1. burns 36 (2010) 599–605
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/burns
Review
Glucose metabolism in burn patients: The role of insulin and
other endocrine hormones
Nikiforos Ballian a, Atoosa Rabiee b,c, Dana K. Andersen b, Dariush Elahi b,c,*, B. Robert Gibson b
a
Department of Surgery, University of Wisconsin, Madison, WI, United States
b
Department of Surgery, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, United States
c
Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, United States
article info abstract
Article history: Severe burn causes a catabolic response with profound effects on glucose and muscle
Accepted 11 November 2009 protein metabolism. This response is characterized by hyperglycemia and loss of muscle
mass, both of which have been associated with significantly increased morbidity and
Keywords: mortality. In critically ill surgical patients, obtaining tight glycemic control with intensive
Insulin insulin therapy was shown to reduce morbidity and mortality and has increasingly become
GLP-1 the standard of care. In addition to its well-known anti-hyperglycemic action and reduc-
Burn ICU tion in infections, insulin promotes muscle anabolism and regulates the systemic inflam-
Glycemic control 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.
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
* 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.
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

2. 600 burns 36 (2010) 599–605
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
1. Introduction regulating glucose metabolism and have complex effects
(Table 1). The main contributors to burn-induced hyperglycemia
Despite advances in the resuscitation and surgical treatment are increased gluconeogenesis and insulin resistance [9–11].
of burn patients, metabolic dysfunction remains a significant
cause of morbidity and mortality [1]. Significant thermal injury 2.1. Gluconeogenesis
is characterized by hypermetabolism and catabolism propor-
tional to burn surface area. This metabolic profile includes Enhanced gluconeogenesis primarily occurs in the liver and its
changes in glucose homeostasis and muscle protein metabo- purpose is to increase energy supply to the wound. Gluconeo-
lism that persist from the first few days following injury to as genesis accounts for 11% of increased energy expenditure in
long as three years later [2]. Healing of burn wounds is an burn patients [12,13] and its main substrates are amino acids
anabolic process which consumes massive amounts of amino derived from muscle catabolism and lactate produced by the
acids, supplied by breakdown of skeletal muscle [3–5]. burn wound itself [12,13]. Although in vivo studies have shown
Hyperglycemia and loss of muscle mass that are attendant an increase in hepatic gluconeogenesis [14–16], Yamaguchi
with catabolism have a central role in determining the and coworkers showed that gluconeogenesis in isolated
prognosis of these patients [1]. perfused rat livers after burn is not increased compared to
Insulin therapy has been shown to reduce mortality and sham-burned animals [15]. Hence, it seems that increased
morbidity in surgical patients [6] and has both anti-hyperglyce- gluconeogenesis does not result from intrinsic hepatic
mic and anabolic effects in muscle. Although the role of insulin changes, but from the release of systemic mediators that
in maintaining muscle mass after burn has been investigated act on the liver [8,17,18]. In critical illness, systemic mediators
[6,7], the potential influence on mortality is unknown. Since of gluconeogenesis include glucagon, catecholamines and
patients with significant burns have the most intense and corticosteroids. Specifically in the setting of burn injury,
prolonged catabolic response of all ‘surgical’ ICU patients, one glucagon has been shown to be a significant stimulator of
might conclude that the most robust clinical benefit of insulin gluconeogenesis [8]. On the other hand, catecholamines do not
treatment in terms of a potential reduction in morbidity and seem to contribute to increased glucose production, since
mortality may be obtained in the burn population. In this review, adrenergic blockade potentiates glucose production [19]. Of
we present an overview of glucose regulation after burn injury note, glucose oxidation is increased after thermal injury and
and describe the role of insulin and other endocrine hormones does not contribute to increased gluconeogenesis [11].
in improving glycemic control and reversing catabolism. Increased gluconeogenesis after burn is characterized by
inefficient use of metabolic substrates. For example, the total
rate of gluconeogenesis and glycolysis, which are opposing
2. Glucose metabolism in burn patients metabolic pathways, is increased 2.5-fold, leading to increased
energy expenditure [20]. Although one would expect increased
Glucose metabolism is altered after significant burn, leading to gluconeogenesis to cause a net increase in hepatic glucose
hyperglycemia [8,9]. Numerous mediators are involved in production, some studies have shown this not to be the case
Table 1 – Endocrine mediators of glucose regulation in burn patients.
