Crit Care Clin 22 (2006) 119 129

Glucose Metabolism and Insulin Therapy

Lies Langouche, PhD, Greet Van den Berghe, MD, PhDT
Department of Intensive Care Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium

The hypermetabolic stress response that usually follows any type of major trauma or acute illness is associated with hyperglycemia and insulin resistance, often referred to as stress diabetes or diabetes of injury [1,2]. In critically ill patients, even in those who were not previously diagnosed with diabetes, glucose uptake is reduced in peripheral insulin sensitive tissues, whereas endogenous glucose production is increased, resulting in hyperglycemia. It has long been generally accepted that a moderate hyperglycemia in critically ill patients is beneficial to ensure the supply of glucose as a source of energy to organs that do not require insulin for glucose uptake, among which are the brain and the immune system. An increasing body of evidence, however, associates the upon-admission degree of hyperglycemia and the duration of hyperglycemia during critical illness with adverse outcome. Moreover, a recent randomized, controlled trial in a large group of surgical intensive care patients demonstrated that tight blood glucose control with insulin therapy significantly improves morbidity and mortality [3]. Blood glucose control and glucose-independent actions of insulin seem to contribute to the beneficial effects of the therapy [4].

Hyperglycemia and outcome in critical illness The development of stress-induced hyperglycemia is associated with several clinically important problems in a wide array of patients with severe illness or injury. An increasing number of reports associate the upon-admission degree of hyperglycemia and the duration of hyperglycemia during critical illness with
Dr. Langouche is a Post Doctoral Fellow of the FWO Flanders Belgium. Dr. Van den Berghe holds an unrestrictive Catholic University of Leuven Novo Nordisk Chair of Research. T Corresponding author. E-mail address: greta.vandenberghe@med.kuleuven.be (G. Van den Berghe). 0749-0704/06/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2005.09.005 criticalcare.theclinics.com

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adverse outcome. In patients who have severe brain injury, hyperglycemia was associated with longer duration of hospital stay, a worse neurologic status, pupillary reaction, higher intracranial pressures, and reduced survival [5,6]. In severely burned children, the incidence of bacteremia and fungemia, the number of skin grafting procedures, and the risk for death were higher in hyperglycemic than in normoglycemic patients [7]. In trauma patients, elevated glucose levels early after injury have been associated with infectious morbidity, a lengthier ICU and hospital stay, and increased mortality [8,9]. Furthermore, this effect seemed to be independent of the associated shock or the severity of injury [9]. Trauma patients with persistent hyperglycemia had a significantly greater degree of morbidity and mortality [10]. A meta-analysis on myocardial infarction revealed an association between hyperglycemia and increased risk for congestive heart failure or cardiogenic shock and in-hospital mortality [11]. Higher blood glucose levels predicted a higher risk for death after stroke and a poor functional recovery in those patients who survived [12]. A retrospective review of a heterogeneous group of critically ill patients indicated that even a modest degree of hyperglycemia occurring after intensive care unit admission was associated with a substantial increase in hospital mortality [13]. A retrospective study on nondiabetic pediatric critically ill patients revealed a correlation of hyperglycemia with a greater in-hospital mortality rate and longer length of stay [14].

Blood glucose control with intensive insulin therapy A landmark prospective, randomized, controlled clinical trial of intensive insulin therapy in a large group of patients admitted to the intensive care unit after extensive or complicated surgery or trauma revealed major clinical benefits on morbidity and mortality [3]. In the conventional management of hyperglycemia, insulin was administered only when blood glucose levels exceeded 220 mg/dL, with the aim of keeping concentrations between 180 and 200 mg/dL, resulting in mean blood glucose levels of 150 to 160 mg/dL (hyperglycemia). In the intensive insulin therapy group, insulin was administered to the patients by insulin infusion titrated to maintain blood glucose levels between 80 and 110 mg/dL, which resulted in mean blood glucose levels of 90 to 100 mg/dL (normoglycemia). This intervention seemed safe, because no hypoglycemia-induced adverse events were reported. Maintaining normoglycemia with insulin strikingly lowered intensive care mortality by 43% (from 8.0% to 4.6%), the benefit being most pronounced in the group of patients who required intensive care for more than 5 days, with a mortality reduction from 20.2% to 10.6% (Fig. 1). Also, in-hospital mortality was lowered from 10.9% to 7.2% in the total group and from 26.3% to 16.8% in the group of long-stayers. Besides saving lives, insulin therapy largely prevented several critical illness-associated complications. The development of bloodstream infections was reduced by 46%, acute renal failure requiring dialysis or hemofiltration by 41%, bacteremia by 46%, the incidence of critical illness polyneuropathy was reduced by 44%, and the number of red blood cell transfusions

