Department of Intensive Care Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
J Clin Endocrinol Metab. 2012 Jan;97(1):E59-64. doi: 10.1210/jc.2011-1760. Epub 2011 Oct 19.
Critical illness induces swelling, enlargement, and dysfunction of mitochondria, which in liver, but not in muscle, is aggravated by excessive hyperglycemia. We previously demonstrated impaired autophagic clearance of damaged mitochondria in fed prolonged critically ill patients. Impaired fusion/fission-mediated repair and/or renewal through biogenesis may further accentuate mitochondrial abnormalities.
We studied mitochondrial fusion/fission and biogenesis and how these are affected by preventing hyperglycemia with insulin during critical illness.
Patients admitted to a university hospital surgical/medical intensive-care unit participated in a randomized study.
We studied adult prolonged critically ill patients vs. controls.
Tolerating hyperglycemia up to 215 mg/dl was compared with intensive insulin therapy targeting normoglycemia (80-110 mg/dl).
In liver and skeletal muscle, we quantified levels of several proteins involved in mitochondrial fusion/fission and biogenesis.
Key players in mitochondrial fusion/fission and biogenesis were up-regulated in postmortem liver (1.4- to 3.7-fold) and rectus abdominis (1.2- to 4.2-fold) but not in in vivo or postmortem vastus lateralis biopsies of critically ill patients. Maintaining normoglycemia with insulin attenuated the hepatic response in the mitochondrial fusion/fission process but did not affect the markers of mitochondrial biogenesis in liver or muscle.
Our observations suggest tissue-dependent attempts of compensatory activation of mitochondrial repair mechanisms during critical illness. Considering the previously observed persistent mitochondrial damage, this activation may be insufficient and contribute to mitochondrial dysfunction. Suppressed activation of fusion/fission when excessive hyperglycemia is prevented with insulin may reflect reduced need for diluting (less) damage during normoglycemia or, alternatively, a suppressive effect of insulin on repair.
危重病会导致线粒体肿胀、增大和功能障碍，而在肝脏中，这种情况会因过度高血糖而加重，但在肌肉中则不会。我们之前已经证明，在喂养的长时间危重病患者中，受损线粒体的自噬清除受损。受损的融合/裂变介导的修复和/或通过生物发生进行的更新可能会进一步加剧线粒体异常。
我们研究了线粒体融合/裂变和生物发生，以及在危重病期间通过胰岛素预防高血糖如何影响这些过程。
入住大学医院外科/内科重症监护病房的患者参加了一项随机研究。
我们研究了成年长时间危重病患者与对照者。
将高血糖耐受至 215mg/dl 与靶向正常血糖（80-110mg/dl）的强化胰岛素治疗进行比较。
在肝脏和骨骼肌中，我们量化了几种参与线粒体融合/裂变和生物发生的蛋白质的水平。
线粒体融合/裂变和生物发生的关键因子在肝组织（1.4-3.7 倍）和腹直肌（1.2-4.2 倍）中上调，但在危重病患者的体内或死后股外侧肌活检中未上调。用胰岛素维持正常血糖水平可减轻肝脏中线粒体融合/裂变过程中的反应，但不影响肝脏或肌肉中线粒体生物发生的标志物。
我们的观察结果表明，在危重病期间，组织依赖性尝试代偿性激活线粒体修复机制。考虑到之前观察到的持续线粒体损伤，这种激活可能不足，并导致线粒体功能障碍。用胰岛素预防过度高血糖时融合/裂变激活受到抑制可能反映了在正常血糖时需要稀释（减少）损伤的需求减少，或者胰岛素对修复的抑制作用。