Mediator Levels Direct effects Indirect effects References
Insulin " # Gluconeogenesis
# Glycogenolysis
Glucagon " " Gluconeogenesis Insulin resistance [73]
" Glycogenolysis [73]
# Glycogenesis
Catecholamines " " Gluconeogenesis Insulin resistance [74]
" Glycogenolysis [74]
Impaired glucose transport [75]
Corticosteroids " " Gluconeogenesis Insulin resistance [76]
TNF " Altered insulin signaling [77]
IL-6 " Altered insulin signaling [77]
MCP-1 " Altered insulin signaling [78]
Growth hormone " Improved glucose disposal " IGF-1 [79]
# Gluconeogenesis [80]
IGF-1 – Improved glucose disposal Reduced insulin secretion [81]
TNF, tumor necrosis factor; IL, interleukin; MCP, monocyte chemotactic protein; IGF, insulin-like growth factor.

3. burns 36 (2010) 599–605 601
[18,21]. In an animal model of burn, Lee et al found that this increased morbidity and mortality are thought to be
gluconeogenesis was significantly upregulated and glucose involved. Impairment of the immune system and an increased
was diverted to the pentose phosphate pathway to support the risk of infection have been demonstrated, and there is
production of antioxidants [21]. Hence, the net glucose output evidence that these effects result from leukocyte dysfunction,
was not increased compared to control animals [21]. changes in immunoglobulin structure, proinflammatory
changes and leukopenia [32–34]. Particularly important in
2.2. Insulin resistance burn patients are the defects in wound and skin graft healing,
and increased muscle catabolism associated with hypergly-
Insulin resistance is a critical part of the etiology of cemia [5,9,33,35,36].
hyperglycemia after burn and its etiology is poorly understood Some of the deleterious effects of hyperglycemia have been
[22]. The first 48 h after thermal injury (‘ebb’ phase) are elucidated at the cellular and molecular level. Hyperglycemia
characterized by decreased metabolic rate and soon give way contributes to endothelial dysfunction, one of the main
to hypermetabolism (‘flow’ phase) accompanied by hyper- pathways to organ failure in critical illness. Endothelial
insulinemia and hyperglycemia, the hallmark of insulin dysfunction leads to activation of the inflammatory response,
resistance [23]. Insulin resistance is thought to be mediated platelet degranulation and coagulopathy [32,37,38]. In turn,
by local and systemic release of hormones and factors that these effects create a prothrombotic state that contributes to
oppose insulin action, among which are glucagon, corticos- organ hypoperfusion [32,37]. Langouche et al showed that
teroids and catecholamines [24]. Insulin resistance results correction of hyperglycemia in critically ill patients reduces
both from reduced insulin-mediated glucose uptake in endothelial activation by suppressing production of inducible
skeletal muscle and by loss of muscle mass, the most nitric oxide synthase, a key enzyme in nitric oxide production
important tissue for glucose disposal [9,25]. Indeed, there is and endothelial activation [38]. Furthermore, in an animal
evidence that cytokine release after burn injury can reduce model of burn, Vanhorebeek et al. demonstrated that
glucose uptake by skeletal muscle [26]. Perhaps the most hyperglycemia impairs mitochondrial function despite ade-
important contributor to insulin resistance is muscle wasting. quate tissue oxygenation and perfusion [10]. In their study,
Other studies suggest an increased rate of glucose uptake by hyperglycemia was shown to upregulate glycolysis, leading to
tissues other than skeletal muscle, such as skin, wound and accumulation of excessive amounts of metabolites which
intestine [24]. were toxic to mitochondria [10]. Interestingly, this effect of
Although insulin seems to retain its biological effective- hyperglycemia was more pronounced in the presence of
ness in burn patients, there is significant evidence of insulin hyperinsulinemia.
resistance in response to injury [17], which tends to progress Besides causing hyperglycemia, thermal injury has direct
with time [27]. Studies in animal models on the molecular effects on glucose utilization by tissues and organs. In an
basis of burn-induced insulin resistance have revealed animal model of burn, deregulated expression of enzymes and
defects in activation of the insulin receptor itself and of transporters involved in glucose uptake and utilization caused
downstream intracellular pathways which are activated by dysfunction of muscle mitochondria [39].