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Fig. 1. Intensive insulin therapy saves lives in the Intensive Care Unit (ICU). Kaplan-Meier survival plots of patients from the Leuven study who received intensive insulin treatment (blood glucose maintained below 110 mg/dl; black) or conventional treatment (insulin administration only when blood glucose exceeded 220 mg/dl; gray) in the ICU. The upper panels display results from all patients; the lower panels display results for long-stay (N 5 days) ICU patients only. P values were determined with the use of the Mantel-Cox log-rank test. (Modified from van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345(19): 135967; with permission.)

by 50%. Patients were also less dependent on prolonged mechanical ventilation and needed fewer days in intensive care. Although a large number of patients included in this study recovered from complicated cardiac surgery, the clinical benefits of this therapy were equally present in most other diagnostic subgroups. In the patients who had isolated brain injury, tight glycemic control protected the central and peripheral nervous system from secondary insults and improved longterm rehabilitation [15]. Following this study, Jamie Krinsley evaluated the impact of implementing strict blood glucose control in a heterogeneous medical/surgical ICU population [16]. A less strict blood glucose control was aimed for, a regimen chosen primarily to avoid inadvertent hypoglycemia; in this setting insulin therapy lowered mean blood glucose levels of 152 mg/dL in the baseline period to 131 mg/dL in the protocol period. Comparison with patient data before the implementation of the protocol showed a 29.3% reduction in hospital mortality and 10.8% decrease in length of ICU stay. Development of new renal insufficiency was 75% lower, and 18.7% fewer patients required red blood cell transfusion. The number of patients acquiring infections did not change significantly, but the incidence was already low at baseline in this patient group [16]. Another small, prospective, randomized, controlled trial by Gray and colleagues conducted in a predominantly surgical ICU confirmed the beneficial effect of tight blood glucose control on the number of serious infections [17]. In this study, insulin therapy was targeted to glucose

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levels between 80 and 120 mg/dL, which resulted in mean daily glucose levels of 125 mg/dL versus 179 mg/dL in the standard glycemic control group. A significant reduction in the incidence of total nosocomial infections, including intravascular device, bloodstream, intravascular device-related bloodstream, and surgical site infections was observed in the insulin group compared with the conventional approach [17].

Insulin resistance and hyperglycemia The stress imposed by any type of acute illness or injury leads to the development of insulin resistance, glucose intolerance, and hyperglycemia. Hepatic glucose production is upregulated in the acute phase of critical illness, despite high blood glucose levels and abundantly released insulin. Elevated levels of cytokines, growth hormone, glucagon, and cortisol might play a role in the increased gluconeogenesis [1822]. Several effects of these hormones oppose the normal action of insulin, resulting in an increased lipolysis and proteolysis, which provides substrates for gluconeogenesis. Catecholamines, which are released in response to acute injury, enhance hepatic glycogenolysis and inhibit glycogenesis [23]. Apart from the upregulated glucose production, glucose uptake mechanisms also are affected during critical illness and contribute to the development of hyperglycemia. Because of immobilization of the critically ill patient, exercisestimulated glucose uptake in skeletal muscle totally disappears [24,25]. Furthermore, because of impaired insulin-stimulated glucose uptake by the glucose transporter 4 (GLUT-4) and impaired glycogen synthase activity, glucose uptake in heart, skeletal muscle, and adipose tissue is compromised [2629]. Total body glucose uptake is massively increased, however, but is accounted for by tissues that do not depend on insulin for glucose uptake, such as brain and blood cells [1,30]. The higher levels of insulin, impaired peripheral glucose uptake and elevated hepatic glucose production reflect the development of insulin resistance during critical illness. The mechanism by which insulin therapy decreases blood glucose in critically ill patients is not completely clear. These patients are believed to suffer from hepatic and skeletal muscle insulin resistance, but data from liver and skeletal muscle biopsies harvested from nonsurvivors in the Leuven study suggest that glucose levels are lowered mainly by way of stimulation of skeletal muscle glucose uptake. Indeed, insulin therapy did increase mRNA levels of GLUT-4, which controls insulin-stimulated glucose uptake in muscle, and of hexokinase-II, the rate-limiting enzyme in intracellular insulin-stimulated glucose metabolism [31]. Hepatic insulin resistance in these patients is not overcome by insulin therapy. The hepatic expression of phosphoenolpyruvate carboxykinase, the ratelimiting enzyme in gluconeogenesis, and of glucokinase, the rate-limiting enzyme for insulin-mediated glucose uptake and glycogen synthesis, were unaffected by insulin therapy [31,32]. Moreover, circulating levels of insulin-like growth factor binding protein-1, normally under inhibitory control of insulin,

