AJP - Endo Watch the video to learn how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 294: E1-E9, 2008. First published October 23, 2007; doi:10.1152/ajpendo.00562.2007
0193-1849/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/1/E1    most recent
00562.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cree, M. G.
Right arrow Articles by Wolfe, R. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cree, M. G.
Right arrow Articles by Wolfe, R. R.

INVITED REVIEW

Postburn trauma insulin resistance and fat metabolism

Melanie G. Cree and Robert R. Wolfe

Donald W. Reynolds Institute on Aging, Little Rock, Arkansas


   ABSTRACT
TOP
 ABSTRACT
GRANTS
 REFERENCES
 
Hyperglycemia and insulin resistance have long been recognized in severe burn patients. More recently, it has been observed that controlling hyperglycemia, or alleviating insulin resistance, is associated with improved outcomes. This has led to a renewed interest in the etiology of insulin resistance in this population. The postinjury hyperglycemic response appears to be associated with multiple metabolic abnormalities, such as elevated basal energy expenditure, increased protein catabolism, and, notably, significant alterations in fat metabolism. The synergy of all of the responses is not understood, although many studies have been conducted. In this article we will review the present understanding of the relationship between fat metabolism and insulin resistance posttrauma, and discuss some of the recent discoveries and potential therapeutic measures. We propose that the insulin resistance is likely related to the development of "ectopic" fat stores, i.e., triglyceride (TG) storage in sites such as the liver and muscle cells. Deposition of TG in ectopic sites is due to an increase in free fatty acid delivery secondary to catecholamine-induced lipolysis, in conjunction with decreased β-oxidation within muscle and decreased hepatic secretion of fats. The resultant increases in intracellular TG or related lipid products may in turn contribute to alterations in insulin signaling.

burn trauma, glucose metabolism; intracellular triglycerides

MULTIPLE STUDIES HAVE DOCUMENTED hyperglycemia and insulin resistance posttrauma (32, 50, 109). Several studies have used hyperinsulinemic-euglycemic clamps to quantify the level of insulin resistance in trauma patients. Adult trauma patients had one-half the glucose uptake during hyperinsulinemia compared with healthy controls (68). Black et al. (12) found that, at approximately 1 wk postinjury, glucose uptake in response to four varied levels of insulin was impaired by at least one-third compared with controls. We recently found that within 1 wk postburn, insulin-stimulated glucose uptake was one-half of that in severely burned children compared with healthy children (24). The insulin resistance seen with injury is, largely, not due to the inactivity imposed by the injury, as patients undergoing surgery had decreased whole body glucose uptake and increased hepatic glucose release during a hyperinsulinemic clamp compared with healthy subjects confined to strict bed rest, although there were minor alteration in glucose metabolism following 7 days of bed rest in healthy individuals (79, 89). Therefore, severe insulin resistance in these patients is a direct consequence of the trauma.

Insulin resistance in these patients is of serious clinical concern, as several studies indicate that insulin resistance and related liver dysfunction may be implicated in increasing the morbidity and mortality of surgical and burned patients (38, 98–100, 104). Retrospective reviews have indicated that burned patients with higher plasma glucose levels over the duration of care have increased mortality (40, 48). Furthermore, the degree of hyperglycemia in the first 48 h is also correlated with mortality (48). In burn patients, higher plasma glucose levels are associated with increased graft loss and sepsis (40, 76). These outcome studies underscore the importance of a better understanding of insulin resistance in this patient population.

Fat metabolism is also altered postburn; this may be related to changes in insulin resistance. Burn patients experience increases in lipolysis, inadequate increases in the β-oxidation of fats relative to energy needs, and deposition of triglycerides in "ectopic sites," or tissues other than adipose tissue, such as muscle and hepatic tissue (10, 73, 115). Recent studies in other models of insulin resistance, such as type 2 diabetes mellitus (T2DM), have found a strong relationship between fat and glucose metabolism (51, 83, 84). It appears that some, but not all, of the mechanisms found in this model can be found in burns. In this review, we will describe present research as it relates to muscle and hepatic insulin sensitivity and fat metabolism postburn trauma.