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 4. Pharmacological agents and burn-related
insulin in skeletal muscle is impaired following burn and may metabolic abnormalities
be involved in the impaired metabolism and muscle wasting
found in these patients [28]. However, insulin administration 4.1. Insulin therapy
following burn increases protein turnover but does not result
in a positive protein balance [29,30]. To further complicate Peak serum glucose concentrations and duration of hypergly-
muscle protein dynamics, burn patients seem to have a cemia are independently associated with increased morbidity
different response to insulin therapy than healthy volun- and mortality in critically ill adults and children [40–42]. In
teers. Sakurai et al. found that 7-day systemic high-dose response to the deleterious effects of hyperglycemia, insulin
insulin infusion increased muscle proteolysis in burn patients treatment has been the mainstay of glucose control in the
and attributed this paradox to adaptation to hyperinsuline- critically ill [43].
mia [7]. These investigators hypothesized that insulin acutely Intravenous insulin infusion inhibits proteolysis, an effect
stimulates protein synthesis, leading to depletion of the which is maximal in the splanchnic region and less potent in
intracellular amino acid pool, and that this acute phase is skeletal muscle [44]. In addition, insulin administration
then followed by stimulation of proteolysis to maintain stimulates protein synthesis and intracellular transport of
intracellular amino acid concentrations during prolonged certain amino acids [45]. These effects are dependent not only
insulin infusion [7]. 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
3. Deleterious effects of hyperglycemia muscle proteolysis due to depletion of the intracellular amino
acid pool and decreases in intracellular amino acid transport.
Despite its uncertain pathogenesis, hyperglycemia in the The net effect of exogenous insulin and amino acid adminis-
immediate post-burn injury period is associated with in- tration is to create a net positive nitrogen balance. Interest-
creased morbidity and mortality [31]. Multiple mechanisms for ingly, the beneficial effects of insulin on muscle protein are

4. 602 burns 36 (2010) 599–605
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 Fig. 1 – Scatter plot of third day average glucose level as a
direct effects unrelated to glucose homeostasis that are function of age and glycemic control with regard to follow
beneficial in critically ill patients. In the critically ill cardiac up outcome of sepsis and mortality.
surgery population, infusion of glucose, insulin and potassium
(GIK) improves cardiovascular and cerebral function in
patients with cardiac or cerebral ischemia [32]. Insulin has acute cardiac ischemia treated with intravenous insulin to
been shown to regulate the systemic inflammatory response maintain normoglycemia [61] (126–196 mg/dl). In addition,
to critical illness, which is thought to be important in reducing hypoglycemia was more frequently observed in severely
multi-organ dysfunction in critically ill patients [51,52]. Insulin burned children receiving insulin therapy to maintain
markedly reduces the hepatic acute phase response, which is normoglycemia [58]. In a separate study of intensive insulin
implicated in the systemic inflammatory reaction and therapy in burn patients, the incidence of hypoglycemia was
catabolic response after thermal injury [53,54]. Jeschke et al. 5% and did not result in significance adverse effects [57].
demonstrated that insulin therapy significantly improves Although the authors of the above studies concluded that
hepatic morphology and function in rat models of burn and intensive insulin therapy is safe, hypoglycemia is a significant
endotoxemia [55,56]. Although the role of insulin in main- problem even in an ICU setting where blood glucose can be
taining muscle mass after burn has been investigated [6,7], the closely monitored.
potential benefit on other outcomes in burn patients, includ- Furthermore, there are significant barriers to implement-
ing mortality, is unknown. In a recent study, intensive insulin ing intensive insulin protocols in the ICU. For instance, in their
therapy was shown to be successful in achieving normogly- study of insulin therapy in severely burned children, Pham
cemia in adult burn patients [57]. et al. emphasized the difficulty of convincing health care
Despite the absence of published trials, there is good reason professionals of the need to maintain subjects on an
to suspect a clinical benefit of tight glucose control achieved by intravenous insulin infusion when serum glucose remained
insulin infusion therapy in the adult burn population. In at levels considered ‘acceptable’ [58]. They reported that,
children with severe burns, Pham et al. found that intensive during the initial study period, ICU staff were concerned about
glycemic control (90–120 mg/dl) achieved by insulin infusion insulin-induced hypoglycemia and tended to inappropriately
reduces rates of urinary tract infection and overall mortality terminate insulin infusion, resulting in rebound hyperglyce-
[58]. In our own study of adult patients in the burn ICU and mia. In addition, further research into staff resistance to tight
surgical ICU, intensive insulin therapy which achieved a mean glycemic control protocols has been likened to selling ‘‘root
blood glucose level of no more than 150 mg/dl by day 3 of the canals’’ to the ICU staff [62]. Hence, a significant ‘learning
infusion was shown to have a similar survival benefit in the curve’ occurs during implementation of intensive insulin
burn population as in the mixed surgical ICU population [59] therapy [58].
