Patients requiring prolonged intensive care are at high risk for multiple organ failure and death. Insulin resistance and hyperglycemia accompany critical illness, and the severity of this “diabetes of stress” reflects the risk of death. Recently it was shown that preventing hyperglycemia with insulin substantially improves outcome of critical illness. This article examines some potential mechanisms underlying prevention of glucose toxicity as well as the effects of insulin independent of glucose control. Unraveling the molecular mechanisms will provide new insights into the pathogenesis of multiple organ failure and open avenues for novel therapeutic strategies.

The 1952 Scandinavian epidemic of poliomyelitis necessitated mechanical ventilation of a large number of patients with respiratory failure, an intervention that reduced mortality from 80% to 40% (1). Since then, development of sophisticated mechanical devices to support all vital organ functions, a wide array of powerful drugs, and high-tech monitoring systems have revolutionized modern intensive-care medicine. This evolution improved short-term survival of previously lethal conditions such as multiple trauma, extensive burns, major surgery, and severe sepsis. Many patients nowadays indeed survive the initial shock phase of such conditions but often subsequently enter a chronic phase of critical illness. Mortality among such patients requiring intensive care for more than a few days has remained around 20% worldwide, to a large extent irrespective of the initial disease or trauma for which they were admitted to the intensive care unit (ICU). Most deaths in the ICU occurring beyond the first few days of critical illness are attributable to nonresolving failure of multiple organ systems, either due to or coinciding with sepsis. An increased susceptibility to infectious complications and the functional and structural sequelae of the systemic inflammatory response to infection and cellular injury play a role (2). Several lines of evidence support the concept that disturbed cellular energy metabolism contributes to organ failure (3, 4). This was originally ascribed exclusively to inadequate tissue perfusion and cellular hypoxia. Recent studies, however, also point to a disturbance in oxygen utilization rather than delivery, which has been termed cytopathic hypoxia (3, 5, 6). Although extensive research efforts during the last decade focused on strategies to prevent or reverse the potentially lethal multiple organ failure, only few of them revealed positive results (7–10). One of these strategies is tight blood glucose control with insulin (10).

