Glucose Metabolism and Insulin Therapy

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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 donot 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

0749-0704/06/$ see front matterD 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.ccc.2005.09.005 criticalcare.theclinics.com

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: [email protected] (G. Van den Berghe).

Crit Care Clin 22 (2006) 119129
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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]. Inseverely 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 heartfailure 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 hyper-

glycemia occurring after intensive care unit admission was associated with a

substantial increase in hospital mortality [13]. A retrospective study on non-

diabetic 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 inmean 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 waslowered 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 hemo-

filtration by 41%, bacteremia by 46%, the incidence of critical illness poly-

neuropathy was reduced by 44%, and the number of red blood cell transfusions

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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 long-term 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, and18.7% 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

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.)

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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 sig-

nificant reduction in the incidence of total nosocomial infections, includingintravascular device, bloodstream, intravascular device-related bloodstream, and

surgical site infections was observed in the insulin group compared with the con-

ventional approach [17].

Insulin resistance and hyperglycemia

The stress imposed by any type of acute illness or injury leads to the devel-

opment of insulin resistance, glucose intolerance, and hyperglycemia. Hepaticglucose 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 in-

creased 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 ofhyperglycemia. Because of immobilization of the critically ill patient, exercise-

stimulated glucose uptake in skeletal muscle totally disappears [24,25]. Further-

more, 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 resistanceduring 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 rate-

limiting enzyme in gluconeogenesis, and of glucokinase, the rate-limiting

enzyme for insulin-mediated glucose uptake and glycogen synthesis, were un-

affected 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 non-

survivors [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 anaccelerated 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 locali-

zation of GLUT-1 and GLUT-3 in different cell types [3539]. This upregulationmight overrule the normal downregulatory protective response against hyper-

glycemia. 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. Hyper-

glycemia 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 mito-

chondrial complexes I and IV [41].

The authors recently demonstrated that prevention of hyperglycemia with

insulin therapy protected ultrastructure and function of the hepatocytic mito-

chondrial compartment of critically ill patients, but no obvious morphologic orpronounced 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 criticallyill 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] andprevented 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 pre-

ventive 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, admin-

istration 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, pre-

vention of hyperglycemia may be crucial also. Hyperglycemia inactivates immuno-

globulins by glycosylation and therefore contributes to the risk for infection [63].

High glucose levels also negatively affected polymorphonuclear neutrophil func-

tion 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 exces-

sive iNOS-induced NO release [76] and by way of reduction of circulating levels

of asymmetric dimethylarginine, which inhibits the constitutive enzyme eNOSand 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 outcomeof 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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Glucose Metabolism and Insulin Therapy