(Fig. 1). In burn patients, the frequent need to return to the
While potentially beneficial in critically ill patients and operating room for grafting and other procedures often results
those with severe burn, insulin therapy is not without risk. in a mandated suspension of the insulin infusion during
Van den Berghe et al. found that the incidence of hypoglyce- anesthesia. This is counter-productive in that rebound
mia was up to eight times greater in patients receiving hyperglycemia frequently occurs with suspension of the
intensive insulin therapy than in controls [47]. In a second insulin infusion. In cardiac surgery patients, intra-operative
study by Van den Berghe et al. in medical ICU patients, insulin therapy has been found to be safe and effective in
hypoglycemia was identified as an independent risk factor for maintaining euglycemia, and is thought to be an important
death and possibly reduced the beneficial effect of insulin in component of achieving and maintaining euglycemia [63]. In
the treatment arm of the study [47,60]. Despite improved addition, the frequent use of enteral tube feeding in burn
mortality, hypoglycemia occurred in 18% of patients with patients makes intensive insulin therapy more problematic,

5. burns 36 (2010) 599–605 603
particularly if the enteral feedings are temporarily suspended numerous metabolic abnormalities present in this patient
during operative procedures. Despite these aspects of routine population. In a recent randomized trial, fenofibrate, a PPAR-g
burn care, insulin infusions can be maintained with appropri- agonist, was shown to improve insulin-mediated glucose
ate attention to frequent blood glucose determinations. disposal and insulin-mediated inhibition of hepatic glucose
Another potential concern with insulin and glucose admin- release in children with significant burns [70]. In addition,
istration is hepatic injury. Burned patients are predisposed to growth hormone and insulin-like growth factor-1 therapy
hepatic steatosis, even in the absence of insulin and glucose have been studied for their potential anabolic effects and have
therapy. Contributing factors are thought to include: insulin- been associated with decreased mortality in burn patients. It is
induced hepatic lipogenesis, increased hepatic delivery of unknown whether this clinical benefit arises through an
glucose, and increased fatty acid release from adipose tissue anabolic effect or through an insulin-mediated effect [71].
[7,64,65]. Importantly, in studies that used continuous insulin Finally, despite its lack of direct effects on glucose
infusion at 28 units/h, caloric needs in the form of glucose metabolism, oxandrolone stimulates protein synthesis and
increased twofold, however; hepatic steatosis did not occur has proven benefits in burn patients, including improved
[7,66]. The authors attributed this absence of steatosis to the wound healing and decreased hospital length of stay
concurrent infusion of insulin, directing excess glucose to [45,72,73]. Unfortunately, a prolonged ventilation requirement
tissues with insulin-dependent glucose uptake such as skeletal is a potential concern with oxandrolone administration [28]. In
muscle and adipose tissue, and not to the liver, where glucose one study, where oxandrolone administration was found to
uptake is insulin-independent and proportional to portal vein prolong the need for ventilatory support, it was proposed that
glucose levels. It appears that when normoglycemia is main- the prolongation was due to increased pulmonary collagen
tained, burn patients do not get hepatic steatosis [66]. A recent deposition [28].
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 5. Conclusion
steatosis, which can progress to severe hepatic dysfunction [67].
Of note, both insulin-induced peripheral glucose uptake and its Thermal injury leads to a systemic catabolic response with
conversion to triglycerides were found to be normal in burn adverse effects on glucose homeostasis and muscle protein
patients [7,68]. balance. Morbidity and mortality outcomes in critically ill
Unfortunately, low-dose insulin therapy has not been found patients, including burn patients, depend in part on the
to prevent hyperglycemia in burn patients and does not affect control of these metabolic changes. Numerous strategies,
muscle glucose uptake; therefore, it does not change patient including nutritional support and treatment with anabolic
caloric demands [6]. Since most of the observed benefit of insulin hormones, have been examined in an effort to reverse the
therapy results from maintaining normoglycemia [49,50], low- catabolic response to burn injury. Intensive insulin therapy in
dose insulin therapy which does not result in euglycemia would the ICU setting has been shown to reduce patient morbidity
be expected to have reduced impact on overall outcomes. and mortality and is being widely used in surgical patients.
Although problematic in burn patients, intensive insulin
4.2. Metformin therapy holds the potential to reduce the incidence of
complications such as sepsis through improved glycemic
The role of metformin has been examined in an effort to reduce control, and may improve overall outcomes in critically ill
hyperglycemic complications in the immediate post-burn burn patients.
period, while attempting to avoid the attendant risk of
hypoglycemia noted with intensive insulin therapy. Metformin
acts by reducing hepatic gluconeogenesis and improving Conflict of interest
peripheral insulin sensitivity, which are the most significant
pathophysiologic alterations responsible for hyperglycemia None of the authors have anything to disclose.
following burn injury [69]. In addition, there is evidence that
metformin acts by an additional mechanism in burn patients:
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