Pro-inflammatory cytokines attenuate glucose-stimulated insulin secretion from INS-1E insulinoma cells by restricting mitochondrial pyruvate oxidation capacity - Novel mechanistic insight from real-time analysis of oxidative phosphorylation.
Pro-inflammatory cytokines attenuate glucose-stimulated insulin secretion from INS-1E insulinoma cells by restricting mitochondrial pyruvate oxidation capacity - Novel mechanistic insight from real-time analysis of oxidative phosphorylation.
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DOI：
10.1371/journal.pone.0199505
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Affourtit C
中科院分区：
文献类型：
--
作者：
Barlow J;Solomon TPJ;Affourtit C
在2型糖尿病的发展过程中，促炎细胞因子引起胰腺β细胞衰竭。这种β细胞衰竭与线粒体功能障碍有关，但细胞因子对线粒体呼吸的确切影响尚不清楚。为了验证促炎细胞因子通过抑制氧化ATP合成损害葡萄糖刺激胰岛素分泌（GSIS）的假设，我们探测了暴露于2 ng/mL白细胞介素-1- β和50 ng/mL干扰素- γ联合作用的大鼠INS-1E胰岛素瘤细胞的胰岛素释放和实时线粒体呼吸。我们发现，暴露于这些细胞因子24小时可以抑制葡萄糖和丙酮酸刺激的胰岛素分泌（分别为P < 0.0001和P < 0.05），但不影响kcl诱导的胰岛素释放。与分泌缺陷类似，细胞因子暴露后葡萄糖和丙酮酸刺激的线粒体呼吸降低（P < 0.01）。进一步的分析证实，无论燃料氧化是否与ATP合成偶联或不偶联，细胞因子诱导的线粒体呼吸缺陷都会发生。这些观察结果表明，促炎细胞因子通过限制线粒体丙酮酸氧化能力来减弱GSIS。白细胞介素-1- β和干扰素- γ也增加线粒体超氧化物水平（P < 0.05），这可能加强对丙酮酸氧化的抑制，并导致INS-1E细胞适度（20%）但显著（P < 0.01）的损失。细胞因子诱导的INS-1E细胞衰竭对棕榈油酸和亚油酸不敏感，这与不饱和脂肪酸对营养过剩造成的细胞保护作用不一致。我们的数据揭示了INS-1E细胞中细胞因子受损的GSIS的线粒体机制，并表明炎症和营养相关的β细胞衰竭至少部分通过不同的途径出现。
Pro-inflammatory cytokines cause pancreatic beta cell failure during the development of type 2 diabetes. This beta cell failure associates with mitochondrial dysfunction, but the precise effects of cytokines on mitochondrial respiration remain unclear. To test the hypothesis that pro-inflammatory cytokines impair glucose-stimulated insulin secretion (GSIS) by inhibiting oxidative ATP synthesis, we probed insulin release and real-time mitochondrial respiration in rat INS-1E insulinoma cells that were exposed to a combination of 2 ng/mL interleukin-1-beta and 50 ng/mL interferon-gamma. We show that 24-h exposure to these cytokines dampens both glucose- and pyruvate-stimulated insulin secretion (P < 0.0001 and P < 0.05, respectively), but does not affect KCl-induced insulin release. Mirroring secretory defects, glucose- and pyruvate-stimulated mitochondrial respiration are lowered after cytokine exposure (P < 0.01). Further analysis confirms that cytokine-induced mitochondrial respiratory defects occur irrespective of whether fuel oxidation is coupled to, or uncoupled from, ATP synthesis. These observations demonstrate that pro-inflammatory cytokines attenuate GSIS by restricting mitochondrial pyruvate oxidation capacity. Interleukin-1-beta and interferon-gamma also increase mitochondrial superoxide levels (P < 0.05), which may reinforce the inhibition of pyruvate oxidation, and cause a modest (20%) but significant (P < 0.01) loss of INS-1E cells. Cytokine-induced INS-1E cell failure is insensitive to palmitoleate and linoleate, which is at odds with the cytoprotection offered by unsaturated fatty acids against harm caused by nutrient excess. Our data disclose a mitochondrial mechanism for cytokine-impaired GSIS in INS-1E cells, and suggest that inflammatory and nutrient-related beta cell failure emerge, at least partly, through distinct paths.
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胰腺β细胞对促炎细胞因子的反应性死亡不同于真正的细胞凋亡。
影响因子：
3.7
作者：
Collier JJ;Burke SJ;Eisenhauer ME;Lu D;Sapp RC;Frydman CJ;Campagna SR
通讯作者：
Campagna SR
影响因子：
3.5
作者：
BEGGS, M;BERESFORD, G;HAMMONDS, P
通讯作者：
HAMMONDS, P
影响因子：
7.7
作者：
Azevedo-Martins, AK;Lortz, S;Tiedge, M
通讯作者：
Tiedge, M
影响因子：
11.4
作者：
Barlow, Jonathan;Jensen, Verena Hirschberg;Affourtit, Charles
通讯作者：
Affourtit, Charles
DOI：
10.1073/pnas.90.5.1731
发表时间：
1993-03-01
影响因子：
11.1
作者：
CORBETT, JA;SWEETLAND, MA;MCDANIEL, ML
通讯作者：
MCDANIEL, ML