This article tells the story of our long search for the answer to one question: is stress hyperglycemia in critically illness adaptive or mal-adaptive? Our earlier work had suggested lack of hepatic insulin effect and hyperglycemia jointly predicting poor outcome. We therefore hypothesized that insulin infusion to reach normoglycemia, tight-glucose-control, improves outcome. In 3 RCTs, we found morbidity and mortality benefit with tight-glucose-control. Moving from the bed to the bench, we attributed benefits to prevention of glucose toxicity in cells taking up glucose in an insulin-independent, glucose concentration gradient-dependent manner, counteracted rather than synergized by insulin. Several subsequent RCTs did not confirm benefit and the large 'NICE-SUGAR' trial found increased mortality with tight-glucose-control associated with severe hypoglycemia. Our subsequent clinical and mechanistic research revealed that early use of parenteral nutrition, the context of our initial RCTs, had been a confounder. Early parenteral nutrition aggravated hyperglycemia, suppressed vital cell damage removal and hampered recovery. Therefore, in our next and largest 'TGC-fast' RCT, we re-tested our hypothesis, without use of early parenteral nutrition and with a computer algorithm for tight-glucose-control that avoided severe hypoglycemia. In this trial, tight-glucose-control prevented kidney and liver damage though with much smaller effect size than in our initial RCTs without affecting mortality. Our quest ends with the strong recommendation to omit early parenteral nutrition for ICU patients, as this reduces need of blood glucose control and allows cellular housekeeping systems to play evolutionary selected roles in the recovery process. Once again, less is more in critical care.

中文翻译：

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我们的科学之旅经历了 ICU 血糖控制的起起落落。

本文讲述了我们长期寻找一个问题答案的故事：危重病中的应激性高血糖是适应性还是适应不良？我们早期的工作表明缺乏肝脏胰岛素作用和高血糖共同预测不良结果。因此，我们假设输注胰岛素以达到正常血糖，严格控制血糖，可以改善结果。在 3 项随机对照试验中，我们发现严格血糖控制可降低发病率和死亡率。从床转移到长凳，我们将其益处归因于预防细胞以不依赖于胰岛素、葡萄糖浓度梯度依赖的方式吸收葡萄糖的葡萄糖毒性，这种毒性是由胰岛素抵消的，而不是协同的。随后的几项随机对照试验并未证实其益处，大型“NICE-SUGAR”试验发现，严格血糖控制与严重低血糖相关，死亡率增加。我们随后的临床和机制研究表明，早期使用肠外营养（我们最初的随机对照试验的背景）一直是一个混杂因素。早期肠外营养加重了高血糖，抑制了重要细胞损伤的清除并阻碍了恢复。因此，在我们的下一个也是最大的“TGC-fast”随机对照试验中，我们重新测试了我们的假设，没有使用早期肠外营养，而是使用计算机算法来严格控制血糖，避免严重低血糖。在这项试验中，严格的血糖控制预防了肾脏和肝脏损伤，尽管其效果比我们最初的随机对照试验小得多，但不影响死亡率。我们的探索最终强烈建议 ICU 患者省略早期肠外营养，因为这减少了血糖控制的需要，并允许细胞管家系统在恢复过程中发挥进化选择的作用。在重症监护领域，少即是多。