A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells.
A role for cytosolic isocitrate dehydrogenase as a negative regulator of glucose signaling for insulin secretion in pancreatic ß-cells.
复制标题
DOI：
10.1371/journal.pone.0077097
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Prentki M
中科院分区：
文献类型：
--
作者：
Guay C;Joly E;Pepin E;Barbeau A;Hentsch L;Pineda M;Madiraju SR;Brunengraber H;Prentki M
胞浆NADPH可能是胰腺β细胞葡萄糖代谢与胰岛素分泌的信号之一。细胞质中的NADPH水平主要由苹果酸酶和异柠檬酸脱氢酶（IDHc）的胞质异构体控制。一些研究已经提供了苹果酸酶通过丙酮酸循环在葡萄糖诱导的胰岛素分泌（GIIS）中的作用的证据，但是IDHc在胰岛细胞信号传导中的作用是不确定的。IDHc是异柠檬酸/α-酮戊二酸穿梭的一种已确定的组分，可将还原当量（NADPH）从胞浆转移至胞质溶胶。这种穿梭是耗能的，因为它与烟酰胺核苷酸转氢酶偶联，该酶使用线粒体质子梯度从NADP+和NADH产生线粒体NADPH和NAD+。为了确定通过IDHc的通量与GIIS是正相关还是负相关，我们在GIIS细胞中进行了RNAi敲低实验。INS 832/13细胞和分离的大鼠胰岛β细胞中IDHc表达的降低导致GIIS增强。这种效应至少部分通过GIIS的KATP非依赖性扩增臂介导。INS 832/13细胞中IDHc敲低不改变葡萄糖氧化，但其减少脂肪酸氧化并增加葡萄糖的脂肪生成。INS 832/13细胞中的代谢物组分析表明，IDHc敲低增加了异柠檬酸和NADP+水平。它还增加了与GIIS相关的几种代谢物的细胞含量，特别是一些克雷布斯循环中间体，乙酰辅酶A，谷氨酸，cAMP和ATP。结果将IDHc确定为负调节GIIS的新兴途径的组成部分。
Cytosolic NADPH may act as one of the signals that couple glucose metabolism to insulin secretion in the pancreatic ß-cell. NADPH levels in the cytoplasm are largely controlled by the cytosolic isoforms of malic enzyme and isocitrate dehydrogenase (IDHc). Some studies have provided evidence for a role of malic enzyme in glucose-induced insulin secretion (GIIS) via pyruvate cycling, but the role of IDHc in ß-cell signaling is unsettled. IDHc is an established component of the isocitrate/α–ketoglutarate shuttle that transfers reducing equivalents (NADPH) from the mitochondrion to the cytosol. This shuttle is energy consuming since it is coupled to nicotinamide nucleotide transhydrogenase that uses the mitochondrial proton gradient to produce mitochondrial NADPH and NAD+ from NADP+ and NADH. To determine whether flux through IDHc is positively or negatively linked to GIIS, we performed RNAi knockdown experiments in ß-cells. Reduced IDHc expression in INS 832/13 cells and isolated rat islet ß-cells resulted in enhanced GIIS. This effect was mediated at least in part via the KATP-independent amplification arm of GIIS. IDHc knockdown in INS 832/13 cells did not alter glucose oxidation but it reduced fatty acid oxidation and increased lipogenesis from glucose. Metabolome profiling in INS 832/13 cells showed that IDHc knockdown increased isocitrate and NADP+ levels. It also increased the cellular contents of several metabolites linked to GIIS, in particular some Krebs cycle intermediates, acetyl-CoA, glutamate, cAMP and ATP. The results identify IDHc as a component of the emerging pathways that negatively regulate GIIS.
登录
查看更多内容
DOI：
10.1111/j.1463-1326.2009.01114.x
发表时间：
2009-11
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Kebede MA;Alquier T;Latour MG;Poitout V
通讯作者：
Poitout V
影响因子：
4.8
作者：
Brown, Laura J.;Longacre, Melissa J.;MacDonald, Michael J.
通讯作者：
MacDonald, Michael J.
影响因子：
4.8
作者：
Hasan, Noaman M.;Longacre, Melissa J.;MacDonald, Michael J.
通讯作者：
MacDonald, Michael J.
影响因子：
4.8
作者：
Guay, Claudiane;Madiraju, S. R. Murthy;Prentki, Marc
通讯作者：
Prentki, Marc
影响因子：
4.8
作者：
Khan, A;Ling, ZC;Landau, BR
通讯作者：
Landau, BR