In critically ill patients, preventing hyperglycemia (HG) with insulin therapy partially prevented organ dysfunction and protected mitochondria. A study in a rabbit model of critical illness indicated that lower blood glucose level, rather than higher insulinemia, is a key factor in such organ protection. In this model, we now investigated the impact of blood glucose lowering vs. hyperinsulinemia (HI) on mitochondria in relation to organ damage. We assessed whether such effects on mitochondria are mediated indirectly via organ perfusion or directly via reducing cellular glucose toxicity.
Prospective, randomized laboratory investigation.
Three-month-old male rabbits.
After induction of critical illness by burn injury, followed by fluid-resuscitation and parenteral nutrition, rabbits were allocated to four groups, each a combination of normal or elevated blood glucose levels with normal or elevated insulin levels. This required alloxan administration, immediately followed by intravenous insulin and glucose infusions titrated to the respective targets.
In liver, the reduced damage by glucose lowering was not explained by better perfusion/oxygen delivery. Abnormal mitochondrial ultrastructure and function was present in the two hyperglycemic groups, most pronounced with concomitant HI. Affected mitochondrial respiratory chain enzyme activities were reduced to 25% to 62% of values in healthy rabbits, in the presence of up to five-fold increased tissue levels of glucose. This was accompanied by elevated levels of dicarbonyls, which may mediate direct toxicity of cellular glucose overload and accelerated glycolysis. The abnormalities were also present in myocardium, although to a lesser extent, and absent in skeletal muscle.
In a rabbit model of critical illness, HG evokes cellular glucose overload in liver and myocardium inducing mitochondrial dysfunction, which explained the HG-induced organ damage. Maintenance of normoglycemia, but not HI, protects against such mitochondrial and organ damage.
"However, after 6 weeks of diabetes, lipid peroxidation was increased and levels of vascular endothelial growth factor and plasma nitric oxide were reduced compared with controls or rats diabetic for 2 weeks. These studies differ from those of Van den Berghe and colleagues [37,38], who in experimental models have demonstrated that acute hyperglycemia induces mitochondrial and organ dysfunction. However, it must be recognized that similar to their 'landmark' study in critically ill patients , these animals received parenteral nutrition. "
[Show abstract][Hide abstract] ABSTRACT: Stress hyperglycemia is common in critically ill patients and appears to be a marker of disease severity. Furthermore, both the admission as well as the mean glucose level during the hospital stay is strongly associated with patient outcomes. Clinicians, researchers and policy makers have assumed this association to be causal with the widespread adoption of protocols and programs for tight in-hospital glycemic control. However, a critical appraisal of the literature has demonstrated that attempts at tight glycemic control in both ICU and non-ICU patients do not improve health care outcomes. We suggest that hyperglycemia and insulin resistance in the setting of acute illness is an evolutionarily preserved adaptive responsive that increases the host's chances of survival. Furthermore, attempts to interfere with this exceedingly complex multi-system adaptive response may be harmful. This paper reviews the pathophysiology of stress hyperglycemia and insulin resistance and the protective role of stress hyperglycemia during acute illness.
"In depth analyses of the results suggested that the prevention of hyperglycemia, not the infusion of insulin per se, explained most of these benefits [13,14]. Studies in animal models of critical illness and in cell culture models further unraveled this important aspect of glucose toxicity, and pointed to direct damaging effects of hyperglycemia on cell integrity in liver, kidney, the endothelium, immune cells and the heart [15,16,17,18,19,20,21]. "
[Show abstract][Hide abstract] ABSTRACT: Drugs used in the perioperative period could have an effect on survival as recently pointed out by an international consensus conference on the reduction in mortality in cardiac anesthesia and intensive care. Insulin infusion to achieve a strict glycemic control is the best example of how an ancillary (i.e. non-surgical) drug/technique/strategy might influence survival rates in patients undergoing cardiac surgery. The author of this "expert opinion" presents her insights into the use of insulin in this setting and suggest that based on available evidence based medicine, insulin infusion, titrated to "normoglycemia" is a complex intervention, that not only requires the simple administration of a "drug", the hormone insulin, but also needs tools and skills to accurately measure and control blood glucose to achieve normoglycemia while avoiding hypoglycemia and large glucose fluctuations.
[Show abstract][Hide abstract] ABSTRACT: This issue's Recently published papers commentary considers the popular and muddy waters of glycaemic control, stops briefly to ponder the incidence of pulmonary embolus in acute exacerbations of chronic obstructive pulmonary disease, promotes novel studies in the areas of traumatic brain injury and extracorporeal circuits, and rounds off with a potentially dogma-challenging study in cardiac arrest.
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