burns 36 (2010) 599–605 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/burnsReviewGlucose metabolism in burn patients: The role of insulin andother endocrine hormonesNikiforos Ballian a, Atoosa Rabiee b,c, Dana K. Andersen b, Dariush Elahi b,c,*, B. Robert Gibson ba Department of Surgery, University of Wisconsin, Madison, WI, United Statesb Department of Surgery, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, United Statesc Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, United Statesarticle info abstractArticle history: Severe burn causes a catabolic response with profound effects on glucose and muscleAccepted 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 andKeywords: mortality. In critically ill surgical patients, obtaining tight glycemic control with intensiveInsulin insulin therapy was shown to reduce morbidity and mortality and has increasingly becomeGLP-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: email@example.com (D. Elahi).0305-4179/$36.00 # 2009 Elsevier Ltd and ISBI. All rights reserved.doi:10.1016/j.burns.2009.11.008
600 burns 36 (2010) 599–605 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6031. Introduction regulating glucose metabolism and have complex effects (Table 1). The main contributors to burn-induced hyperglycemiaDespite advances in the resuscitation and surgical treatment are increased gluconeogenesis and insulin resistance [9–11].of burn patients, metabolic dysfunction remains a signiﬁcantcause of morbidity and mortality . Signiﬁcant thermal injury 2.1. Gluconeogenesisis characterized by hypermetabolism and catabolism propor-tional to burn surface area. This metabolic proﬁle includes Enhanced gluconeogenesis primarily occurs in the liver and itschanges 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 inlong as three years later . Healing of burn wounds is an burn patients [12,13] and its main substrates are amino acidsanabolic process which consumes massive amounts of amino derived from muscle catabolism and lactate produced by theacids, supplied by breakdown of skeletal muscle [3–5]. burn wound itself [12,13]. Although in vivo studies have shownHyperglycemia and loss of muscle mass that are attendant an increase in hepatic gluconeogenesis [14–16], Yamaguchiwith catabolism have a central role in determining the and coworkers showed that gluconeogenesis in isolatedprognosis of these patients . perfused rat livers after burn is not increased compared to Insulin therapy has been shown to reduce mortality and sham-burned animals . Hence, it seems that increasedmorbidity in surgical patients  and has both anti-hyperglyce- gluconeogenesis does not result from intrinsic hepaticmic and anabolic effects in muscle. Although the role of insulin changes, but from the release of systemic mediators thatin 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 andpatients 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 ofmight conclude that the most robust clinical beneﬁt of insulin gluconeogenesis . On the other hand, catecholamines do nottreatment in terms of a potential reduction in morbidity and seem to contribute to increased glucose production, sincemortality may be obtained in the burn population. In this review, adrenergic blockade potentiates glucose production . Ofwe present an overview of glucose regulation after burn injury note, glucose oxidation is increased after thermal injury andand describe the role of insulin and other endocrine hormones does not contribute to increased gluconeogenesis .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 opposing2. Glucose metabolism in burn patients metabolic pathways, is increased 2.5-fold, leading to increased energy expenditure . Although one would expect increasedGlucose metabolism is altered after signiﬁcant burn, leading to gluconeogenesis to cause a net increase in hepatic glucosehyperglycemia [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  " Glycogenolysis  # Glycogenesis Catecholamines " " Gluconeogenesis Insulin resistance  " Glycogenolysis  Impaired glucose transport  Corticosteroids " " Gluconeogenesis Insulin resistance  TNF " Altered insulin signaling  IL-6 " Altered insulin signaling  MCP-1 " Altered insulin signaling  Growth hormone " Improved glucose disposal " IGF-1  # Gluconeogenesis  IGF-1 – Improved glucose disposal Reduced insulin secretion  TNF, tumor necrosis factor; IL, interleukin; MCP, monocyte chemotactic protein; IGF, insulin-like growth factor.
