Review

Glucose metabolism in burn patients: The role of insulin andother endocrine hormones

Nikiforos Ballian a, Atoosa Rabiee b,c, DanaK. Andersen b, Dariush Elahi b,c,*, B. Robert Gibson b

aDepartment of Surgery, University of Wisconsin, Madison, WI, United StatesbDepartment of Surgery, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, United StatescDepartment of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, United States

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600

2. Glucose metabolism in burn patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600

2.1. Gluconeogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600

2.2. Insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

3. Deleterious effects of hyperglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

4. Pharmacological agents and burn-related metabolic abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

4.1. Insulin therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

4.2. Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603

4.3. Other agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603

b u r n s 3 6 ( 2 0 1 0 ) 5 9 9 – 6 0 5

a r t i c l e i n f o

Article history:

Accepted 11 November 2009

Keywords:

Insulin

GLP-1

Burn ICU

Glycemic control

a b s t r a c t

Severe burn causes a catabolic response with profound effects on glucose and muscle

protein metabolism. This response is characterized by hyperglycemia and loss of muscle

mass, both of which have been associated with significantly increased morbidity and

mortality. In critically ill surgical patients, obtaining tight glycemic control with intensive

insulin therapy was shown to reduce morbidity and mortality and has increasingly become

the standard of care. In addition to its well-known anti-hyperglycemic action and reduc-

tion in infections, insulin promotes muscle anabolism and regulates the systemic inflam-

matory response. Despite a demonstrated benefit of insulin administration on the

maintenance of skeletal muscle mass, it is unknown if this effect translates to improved

clinical outcomes in the thermally injured. Further, insulin therapy has the potential to

cause hypoglycemia and requires frequent monitoring of blood glucose levels. A better

understanding of the clinical benefit associated with tight glycemic control in the burned

patient, as well as newer strategies to achieve and maintain that control, may provide

improved methods to reduce the clinical morbidity and mortality in the thermally injured

patient.

# 2009 Elsevier Ltd and ISBI. All rights reserved.

* Corresponding author at: Department of Surgery, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center,4940 Eastern Avenue, A5, Baltimore, MD 21224, United States. Tel.: +1 410 550 2385; fax: +1 410 550 1895.

avai lab le at www.sc iencedi rect .com

journal homepage: www.elsevier.com/locate/burns

E-mail address: delahi1@jhmi.edu (D. Elahi).

0305-4179/$36.00 # 2009 Elsevier Ltd and ISBI. All rights reserved.doi:10.1016/j.burns.2009.11.008

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603

b u r n s 3 6 ( 2 0 1 0 ) 5 9 9 – 6 0 5600

1. Introduction

Despite advances in the resuscitation and surgical treatment

of burn patients, metabolic dysfunction remains a significant

cause of morbidity and mortality [1]. Significant thermal injury

is characterized by hypermetabolism and catabolism propor-

tional to burn surface area. This metabolic profile includes

changes in glucose homeostasis and muscle protein metabo-

lism that persist from the first few days following injury to as

long as three years later [2]. Healing of burn wounds is an

anabolic process which consumes massive amounts of amino

acids, supplied by breakdown of skeletal muscle [3–5].

Hyperglycemia and loss of muscle mass that are attendant

with catabolism have a central role in determining the

prognosis of these patients [1].

Insulin therapy has been shown to reduce mortality and

morbidity in surgical patients [6] and has both anti-hyperglyce-

mic and anabolic effects in muscle. Although the role of insulin

in maintaining muscle mass after burn has been investigated

[6,7], the potential influence on mortality is unknown. Since

patients with significant burns have the most intense and

prolonged catabolic response of all ‘surgical’ ICU patients, one

might conclude that the most robust clinical benefit of insulin

treatment in terms of a potential reduction in morbidity and

mortality may beobtained inthe burn population. Inthis review,

we present an overview of glucose regulation after burn injury

and describe the role of insulin and other endocrine hormones

in improving glycemic control and reversing catabolism.

2. Glucose metabolism in burn patients

Glucose metabolism is altered after significant burn, leading to

hyperglycemia [8,9]. Numerous mediators are involved in

Table 1 – Endocrine mediators of glucose regulation in burn p

Mediator Levels Direct effects

Insulin " # Gluconeogenesis

# Glycogenolysis

Glucagon " " Gluconeogenesis

" Glycogenolysis

# Glycogenesis

Catecholamines " " Gluconeogenesis

" Glycogenolysis

Impaired glucose transp

Corticosteroids " " Gluconeogenesis

TNF " Altered insulin signalin

IL-6 " Altered insulin signalin

MCP-1 " Altered insulin signalin

Growth hormone " Improved glucose dispo

# Gluconeogenesis

IGF-1 – Improved glucose dispo

TNF, tumor necrosis factor; IL, interleukin; MCP, monocyte chemotactic

regulating glucose metabolism and have complex effects

(Table 1).The maincontributors to burn-inducedhyperglycemia

are increased gluconeogenesis and insulin resistance [9–11].