One hundred fifty years ago, Reyboso observed glucosuria, a condition induced by ether anesthesia, in which glucose is discharged in the urine, and in 1877 Claude Bernard described hyperglycemia during hemorrhagic shock (11). Today, it is well known that any type of acute illness or injury results in insulin resistance, glucose intolerance, and hyperglycemia, a constellation termed “diabetes of injury” (12, 13). Illness or trauma increases hepatic glucose production with ongoing gluconeogenesis despite hyperglycemia and abundantly released insulin. Hepatic insulin resistance is further characterized by elevated circulating levels of IGF–binding protein–1 (IGFBP-1) (14, 15). Also, in skeletal muscle and heart, insulin-stimulated glucose uptake is impaired (16, 17). Overall, glucose uptake in critically ill patients, however, is increased but takes place mainly in the tissues that are not dependent on insulin for glucose uptake, such as, among others, the nervous system and the blood cells (13, 18). The most severe cases of stress-induced hyperglycemia (13) and highest levels of circulating IGFBP-1 (14, 15) are observed in patients with the highest risk of death. Orchestrated “counterregulatory” hormonal responses, cytokine release, and signals from the nervous system, all affecting glucose metabolic pathways, bring about the diabetes of injury. The hormones involved include catecholamines, cortisol, glucagon, and growth hormone (GH). Proinflammatory cytokines affect glucose homeostasis indirectly, by stimulating counterregulatory hormone secretion, and directly, by altering insulin receptor signaling (Figure (Figure1)1) (13, 19, 20). Although insulin receptor signaling is still incompletely understood, generation of SOCS-1 and SOCS-3 may be involved. Indeed, IL-6–stimulated SOCS-3 generation has been shown to inhibit insulin receptor tyrosine phosphorylation and downstream signal transduction (21), and both SOCS-1 and SOCS-3 have been shown to degrade insulin receptor substrate–1 (IRS-1) and IRS-2 (22). Furthermore, both endogenous and exogenous catecholamines promptly inhibit insulin secretion from β cells, and catecholamines as well as angiotensin II exert anti-insulin effects. Abnormalities in insulin signaling have been described in a rat model of critical illness resulting from prolonged administration of a nonlethal dose of endotoxin and concomitant starvation partly mimicking the condition of human sepsis (23). In the liver, abundance and tyrosine phosphorylation of the insulin receptor, IRS-1, and IRS-2 were reduced. Furthermore, there was reduced association of PI3K with IRS-1. In skeletal muscle, similar abnormalities were observed, except that the number of insulin receptors and the abundance of the IRSs were normal. Furthermore, the insulin signaling defects in the muscle were not seen when rats were studied shortly after injection of endotoxin or under conditions of adequate nutrition (23). Apart from these insights generated from in vitro or animal models, little is known about the exact molecular basis of insulin resistance in critically ill patients. Type 2 diabetes mellitus, and to a lesser extent obesity, are also characterized by hyperglycemia, reduced glucose uptake and oxidation, unsuppressed gluconeogenesis, and impaired glycogen and NO synthesis. Here, the metabolic consequences of insulin resistance are mediated predominantly by abnormalities along the IRS-1–PI3K pathway of insulin signaling (Figure (Figure1).1). However, a disrupted PI3K pathway does not necessarily mean that the other insulin signaling pathways are equally unresponsive. Indeed, signaling through the Ras-MAPK cascade, for example, via Erk 1 and Erk 2, may retain normal sensitivity. Compensatory hyperinsulinemia may thus still exert mitogenic actions in certain cell types, while the PI3K-dependent metabolic actions of insulin are suppressed (24–28). This discrepancy may occur in vascular smooth muscle cells and in specific capillary endothelial cells of patients with type 2 diabetes and obesity. Proliferation of retinal capillary endothelial cells results in microaneurysms and neovascularization. Excessive proliferation of arterial smooth muscle cells and increased extracellular matrix lead to atherosclerosis. Hence, compensatory hyperinsulinemia, due to metabolic insulin resistance, may contribute to some of the vascular complications of type 2 diabetes and obesity through overstimulation of the mitogenic, insulin-sensitive MAPK signaling pathway. Whether or not insulin resistance is similarly “selective” during critical illness, and whether hyperinsulinemia exerts deleterious effects through this pathway in the acute setting of severe illness, is at present unknown. The diabetes of injury used to be interpreted as an adaptive stress response and as such important for survival. Particularly, the overall increase in glucose turnover and the fact that hyperglycemia persists despite abundantly released insulin were considered arguments in favor of tolerating moderately elevated blood glucose levels during critical illness. Indeed, if one considers hyperglycemia of injury as beneficial in promoting cellular glucose uptake in non–insulin-dependent tissues, tolerating modest degrees of hyperglycemia is beneficial. Consequently, blood glucose concentrations of 160–200 mg/dl were recommended to maximize cellular glucose uptake while avoiding hyperosmolarity (18). In addition, moderate hyperglycemia was often viewed as a buffer against hypoglycemia-induced brain damage. In 2001, however, the critical care community was forced to reconsider this dogma (29), as a large, randomized, controlled, clinical study — hereafter referred to as “the Leuven study” — showed that preventing even moderate hyperglycemia during critical illness substantially improved outcome (10).

The Leuven study of critically ill patients, the majority of whom did not previously have diabetes, showed that titrating insulin infusion during intensive care to strict normoglycemia (below 110 mg/dl) strikingly reduced mortality when compared with the conventional insulin treatment (Figure (Figure2).2). The latter comprised insulin infusion only when blood glucose exceeded 200 mg/dl, leading to average blood glucose levels of 150–160 mg/dl (10). Although the Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction study previously showed that avoiding excessive hyperglycemia (blood glucose >200 mg/dl) after acute myocardial infarction in patients with diabetes mellitus improved long-term outcome (30), the Leuven study (10) on nondiabetic ICU patients aimed for a much lower level of blood glucose. The benefit of intensive insulin therapy in the ICU was particularly apparent among patients with prolonged critical illness, requiring intensive care for more than 5 days, with mortality reduced from 20.2% to 10.6%. Besides saving lives, intensive insulin therapy also prevented complications such as severe nosocomial infections, acute renal failure, liver dysfunction, critical illness polyneuropathy, muscle weakness, and anemia and thus reduced the time that patients were dependent on intensive care. Although intensive insulin therapy induced a slightly higher incidence of hypoglycemia as compared with the conventional approach, these episodes were never associated with clinically relevant sequelae. Indeed, the use of an insulin titration algorithm guaranteed that when hypoglycemia occurred, it was always quickly resolved. Although the Leuven study included a large number of patients recovering from cardiac surgery, the beneficial effects of strict glucose control were equally present in most other diagnostic subgroups. Furthermore, Krinsley recently confirmed the survival benefit of implementing tight blood glucose control with insulin in a mixed medical-surgical intensive care population (31). The substantial improvement of outcome with such a simple measure was considered major progress in the modern era of intensive care.