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 begluconeogenesis was signiﬁcantly upregulated and glucose involved. Impairment of the immune system and an increasedwas diverted to the pentose phosphate pathway to support the risk of infection have been demonstrated, and there isproduction of antioxidants . Hence, the net glucose output evidence that these effects result from leukocyte dysfunction,was not increased compared to control animals . changes in immunoglobulin structure, proinﬂammatory changes and leukopenia [32–34]. Particularly important in2.2. 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. The ﬁrst 48 h after thermal injury (‘ebb’ phase) are elucidated at the cellular and molecular level. Hyperglycemiacharacterized by decreased metabolic rate and soon give way contributes to endothelial dysfunction, one of the mainto hypermetabolism (‘ﬂow’ phase) accompanied by hyper- pathways to organ failure in critical illness. Endothelialinsulinemia and hyperglycemia, the hallmark of insulin dysfunction leads to activation of the inﬂammatory response,resistance . 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 tooppose insulin action, among which are glucagon, corticos- organ hypoperfusion [32,37]. Langouche et al showed thatteroids and catecholamines . Insulin resistance results correction of hyperglycemia in critically ill patients reducesboth from reduced insulin-mediated glucose uptake in endothelial activation by suppressing production of inducibleskeletal muscle and by loss of muscle mass, the most nitric oxide synthase, a key enzyme in nitric oxide productionimportant tissue for glucose disposal [9,25]. Indeed, there is and endothelial activation . Furthermore, in an animalevidence that cytokine release after burn injury can reduce model of burn, Vanhorebeek et al. demonstrated thatglucose uptake by skeletal muscle . Perhaps the most hyperglycemia impairs mitochondrial function despite ade-important contributor to insulin resistance is muscle wasting. quate tissue oxygenation and perfusion . In their study,Other studies suggest an increased rate of glucose uptake by hyperglycemia was shown to upregulate glycolysis, leading totissues other than skeletal muscle, such as skin, wound and accumulation of excessive amounts of metabolites whichintestine . were toxic to mitochondria . Interestingly, this effect of Although insulin seems to retain its biological effective- hyperglycemia was more pronounced in the presence ofness in burn patients, there is signiﬁcant evidence of insulin hyperinsulinemia.resistance in response to injury , which tends to progress Besides causing hyperglycemia, thermal injury has directwith time . Studies in animal models on the molecular effects on glucose utilization by tissues and organs. In anbasis of burn-induced insulin resistance have revealed animal model of burn, deregulated expression of enzymes anddefects in activation of the insulin receptor itself and of transporters involved in glucose uptake and utilization causeddownstream intracellular pathways which are activated by dysfunction of muscle mitochondria .insulin binding to its receptors . Akt/PKB is an intracellularenzyme responsible for glucose uptake and glycogen synthe-sis that is activated by insulin . Akt/PKB activation by 4. Pharmacological agents and burn-relatedinsulin in skeletal muscle is impaired following burn and may metabolic abnormalitiesbe involved in the impaired metabolism and muscle wastingfound in these patients . However, insulin administration 4.1. Insulin therapyfollowing burn increases protein turnover but does not resultin 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 morbiditydifferent response to insulin therapy than healthy volun- and mortality in critically ill adults and children [40–42]. Inteers. Sakurai et al. found that 7-day systemic high-dose response to the deleterious effects of hyperglycemia, insulininsulin infusion increased muscle proteolysis in burn patients treatment has been the mainstay of glucose control in theand attributed this paradox to adaptation to hyperinsuline- critically ill .mia . These investigators hypothesized that insulin acutely Intravenous insulin infusion inhibits proteolysis, an effectstimulates protein synthesis, leading to depletion of the which is maximal in the splanchnic region and less potent inintracellular amino acid pool, and that this acute phase is skeletal muscle . In addition, insulin administrationthen followed by stimulation of proteolysis to maintain stimulates protein synthesis and intracellular transport ofintracellular amino acid concentrations during prolonged certain amino acids . These effects are dependent not onlyinsulin infusion . 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 prevent3. 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 . Multiple mechanisms for ingly, the beneﬁcial effects of insulin on muscle protein are