2.1. Gluconeogenesis

Enhanced gluconeogenesis primarily occurs in the liver and its

purpose is to increase energy supply to the wound. Gluconeo-

genesis accounts for 11% of increased energy expenditure in

burn patients [12,13] and its main substrates are amino acids

derived from muscle catabolism and lactate produced by the

burn wound itself [12,13]. Although in vivo studies have shown

an increase in hepatic gluconeogenesis [14–16], Yamaguchi

and coworkers showed that gluconeogenesis in isolated

perfused rat livers after burn is not increased compared to

sham-burned animals [15]. Hence, it seems that increased

gluconeogenesis does not result from intrinsic hepatic

changes, but from the release of systemic mediators that

act on the liver [8,17,18]. In critical illness, systemic mediators

of gluconeogenesis include glucagon, catecholamines and

corticosteroids. Specifically in the setting of burn injury,

glucagon has been shown to be a significant stimulator of

gluconeogenesis [8]. On the other hand, catecholamines do not

seem to contribute to increased glucose production, since

adrenergic blockade potentiates glucose production [19]. Of

note, glucose oxidation is increased after thermal injury and

does not contribute to increased gluconeogenesis [11].

Increased gluconeogenesis after burn is characterized by

inefficient use of metabolic substrates. For example, the total

rate of gluconeogenesis and glycolysis, which are opposing

metabolic pathways, is increased 2.5-fold, leading to increased

energy expenditure [20]. Although one would expect increased

gluconeogenesis to cause a net increase in hepatic glucose

production, some studies have shown this not to be the case

atients.

Indirect effects References

Insulin resistance [73]

[73]

Insulin resistance [74]

[74]

ort [75]

Insulin resistance [76]

g [77]

g [77]

g [78]

sal " IGF-1 [79]

[80]

sal Reduced insulin secretion [81]

protein; IGF, insulin-like growth factor.

b u r n s 3 6 ( 2 0 1 0 ) 5 9 9 – 6 0 5 601

[18,21]. In an animal model of burn, Lee et al found that

gluconeogenesis was significantly upregulated and glucose

was diverted to the pentose phosphate pathway to support the

production of antioxidants [21]. Hence, the net glucose output

was not increased compared to control animals [21].

2.2. Insulin resistance

Insulin resistance is a critical part of the etiology of

hyperglycemia after burn and its etiology is poorly understood

[22]. The first 48 h after thermal injury (‘ebb’ phase) are

characterized by decreased metabolic rate and soon give way

to hypermetabolism (‘flow’ phase) accompanied by hyper-

insulinemia and hyperglycemia, the hallmark of insulin

resistance [23]. Insulin resistance is thought to be mediated

by local and systemic release of hormones and factors that

oppose insulin action, among which are glucagon, corticos-

teroids and catecholamines [24]. Insulin resistance results

both from reduced insulin-mediated glucose uptake in

skeletal muscle and by loss of muscle mass, the most

important tissue for glucose disposal [9,25]. Indeed, there is

evidence that cytokine release after burn injury can reduce

glucose uptake by skeletal muscle [26]. Perhaps the most

important contributor to insulin resistance is muscle wasting.

Other studies suggest an increased rate of glucose uptake by

tissues other than skeletal muscle, such as skin, wound and

intestine [24].

Although insulin seems to retain its biological effective-

ness in burn patients, there is significant evidence of insulin

resistance in response to injury [17], which tends to progress

with time [27]. Studies in animal models on the molecular

basis of burn-induced insulin resistance have revealed

defects in activation of the insulin receptor itself and of

downstream intracellular pathways which are activated by

insulin binding to its receptors [28]. Akt/PKB is an intracellular

enzyme responsible for glucose uptake and glycogen synthe-

sis that is activated by insulin [28]. Akt/PKB activation by

insulin in skeletal muscle is impaired following burn and may

be involved in the impaired metabolism and muscle wasting

found in these patients [28]. However, insulin administration

following burn increases protein turnover but does not result

in a positive protein balance [29,30]. To further complicate

muscle protein dynamics, burn patients seem to have a

different response to insulin therapy than healthy volun-

teers. Sakurai et al. found that 7-day systemic high-dose

insulin infusion increased muscle proteolysis in burn patients

and attributed this paradox to adaptation to hyperinsuline-

mia [7]. These investigators hypothesized that insulin acutely

stimulates protein synthesis, leading to depletion of the

intracellular amino acid pool, and that this acute phase is

then followed by stimulation of proteolysis to maintain

intracellular amino acid concentrations during prolonged

insulin infusion [7].