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also was refractory to the therapy in the total population of survivors and nonsurvivors [31].

Preventing glucose toxicity with intensive insulin therapy It is striking that during the short period that patients need intensive care, avoiding even a moderate level of hyperglycemia with insulin improves the most feared complications of critical illness. In critically ill patients, hyperglycemia thus seems much more acutely toxic than in healthy individuals, for whom cells can protect themselves by downregulation of glucose transporters [33]. This acute toxicity of high levels of glucose in critical illness might be explained by an accelerated cellular glucose overload and more pronounced toxic side effects of glycolysis and oxidative phosphorylation [34]. Hepatocytes, gastrointestinal mucosal cells, pancreatic beta cells, renal tubular cells, endothelial cells, immune cells, and neurons are insulin independent for glucose uptake, which is mediated mainly by the glucose transporters GLUT-1, GLUT-2, or GLUT-3 [1]. Cytokines, angiotensin II, endothelin-1, vascular endothelial growth factor, transforming growth factor-b, and hypoxia, all induced in critical illness, have been shown to upregulate expression and membrane localization of GLUT-1 and GLUT-3 in different cell types [3539]. This upregulation might overrule the normal downregulatory protective response against hyperglycemia. Moreover, GLUT-2 and GLUT-3 allow glucose to enter cells directly in equilibrium with the elevated extracellular glucose level that is present in critical illness [40]. One therefore would expect increased glucose toxicity in tissues in which glucose uptake is mediated by noninsulin-dependent transport. Hyperglycemia has been linked to the development of increased oxidative stress in diabetes, in part because of enhanced mitochondrial superoxide production [4143]. Superoxide interacts with NO to form peroxynitrite, a reactive species able to induce tyrosine nitration of proteins, which affects their normal function [44]. During critical illness, cytokine-induced activation of NO synthase increases NO levels, and hypoxia-reperfusion aggravates superoxide production, resulting in more peroxynitrite being generated [44]. When cells in critically ill patients are overloaded with glucose, high levels of peroxynitrite and superoxide are to be expected, resulting in inhibition of the glycolytic enzyme GAPDH and mitochondrial complexes I and IV [41]. The authors recently demonstrated that prevention of hyperglycemia with insulin therapy protected ultrastructure and function of the hepatocytic mitochondrial compartment of critically ill patients, but no obvious morphologic or pronounced functional abnormalities were detected in skeletal muscle of critically ill patients [45]. Mitochondrial dysfunction with a disturbed energy metabolism is a likely cause of organ failure, the most common cause of death in ICU. Prevention of hyperglycemia-induced mitochondrial dysfunction in other tissues that allow glucose to enter passively might explain some of the protective effects of intensive insulin therapy in critical illness.