602 burns 36 (2010) 599–605maintained during prolonged administration, resulting inimproved outcomes, such as reduced hospital stay . In a landmark study by van den Berghe et al. of surgical ICUpatients, intensive glycemic control with insulin to a serumglucose goal of 80–110 mg/dl signiﬁcantly reduced mortalityand morbidity, regardless of patient diabetic status .Insulin therapy also improved intermediate measures ofmorbidity such as: length of ICU stay, duration of ventilatorysupport, need for renal replacement therapy and the incidenceof critical illness polyneuropathy and septicemia. This studydid include burn patients, however their number was toosmall to allow outcome extrapolations for this subgroup .In the immediate period following burn, hyperglycemia isprevalent and frequently inadequately treated, despite evi-dence that it is associated with increased mortality .Subsequently, van den Burghe and colleagues concluded thatthe mechanism of insulin’s beneﬁt is likely due to theestablishment and maintenance of normoglycemia ratherthan a direct effect of insulin [49,50]. However, insulin has Fig. 1 – Scatter plot of third day average glucose level as adirect effects unrelated to glucose homeostasis that are function of age and glycemic control with regard to followbeneﬁcial 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 inpatients with cardiac or cerebral ischemia . Insulin has acute cardiac ischemia treated with intravenous insulin tobeen shown to regulate the systemic inﬂammatory response maintain normoglycemia  (126–196 mg/dl). In addition,to critical illness, which is thought to be important in reducing hypoglycemia was more frequently observed in severelymulti-organ dysfunction in critically ill patients [51,52]. Insulin burned children receiving insulin therapy to maintainmarkedly reduces the hepatic acute phase response, which is normoglycemia . In a separate study of intensive insulinimplicated in the systemic inﬂammatory reaction and therapy in burn patients, the incidence of hypoglycemia wascatabolic response after thermal injury [53,54]. Jeschke et al. 5% and did not result in signiﬁcance adverse effects .demonstrated that insulin therapy signiﬁcantly improves Although the authors of the above studies concluded thathepatic morphology and function in rat models of burn and intensive insulin therapy is safe, hypoglycemia is a signiﬁcantendotoxemia [55,56]. Although the role of insulin in main- problem even in an ICU setting where blood glucose can betaining 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 theirtherapy was shown to be successful in achieving normogly- study of insulin therapy in severely burned children, Phamcemia in adult burn patients . 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 anto suspect a clinical beneﬁt of tight glucose control achieved by intravenous insulin infusion when serum glucose remainedinsulin infusion therapy in the adult burn population. In at levels considered ‘acceptable’ . They reported that,children with severe burns, Pham et al. found that intensive during the initial study period, ICU staff were concerned aboutglycemic control (90–120 mg/dl) achieved by insulin infusion insulin-induced hypoglycemia and tended to inappropriatelyreduces rates of urinary tract infection and overall mortality terminate insulin infusion, resulting in rebound hyperglyce-. In our own study of adult patients in the burn ICU and mia. In addition, further research into staff resistance to tightsurgical ICU, intensive insulin therapy which achieved a mean glycemic control protocols has been likened to selling ‘‘rootblood glucose level of no more than 150 mg/dl by day 3 of the canals’’ to the ICU staff . Hence, a signiﬁcant ‘learninginfusion was shown to have a similar survival beneﬁt in the curve’ occurs during implementation of intensive insulinburn population as in the mixed surgical ICU population  therapy .(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 resultsthose with severe burn, insulin therapy is not without risk. in a mandated suspension of the insulin infusion duringVan den Berghe et al. found that the incidence of hypoglyce- anesthesia. This is counter-productive in that reboundmia was up to eight times greater in patients receiving hyperglycemia frequently occurs with suspension of theintensive insulin therapy than in controls . In a second insulin infusion. In cardiac surgery patients, intra-operativestudy by Van den Berghe et al. in medical ICU patients, insulin therapy has been found to be safe and effective inhypoglycemia was identiﬁed as an independent risk factor for maintaining euglycemia, and is thought to be an importantdeath and possibly reduced the beneﬁcial effect of insulin in component of achieving and maintaining euglycemia . Inthe treatment arm of the study [47,60]. Despite improved addition, the frequent use of enteral tube feeding in burnmortality, hypoglycemia occurred in 18% of patients with patients makes intensive insulin therapy more problematic,
