Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion.
Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion.
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DOI：
10.1007/s00125-012-2585-2
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发表时间：
2012-09
期刊：
影响因子：
8.2
通讯作者：
Gribble, F. M.
中科院分区：
文献类型：
--
作者：
Parker, H. E.;Adriaenssens, A.;Rogers, G.;Richards, P.;Koepsell, H.;Reimann, F.;Gribble, F. M.
几种葡萄糖敏感途径与葡萄糖触发的肠L细胞胰高血糖素样肽-1（GLP-1）分泌有关。一个涉及葡萄糖代谢和ATP敏感性K+通道的关闭，另一个利用Na+偶联葡萄糖转运蛋白（SGLT）的产电性质。本研究旨在阐明这些不同机制在葡萄糖刺激GLP-1分泌中的作用。用FLII 12 Pglu-700μ S 6葡萄糖传感器监测L细胞（GLUTag细胞或原代培养物中的细胞，使用组合胰高血糖素原启动子驱动的Cre重组酶与ROSA 26 tdRFP报道基因的新转基因小鼠模型）中的葡萄糖摄取。评估了SGLT 1或促进葡萄糖转运（GLUT）的药理学和遗传干扰对细胞内葡萄糖蓄积和代谢（通过NAD（P）H自发荧光测定）、细胞溶质Ca 2+（使用Fura 2监测）和GLP-1分泌（通过ELISA测定）的影响。L细胞葡萄糖摄取主要由GLUT介导的运输，根皮素，但不是根皮苷被废除。NAD（P）H自发荧光是葡萄糖依赖性的，并由葡萄糖激酶激活剂增强。在GLUTag细胞，但不是主要的L细胞，根皮素部分受损的葡萄糖依赖性分泌，并抑制放大作用下去极化高K+条件下的葡萄糖。根皮苷或Sglt 1敲低导致分泌受损，以及葡萄糖未能触发Sglt 1敲除小鼠原代L细胞胞质Ca 2+升高，证明了SGLT 1在GLUTag和原代细胞中的关键重要性。SGLT 1在L细胞中充当管腔葡萄糖传感器，但细胞内葡萄糖浓度在很大程度上由GLUT活性决定。虽然L细胞葡萄糖代谢部分依赖于葡萄糖激酶活性，但这在葡萄糖刺激的GLP-1分泌中仅起次要作用。本文的在线版本（doi：10.1007/s 00125 -012-2585-2）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Several glucose-sensing pathways have been implicated in glucose-triggered secretion of glucagon-like peptide-1 (GLP-1) from intestinal L cells. One involves glucose metabolism and closure of ATP-sensitive K+ channels, and another exploits the electrogenic nature of Na+-coupled glucose transporters (SGLTs). This study aimed to elucidate the role of these distinct mechanisms in glucose-stimulated GLP-1 secretion. Glucose uptake into L cells (either GLUTag cells or cells in primary cultures, using a new transgenic mouse model combining proglucagon promoter-driven Cre recombinase with a ROSA26tdRFP reporter) was monitored with the FLII12Pglu-700μδ6 glucose sensor. Effects of pharmacological and genetic interference with SGLT1 or facilitative glucose transport (GLUT) on intracellular glucose accumulation and metabolism (measured by NAD(P)H autofluorescence), cytosolic Ca2+ (monitored with Fura2) and GLP-1 secretion (assayed by ELISA) were assessed. L cell glucose uptake was dominated by GLUT-mediated transport, being abolished by phloretin but not phloridzin. NAD(P)H autofluorescence was glucose dependent and enhanced by a glucokinase activator. In GLUTag cells, but not primary L cells, phloretin partially impaired glucose-dependent secretion, and suppressed an amplifying effect of glucose under depolarising high K+ conditions. The key importance of SGLT1 in GLUTag and primary cells was evident from the impairment of secretion by phloridzin or Sglt1 knockdown and failure of glucose to trigger cytosolic Ca2+ elevation in primary L cells from Sglt1 knockout mice. SGLT1 acts as the luminal glucose sensor in L cells, but intracellular glucose concentrations are largely determined by GLUT activity. Although L cell glucose metabolism depends partially on glucokinase activity, this plays only a minor role in glucose-stimulated GLP-1 secretion. The online version of this article (doi:10.1007/s00125-012-2585-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
3.8
作者：
Ritzel, U;Fromme, A;Ramadori, G
通讯作者：
Ramadori, G
影响因子：
3.4
作者：
Takanaga, Hitomi;Chaudhuri, Bhavna;Frommer, Wolf B.
通讯作者：
Frommer, Wolf B.
影响因子：
29
作者：
Reimann F;Habib AM;Tolhurst G;Parker HE;Rogers GJ;Gribble FM
通讯作者：
Gribble FM
影响因子：
8.2
作者：
Rorsman, P
通讯作者：
Rorsman, P
DOI：
10.1073/pnas.0706890104
发表时间：
2007-09-18
影响因子：
11.1
作者：
Jang, Hyeung-Jin;Kokrashvili, Zaza;Egan, Josephine M.
通讯作者：
Egan, Josephine M.