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Metabolic and non-metabolic effects of blood glucose control with intensive insulin therapy Similar to the serum lipid profile of patients who have diabetes [46], the lipid metabolism in critically ill patients is strongly deranged. Most characteristically are elevated triglycerides together with low levels of HDL and LDL cholesterol [4749]. Insulin therapy almost completely reversed this hypertriglyceridemia and substantially elevated HDL and LDL and the level of cholesterol associated with these lipoproteins [31]. Insulin treatment also decreased serum triglycerides and free fatty acids in burned children [50]. Multivariate logistic regression analysis revealed that improvement of the dyslipidemia with insulin therapy explained a significant part of the reduced mortality and organ failure in critically ill patients [31]. Given the important role of lipoproteins in transportation of lipid components (cholesterol, triglycerides, phospholipids, lipid-soluble vitamins) and endotoxin scavenging [5153], a contribution to improved outcome indeed might be expected. Critically ill patients become severely catabolic, with loss of lean body mass, despite adequate enteral or parenteral nutrition. Intensive insulin therapy might attenuate this catabolic syndrome of prolonged critical illness, because insulin exerts anabolic actions [5457]. Intensive insulin treatment indeed resulted in higher total protein content in skeletal muscle of critically ill patients [45] and prevented weight loss in a rabbit model of prolonged critical illness [58]. Intensive insulin therapy prevented excessive inflammation, illustrated by decreased CRP and mannose-binding lectin levels [59], independent of its preventive effect on infections [3]. Insulin therapy also attenuated the CRP response in an experimental animal model of prolonged critical illness that was induced by third-degree burn injury [58]. Moreover, critically ill rabbits showed an increased phagocytosis capacity of monocytes and their ability to generate an oxidative burst when blood glucose levels were kept normal [58]. In burned children, administration of insulin resulted in lower proinflammatory cytokines and proteins, whereas the anti-inflammatory cascade was stimulated, although these effects were seen largely only late after the traumatic stimulus [50]. Insulin treatment attenuated the inflammatory response in thermally injured rats and endotoxemic rats and pigs [6062]. Next to these anti-inflammatory effects of insulin, prevention of hyperglycemia may be crucial also. Hyperglycemia inactivates immunoglobulins by glycosylation and therefore contributes to the risk for infection [63]. High glucose levels also negatively affected polymorphonuclear neutrophil function and intracellular bactericidal and opsonic activity [6467]. Critical illness also resembles diabetes mellitus in its hypercoagulation state [68,69]. In diabetes mellitus, vascular endothelium dysfunction, elevated platelet activation and increased clotting factors, and inhibition of the fibrinolytic system all might contribute to this hypercoagulation state [7074]. Insulin therapy indeed protected the myocardium and improved myocardial function after acute myocardial infarction, during open heart surgery, and in congestive heart failure [75]. Prevention of endothelial dysfunction also contributed to the protective

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effects of insulin therapy in critical illness in part by way of inhibition of excessive iNOS-induced NO release [76] and by way of reduction of circulating levels of asymmetric dimethylarginine, which inhibits the constitutive enzyme eNOS and hence the production of endothelial nitric oxide [77].

Glucose control or insulin? Multivariate logistic regression analysis of the results of the Leuven study indicated that blood glucose control and not the insulin dose administered statistically explains most of the beneficial effects of insulin therapy on outcome of critical illness [4]. It seemed crucial to reduce blood glucose levels to less than 110 mg/dL for the prevention of morbidity events such as bacteremia, anemia, and acute renal failure. The level of hyperglycemia was also an independent risk factor for the development of critical illness polyneuropathy [4]. Finney and colleagues confirmed the independent association between hyperglycemia and adverse outcome in surgical ICU patients [78].

Summary Hyperglycemia in critically ill patients is a result of an altered glucose metabolism. Apart from the upregulated glucose production (gluconeogenesis and glycogenolysis), glucose uptake mechanisms also are affected during critical illness and contribute to the development of hyperglycemia. The higher levels of insulin, impaired peripheral glucose uptake and elevated hepatic glucose production reflect the development of insulin resistance during critical illness. Hyperglycemia in critically ill patients has been associated with increased mortality. Simply maintaining normoglycemia with insulin therapy improves survival and reduces morbidity in surgical ICU patients, as shown by a large randomized controlled study. These results were confirmed recently by two studies, one randomized controlled study of surgical intensive care patients and another prospective observational study of a heterogeneous patient population admitted to a mixed medical/surgical intensive care unit. Prevention of glucose toxicity by strict glycemic control but also other metabolic and non-metabolic effects of insulin, independent of glycemic control, contribute to these clinical benefits.

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