3. Deleterious effects of hyperglycemia

Despite its uncertain pathogenesis, hyperglycemia in the

immediate post-burn injury period is associated with in-

creased morbidity and mortality [31]. Multiple mechanisms for

this increased morbidity and mortality are thought to be

involved. Impairment of the immune system and an increased

risk of infection have been demonstrated, and there is

evidence that these effects result from leukocyte dysfunction,

changes in immunoglobulin structure, proinflammatory

changes and leukopenia [32–34]. Particularly important in

burn patients are the defects in wound and skin graft healing,

and increased muscle catabolism associated with hypergly-

cemia [5,9,33,35,36].

Some of the deleterious effects of hyperglycemia have been

elucidated at the cellular and molecular level. Hyperglycemia

contributes to endothelial dysfunction, one of the main

pathways to organ failure in critical illness. Endothelial

dysfunction leads to activation of the inflammatory response,

platelet degranulation and coagulopathy [32,37,38]. In turn,

these effects create a prothrombotic state that contributes to

organ hypoperfusion [32,37]. Langouche et al showed that

correction of hyperglycemia in critically ill patients reduces

endothelial activation by suppressing production of inducible

nitric oxide synthase, a key enzyme in nitric oxide production

and endothelial activation [38]. Furthermore, in an animal

model of burn, Vanhorebeek et al. demonstrated that

hyperglycemia impairs mitochondrial function despite ade-

quate tissue oxygenation and perfusion [10]. In their study,

hyperglycemia was shown to upregulate glycolysis, leading to

accumulation of excessive amounts of metabolites which

were toxic to mitochondria [10]. Interestingly, this effect of

hyperglycemia was more pronounced in the presence of

hyperinsulinemia.

Besides causing hyperglycemia, thermal injury has direct

effects on glucose utilization by tissues and organs. In an

animal model of burn, deregulated expression of enzymes and

transporters involved in glucose uptake and utilization caused

dysfunction of muscle mitochondria [39].

4. Pharmacological agents and burn-relatedmetabolic abnormalities

4.1. Insulin therapy

Peak serum glucose concentrations and duration of hypergly-

cemia are independently associated with increased morbidity

and mortality in critically ill adults and children [40–42]. In

response to the deleterious effects of hyperglycemia, insulin

treatment has been the mainstay of glucose control in the

critically ill [43].

Intravenous insulin infusion inhibits proteolysis, an effect

which is maximal in the splanchnic region and less potent in

skeletal muscle [44]. In addition, insulin administration

stimulates protein synthesis and intracellular transport of

certain amino acids [45]. These effects are dependent not only

on the presence of insulin but also on amino acid availability,

which is paradoxically reduced by insulin infusion [30,46].

Hence, administration of insulin alone will fail to prevent

muscle proteolysis due to depletion of the intracellular amino

acid pool and decreases in intracellular amino acid transport.

The net effect of exogenous insulin and amino acid adminis-

tration is to create a net positive nitrogen balance. Interest-

ingly, the beneficial effects of insulin on muscle protein are

Fig. 1 – Scatter plot of third day average glucose level as a

function of age and glycemic control with regard to follow

up outcome of sepsis and mortality.

b u r n s 3 6 ( 2 0 1 0 ) 5 9 9 – 6 0 5602

maintained during prolonged administration, resulting in

improved outcomes, such as reduced hospital stay [31].

In a landmark study by van den Berghe et al. of surgical ICU

patients, intensive glycemic control with insulin to a serum

glucose goal of 80–110 mg/dl significantly reduced mortality

and morbidity, regardless of patient diabetic status [47].

Insulin therapy also improved intermediate measures of

morbidity such as: length of ICU stay, duration of ventilatory

support, need for renal replacement therapy and the incidence

of critical illness polyneuropathy and septicemia. This study

did include burn patients, however their number was too

small to allow outcome extrapolations for this subgroup [47].

