Endothelial inflammation induced by excess glucose is associated with cytosolic glucose 6-phosphate but not increased mitochondrial respiration.
Endothelial inflammation induced by excess glucose is associated with cytosolic glucose 6-phosphate but not increased mitochondrial respiration.
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DOI：
10.1007/s00125-009-1272-4
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发表时间：
2009-05
期刊：
影响因子：
8.2
通讯作者：
Kim, F.
中科院分区：
文献类型：
--
作者：
Sweet, I. R.;Gilbert, M.;Maloney, E.;Hockenbery, D. M.;Schwartz, M. W.;Kim, F.
关键词：
内皮细胞暴露于高葡萄糖水平可通过IKKβ-NF-κB通路的促炎信号传导抑制对胰岛素的反应，包括诱导内皮一氧化氮合成酶活性。在目前的研究中，我们的目的是确定葡萄糖过量的代谢反应，介导内皮细胞炎症和胰岛素抵抗。由于内皮细胞降低其氧消耗率（OCR）响应于葡萄糖，我们假设，增加线粒体功能不会介导这些细胞的反应过量底物。在培养的人微血管内皮细胞中测量糖酵解和线粒体燃料对糖酵解和氧化代谢的代谢中间产物和终产物（包括葡萄糖-6磷酸（G6 P）、乳酸、CO2、NAD（P）H和OCR）的影响，并将其与IKKβ激活相关联。响应于葡萄糖浓度从低到生理水平（0至5 mM）的增加，G6 P、乳酸盐、NAD（P）H和CO2的产生均如预期地增加，而OCR急剧降低。在葡萄糖浓度高于5 mM时检测到IKKβ激活，这与G6 P水平的平行增加相关，而下游代谢途径对过量底物不敏感。过量葡萄糖激活IKKβ与糖酵解中间体G6 P水平升高相关，但与乳酸生成或OCR无关，后者在生理葡萄糖浓度下被抑制至饱和水平以下。这些发现表明，由于线粒体呼吸增加的氧化应激不太可能介导由过量葡萄糖诱导的内皮炎症，而是提示G6 P积累参与高血糖对内皮细胞的不良影响。
Exposure of endothelial cells to high glucose levels suppresses responses to insulin, including induction of endothelial nitric oxide synthetase activity, through pro-inflammatory signaling via the IKKβ-NF-κB pathway. In the current study, we aimed to identify metabolic responses to glucose excess that mediate endothelial cell inflammation and insulin resistance. Since endothelial cells decrease their rate of oxygen consumption (OCR) in response to glucose, we hypothesized that increased mitochondrial function would not mediate these cell’s response to excess substrate. The effects of glycolytic and mitochondrial fuels on metabolic intermediates and end products of glycolytic and oxidative metabolism, including glucose-6 phosphate (G6P), lactate, CO2, NAD(P)H, and OCR, were measured in cultured human microvascular endothelial cells and correlated with IKKβ activation. In response to increases in glucose concentration from low to physiological levels (0 to 5 mM), production of G6P, lactate, NAD(P)H and CO2 each increased as expected, while OCR was sharply reduced. IKKβ activation was detected at glucose concentrations above 5 mM, which was associated with parallel increases of G6P levels, whereas downstream metabolic pathways were insensitive to excess substrate. Activation of IKKβ by excess glucose correlates with increased levels of the glycolytic intermediate G6P, but not with lactate generation or OCR, which are inhibited well below saturation levels at physiologic glucose concentrations. These findings suggest that oxidative stress due to increased mitochondrial respiration is unlikely to mediate endothelial inflammation induced by excess glucose and suggests instead the involvement of G6P accumulation in the adverse effects of hyperglycemia on endothelial cells.
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DOI：
10.1111/j.1440-1681.2005.04190.x
发表时间：
2005-04-01
影响因子：
2.9
作者：
Fueger, PT
通讯作者：
Fueger, PT
影响因子：
1.8
作者：
Akimoto, Yoshihiro;Hart, Gerald W.;Kawakami, Hayato
通讯作者：
Kawakami, Hayato
影响因子：
4.1
作者：
BOVERIS, A;CHANCE, B
通讯作者：
CHANCE, B
影响因子：
5
作者：
Kim, F;Tysseling, KA;Schwartz, MW
通讯作者：
Schwartz, MW
影响因子：
4.1
作者：
Crabtree, HG
通讯作者：
Crabtree, HG