One immediately wonders how such a simple intervention — preventing a moderate degree of hyperglycemia with insulin — during the relatively short time a patient is in intensive care was able to prevent the most feared complications such as sepsis, multiple organ failure, and death. Normal cells are relatively protected from deleterious effects of brief exposure to moderate hyperglycemia by a downregulation of glucose transporters (32). In diabetes mellitus, prolonged untreated hyperglycemia contributes to the development of chronic debilitating complications. However, except in embryonic development, where hyperglycemia causes acute toxicity, the time required for hyperglycemia to cause disorders in patients with diabetes is several orders of magnitude longer than the time it took to prevent life-threatening complications with insulin therapy in the ICU. In order to understand how metabolic control with insulin proved to be so acutely protective in the critically ill, the following key questions must be answered. Is glycemic control crucial in bringing about the clinical benefits of intensive insulin therapy, or is blood glucose control epiphenomenal to the other metabolic and nonmetabolic effects of insulin? Are there factors predisposing the critically ill to hyperglycemia-induced toxicity? What are the common pathways mediating the plethora of clinical benefits of intensive insulin therapy?

There are two possible explanations, not mutually exclusive, for hyperglycemia to be more acutely toxic in ICU patients than in healthy individuals or patients with diabetes mellitus. The first is accentuated cellular glucose overload, and the second is more pronounced toxic side effects of glycolysis and oxidative phosphorylation.

It is clear that several mechanisms are involved and interrelated in explaining the clinical benefits of intensive insulin therapy in the critically ill (Figure (Figure4).4). Accelerated toxicity of hyperglycemia and lack of insulin effect during critical illness explain why the consequences are so rapidly deleterious in this condition. The direct effects of preventing hyperglycemia as well as the distinct metabolic and nonmetabolic effects of insulin that occur concomitantly with the glycemic control are likely to play a role. The relative contribution of those different mechanisms, however, is presently unknown. Furthermore, several questions await an answer. The exact molecular basis for the increased susceptibility for these toxic effects in the critically ill patient remains to be explored. It also remains unclear which of the insulin signal transduction pathways in different target tissues respond to insulin treatment and how these effects mediate the protection on organ function and overall outcome. Various hypotheses have been advanced, and these can be tested by analysis of tissue samples obtained from patients and from experimental animals in carefully designed studies. Further investigation of the mitochondrial abnormalities in tissues other than the liver and skeletal muscle, such as neurons, kidneys, and endothelial and epithelial cells, as well as the selective impact of insulin and glucose control on this cellular compartment should be investigated in great detail. Furthermore, exploring the molecular link between improved glycemic and lipid control and insulin, endothelial function, inflammation, and clinical outcome will be required. Finally, manipulation of those pathways that are linked with outcome but appear unresponsive to intensive insulin therapy may point to the potential for other therapeutic strategies to further improve survival in the ICU.

The results of the clinical study performed in Leuven demonstrated that a simple metabolic intervention, maintaining normoglycemia with insulin, improved survival and reduced morbidity of critically ill patients. This reflected major clinical progress in the modern era of intensive care. Furthermore, this clinical study has opened a whole new area of basic research besides the ongoing search for additional clinical applications. Indeed, only some of the underlying mechanisms have been studied, and many more pathways need to be investigated in great detail. Results from fundamental research carefully designed to elucidate how the clinical benefits were brought about are likely to set off development of new strategies for further improving outcome of critically ill patients and perhaps also of other target populations within and outside the hospital setting.