burns 36 (2010) 599–605 603particularly if the enteral feedings are temporarily suspended numerous metabolic abnormalities present in this patientduring operative procedures. Despite these aspects of routine population. In a recent randomized trial, fenoﬁbrate, a PPAR-gburn care, insulin infusions can be maintained with appropri- agonist, was shown to improve insulin-mediated glucoseate 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 . In addition,istration is hepatic injury. Burned patients are predisposed to growth hormone and insulin-like growth factor-1 therapyhepatic steatosis, even in the absence of insulin and glucose have been studied for their potential anabolic effects and havetherapy. Contributing factors are thought to include: insulin- been associated with decreased mortality in burn patients. It isinduced hepatic lipogenesis, increased hepatic delivery of unknown whether this clinical beneﬁt arises through anglucose, and increased fatty acid release from adipose tissue anabolic effect or through an insulin-mediated effect .[7,64,65]. Importantly, in studies that used continuous insulin Finally, despite its lack of direct effects on glucoseinfusion at 28 units/h, caloric needs in the form of glucose metabolism, oxandrolone stimulates protein synthesis andincreased 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 stayconcurrent infusion of insulin, directing excess glucose to [45,72,73]. Unfortunately, a prolonged ventilation requirementtissues with insulin-dependent glucose uptake such as skeletal is a potential concern with oxandrolone administration . Inmuscle and adipose tissue, and not to the liver, where glucose one study, where oxandrolone administration was found touptake is insulin-independent and proportional to portal vein prolong the need for ventilatory support, it was proposed thatglucose levels. It appears that when normoglycemia is main- the prolongation was due to increased pulmonary collagentained, burn patients do not get hepatic steatosis . A recent deposition .study showed that insulin can protect the liver from alcohol-induced steatosis in burn patients . Elevated blood alcohol iscommon in patients with burns and contributes to hepatic 5. Conclusionsteatosis, which can progress to severe hepatic dysfunction .Of note, both insulin-induced peripheral glucose uptake and its Thermal injury leads to a systemic catabolic response withconversion to triglycerides were found to be normal in burn adverse effects on glucose homeostasis and muscle proteinpatients [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 theto 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 anaboliccaloric demands . Since most of the observed beneﬁt of insulin hormones, have been examined in an effort to reverse thetherapy results from maintaining normoglycemia [49,50], low- catabolic response to burn injury. Intensive insulin therapy indose insulin therapy which does not result in euglycemia would the ICU setting has been shown to reduce patient morbiditybe expected to have reduced impact on overall outcomes. and mortality and is being widely used in surgical patients. Although problematic in burn patients, intensive insulin4.2. Metformin therapy holds the potential to reduce the incidence of complications such as sepsis through improved glycemicThe role of metformin has been examined in an effort to reduce control, and may improve overall outcomes in critically illhyperglycemic complications in the immediate post-burn burn patients.period, while attempting to avoid the attendant risk ofhypoglycemia noted with intensive insulin therapy. Metforminacts by reducing hepatic gluconeogenesis and improving Conﬂict of interestperipheral insulin sensitivity, which are the most signiﬁcantpathophysiologic alterations responsible for hyperglycemia None of the authors have anything to disclose.following burn injury . In addition, there is evidence thatmetformin acts by an additional mechanism in burn patients: referencesthe augmentation of endogenous insulin release . A parti-cularly appealing advantage of metformin is its ability to achievenormoglycemia without the need of frequent glucose monitor-  Ipaktchi K, Arbabi S. 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