In the immediate period following burn, hyperglycemia is

prevalent and frequently inadequately treated, despite evi-

dence that it is associated with increased mortality [48].

Subsequently, van den Burghe and colleagues concluded that

the mechanism of insulin’s benefit is likely due to the

establishment and maintenance of normoglycemia rather

than a direct effect of insulin [49,50]. However, insulin has

direct effects unrelated to glucose homeostasis that are

beneficial in critically ill patients. In the critically ill cardiac

surgery population, infusion of glucose, insulin and potassium

(GIK) improves cardiovascular and cerebral function in

patients with cardiac or cerebral ischemia [32]. Insulin has

been shown to regulate the systemic inflammatory response

to critical illness, which is thought to be important in reducing

multi-organ dysfunction in critically ill patients [51,52]. Insulin

markedly reduces the hepatic acute phase response, which is

implicated in the systemic inflammatory reaction and

catabolic response after thermal injury [53,54]. Jeschke et al.

demonstrated that insulin therapy significantly improves

hepatic morphology and function in rat models of burn and

endotoxemia [55,56]. Although the role of insulin in main-

taining muscle mass after burn has been investigated [6,7], the

potential benefit on other outcomes in burn patients, includ-

ing mortality, is unknown. In a recent study, intensive insulin

therapy was shown to be successful in achieving normogly-

cemia in adult burn patients [57].

Despite the absence of published trials, there is good reason

to suspect a clinical benefit of tight glucose control achieved by

insulin infusion therapy in the adult burn population. In

children with severe burns, Pham et al. found that intensive

glycemic control (90–120 mg/dl) achieved by insulin infusion

reduces rates of urinary tract infection and overall mortality

[58]. In our own study of adult patients in the burn ICU and

surgical ICU, intensive insulin therapy which achieved a mean

blood glucose level of no more than 150 mg/dl by day 3 of the

infusion was shown to have a similar survival benefit in the

burn population as in the mixed surgical ICU population [59]

(Fig. 1).

While potentially beneficial in critically ill patients and

those with severe burn, insulin therapy is not without risk.

Van den Berghe et al. found that the incidence of hypoglyce-

mia was up to eight times greater in patients receiving

intensive insulin therapy than in controls [47]. In a second

study by Van den Berghe et al. in medical ICU patients,

hypoglycemia was identified as an independent risk factor for

death and possibly reduced the beneficial effect of insulin in

the treatment arm of the study [47,60]. Despite improved

mortality, hypoglycemia occurred in 18% of patients with

acute cardiac ischemia treated with intravenous insulin to

maintain normoglycemia [61] (126–196 mg/dl). In addition,

hypoglycemia was more frequently observed in severely

burned children receiving insulin therapy to maintain

normoglycemia [58]. In a separate study of intensive insulin

therapy in burn patients, the incidence of hypoglycemia was

5% and did not result in significance adverse effects [57].

Although the authors of the above studies concluded that

intensive insulin therapy is safe, hypoglycemia is a significant

problem even in an ICU setting where blood glucose can be

closely monitored.

Furthermore, there are significant barriers to implement-

ing intensive insulin protocols in the ICU. For instance, in their

study of insulin therapy in severely burned children, Pham

et al. emphasized the difficulty of convincing health care

professionals of the need to maintain subjects on an

intravenous insulin infusion when serum glucose remained

at levels considered ‘acceptable’ [58]. They reported that,

during the initial study period, ICU staff were concerned about

insulin-induced hypoglycemia and tended to inappropriately

terminate insulin infusion, resulting in rebound hyperglyce-

mia. In addition, further research into staff resistance to tight

glycemic control protocols has been likened to selling ‘‘root

canals’’ to the ICU staff [62]. Hence, a significant ‘learning

curve’ occurs during implementation of intensive insulin

therapy [58].

In burn patients, the frequent need to return to the

operating room for grafting and other procedures often results

in a mandated suspension of the insulin infusion during

anesthesia. This is counter-productive in that rebound

hyperglycemia frequently occurs with suspension of the

insulin infusion. In cardiac surgery patients, intra-operative

insulin therapy has been found to be safe and effective in

maintaining euglycemia, and is thought to be an important

component of achieving and maintaining euglycemia [63]. In

addition, the frequent use of enteral tube feeding in burn

patients makes intensive insulin therapy more problematic,

b u r n s 3 6 ( 2 0 1 0 ) 5 9 9 – 6 0 5 603

particularly if the enteral feedings are temporarily suspended

during operative procedures. Despite these aspects of routine

burn care, insulin infusions can be maintained with appropri-

ate attention to frequent blood glucose determinations.

