Stevens Joseph R, McMillan Ryan P, Resendes Justin T, Lloyd Shannon K, Ali Mostafa M, Frisard Madlyn I, Hargett Stefan, Keller Susanna R, Hulver Matthew W
Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA.
Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA; Metabolic Phenotyping Core, Virginia Tech, Blacksburg, VA.
Metabolism. 2017 Mar;68:150-162. doi: 10.1016/j.metabol.2016.12.008. Epub 2016 Dec 16.
Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood.
PURPOSE/PROCEDURES: The goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model.
Contrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P<.05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P<.01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production.
This research shows that low-magnitude, short-term changes in LPS can have significant effects on whole body glucose metabolism and this likely occurs through its direct actions on the liver. Additional studies are necessary to understand the mechanisms responsible for altered glucose metabolism in response to low magnitude changes in LPS levels.
与健康的正常体重个体相比，肥胖个体呈现出更高的炎症状态，这与胰岛素抵抗相关。一个被认为导致肥胖和糖尿病状态下炎症增加的因素是血液内毒素水平升高，这种情况被称为代谢性内毒素血症。在非肥胖且胰岛素敏感的个体中，循环内毒素浓度在一天中会有所波动，餐后状态下会升高，在吸收后状态会恢复到基线水平。有证据表明，高脂饮食会改变这些波动，导致内毒素水平全天保持高位。内毒素水平改变对葡萄糖代谢的影响尚不清楚。
目的/方法：本研究的目的是确定低剂量内毒素（脂多糖，LPS）短期和长期增加对人原代细胞系中葡萄糖耐量和胰岛素信号传导的影响，以及短期内毒素处理对C57/Bl6小鼠模型中葡萄糖稳态的影响。首先，我们测试了这样一个假设，即短期低剂量内毒素处理会增强胰岛素信号传导和糖原合成，而长期处理在细胞培养模型中会产生干扰。其次，我们研究了这些短期低剂量内毒素处理是否会在小鼠模型中对全身葡萄糖稳态产生类似的改善作用。
与我们最初的假设相反，短期内毒素处理对胰岛素信号传导或糖原合成没有影响，然而长期处理确实降低了糖原合成（P<0.05）。有趣的是，短期内毒素处理在小鼠模型中导致葡萄糖稳态有显著改善（P<0.01）；这被认为至少部分归因于LPS对肝脏葡萄糖生成的抑制作用。
这项研究表明，LPS的低幅度短期变化可对全身葡萄糖代谢产生显著影响，这可能是通过其对肝脏的直接作用发生的。需要进一步的研究来了解LPS水平低幅度变化时葡萄糖代谢改变的机制。
