Jonathan E. Campbell, Christopher B. Newgard

Issue&Volume: 2020-12-14

Abstract: Metabolic fuels regulate insulin secretion by generating second messengers that driveinsulin granule exocytosis, but the biochemical pathways involved are incompletelyunderstood. Here we demonstrate that stimulation of rat insulinoma cells or primaryrat islets with glucose or glutamine + 2-aminobicyclo-(2,2,1)-heptane-2-carboxylicacid (Gln + BCH) induces reductive, “counter-clockwise” tricarboxylic acid (TCA) cycleflux of glutamine to citrate. Molecular or pharmacologic suppression of isocitratedehydrogenase-2 (IDH2), which catalyzes reductive carboxylation of 2-ketoglutarateto isocitrate, results in impairment of glucose- and Gln + BCH-stimulated reductiveTCA cycle flux, lowering of NADPH levels, and inhibition of insulin secretion. Pharmacologicsuppression of IDH2 also inhibits insulin secretion in living mice. Reductive TCAcycle flux has been proposed as a mechanism for generation of biomass in cancer cells.Here we demonstrate that reductive TCA cycle flux also produces stimulus-secretioncoupling factors that regulate insulin secretion, including in non-dividing cells.

DOI: 10.1016/j.cmet.2020.11.020

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30655-0