Another potential concern with insulin and glucose admin-

istration is hepatic injury. Burned patients are predisposed to

hepatic steatosis, even in the absence of insulin and glucose

therapy. Contributing factors are thought to include: insulin-

induced hepatic lipogenesis, increased hepatic delivery of

glucose, and increased fatty acid release from adipose tissue

[7,64,65]. Importantly, in studies that used continuous insulin

infusion at 28 units/h, caloric needs in the form of glucose

increased twofold, however; hepatic steatosis did not occur

[7,66]. The authors attributed this absence of steatosis to the

concurrent infusion of insulin, directing excess glucose to

tissues with insulin-dependent glucose uptake such as skeletal

muscle and adipose tissue, and not to the liver, where glucose

uptake is insulin-independent and proportional to portal vein

glucose levels. It appears that when normoglycemia is main-

tained, burn patients do not get hepatic steatosis [66]. A recent

study showed that insulin can protect the liver from alcohol-

induced steatosis in burn patients [67]. Elevated blood alcohol is

common in patients with burns and contributes to hepatic

steatosis, which can progress to severe hepatic dysfunction [67].

Of note, both insulin-induced peripheral glucose uptake and its

conversion to triglycerides were found to be normal in burn

patients [7,68].

Unfortunately, low-dose insulin therapy has not been found

to prevent hyperglycemia in burn patients and does not affect

muscle glucose uptake; therefore, it does not change patient

caloricdemands[6].Since mostof theobservedbenefit of insulin

therapy results from maintaining normoglycemia [49,50], low-

dose insulin therapy which does not result in euglycemia would

be expected to have reduced impact on overall outcomes.

4.2. Metformin

The role of metformin has been examined in an effort to reduce

hyperglycemic complications in the immediate post-burn

period, while attempting to avoid the attendant risk of

hypoglycemia noted with intensive insulin therapy. Metformin

acts by reducing hepatic gluconeogenesis and improving

peripheral insulin sensitivity, which are the most significant

pathophysiologic alterations responsible for hyperglycemia

following burn injury [69]. In addition, there is evidence that

metformin acts by an additional mechanism in burn patients:

the augmentation of endogenous insulin release [43]. A parti-

cularlyappealing advantage of metformin is itsability toachieve

normoglycemia without the need of frequent glucose monitor-

ing [43]. However, what prevents metformin therapy from being

ideal in the burn populace is that this agent is associated with

potentially lethal lactic acidosis in patients with septic shock,

hypovolemia and heart failure, which can be common in

patients with significant burns [43]. Therefore, metformin has

not been advocated as routine therapy in burn patients.

4.3. Other agents

A number of other pharmacological agents have been

examined in burn patients in an attempt to reverse the

numerous metabolic abnormalities present in this patient

population. In a recent randomized trial, fenofibrate, a PPAR-g

agonist, was shown to improve insulin-mediated glucose

disposal and insulin-mediated inhibition of hepatic glucose

release in children with significant burns [70]. In addition,

growth hormone and insulin-like growth factor-1 therapy

have been studied for their potential anabolic effects and have

been associated with decreased mortality in burn patients. It is

unknown whether this clinical benefit arises through an

anabolic effect or through an insulin-mediated effect [71].

Finally, despite its lack of direct effects on glucose

metabolism, oxandrolone stimulates protein synthesis and

has proven benefits in burn patients, including improved

wound healing and decreased hospital length of stay

[45,72,73]. Unfortunately, a prolonged ventilation requirement

is a potential concern with oxandrolone administration [28]. In

one study, where oxandrolone administration was found to

prolong the need for ventilatory support, it was proposed that

the prolongation was due to increased pulmonary collagen

deposition [28].

5. Conclusion

Thermal injury leads to a systemic catabolic response with

adverse effects on glucose homeostasis and muscle protein

balance. Morbidity and mortality outcomes in critically ill

patients, including burn patients, depend in part on the

control of these metabolic changes. Numerous strategies,

including nutritional support and treatment with anabolic

hormones, have been examined in an effort to reverse the

catabolic response to burn injury. Intensive insulin therapy in

the ICU setting has been shown to reduce patient morbidity

and mortality and is being widely used in surgical patients.

Although problematic in burn patients, intensive insulin

therapy holds the potential to reduce the incidence of

complications such as sepsis through improved glycemic

control, and may improve overall outcomes in critically ill

burn patients.

Conflict of interest

None of the authors have anything to disclose.

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