Whole Body Changes in Glucose and Fat Metabolism Postburn

Studies in burn trauma patients and animals have long indicated that there appear to be two distinct patterns of metabolic regulation following injury (111). The first phase occurs within the first 48 h from injury and has classically been called the "ebb phase" (28, 111). This phase of the response appears to be related to the magnitude of the trauma and the acute response hormones, including norepinephrine, epinephrine, dopamine, glucagon, and cortisol (33, 94, 95, 98, 116). The initial rise in plasma glucose after injury is seen within 30 min in guinea pigs, 2 h in rats, and 1 h in severely burned children (23, 33, 116). During this acute period, the hyperglycemia is not accompanied by an increase in insulin, perhaps because of the suppressive effect of epinephrine on insulin release (5, 23, 108).

Plasma free fatty acid concentrations immediately following burn injury are variable and have been found to be increased, not changed, and decreased (Table 1). Early studies found that plasma free fatty acids (FFA) increased following burn in humans and animals (5, 106). Other studies found acutely decreased concentrations of FFA in animals. It was determined that the rise in plasma FFA is influenced by the existence of adipose tissue before injury and also the rate of blood flow to adipose tissue, which may vary depending on resuscitation methods (111). Despite the variable concentrations of plasma FFA following burn trauma, the overall cycling of FFA released from adipose triglyceride (TG) back into adipose TG is increased. This is due to the concurrent effects of catecholamines on hormone-sensitive lipase (HSL) to induced lipolysis and upregulated reesterification, partially stimulated by increased lactate concentrations (34, 111). This continuous cycle of breakdown and formation of TGs is often termed futile, as the FFA released are not used for energy production but rather continue to recycle through TG.


View this table:
[in this window]
[in a new window]

  		Table 1. Plasma hormones in T2DM vs. postburn trauma

 
The second phase of the metabolic response, lasting several weeks after injury, has been termed the "flow phase" (28, 46, 99, 111), although more recent studies indicate that this phase may continue in children for at least a year postburn (46). Initial studies in burned animals indicated that glucose uptake in response to exogenous insulin is decreased (103). Additionally, insulin release in trauma patients during this time period was found to be twice that of controls in response to a glucose load (12, 36). In burned children, although plasma glucose decreases after the initial spike, it remains above normal levels, and insulin progressively increases over time, indicating the development of an insulin-resistant state (23). Whereas catecholamines may play a role in this response, plasma cortisol levels begin to decline shortly after the initial injury (71). The persistence of insulin resistance during the flow phase could also be due in part to the catabolic decrease in muscle mass seen with severe injury, since skeletal muscle is responsible for 70–80% of whole body insulin-stimulated glucose uptake (29). Furthermore, 7 days of bed rest was accompanied by moderate decreases in insulin sensitivity and a 1–4% decrease in muscle mass (89).

Lipolysis is increased during the second phase of post-burn injury. Increased lipolysis can be attributed to increased adrenergic activity, as lipolysis is consistently reduced in patients treated acutely with β-adrenergic blockade (47, 114). However, the rate of lipolysis and catecholamines do not always correlate postinjury (36). For example, basal plasma palmitate turnover was significantly increased in trauma patients compared with controls, yet there was no relationship between epinephrine or norepinephrine levels and palmitate turnover (36). Part of the varied relation between catecholamines and the extent of the increase in lipolysis may be due to the amount of subcutaneous fat present following the initial trauma. Lipolysis was elevated in burned children who had the majority of fat removed in the course of surgical treatment of severe burns (fascial excision), but lipolysis was not further increased by infusion of exogenous epinephrine (115). In contrast, epinephrine infusion stimulated lipolysis to an even greater extent in patients in whom subcutaneous fat was maintained in the process of skin grafting (tangential excision). These findings indicate that surgical removal of a significant portion of the body fat limited the increase in whole body lipolysis.

Whereas lipolysis is increased after severe trauma, plasma FFA concentrations continue to be variable. For example, plasma FFA concentrations in adults with large burns were found to be within the normal range, although glycerol concentrations were elevated above normal for the first 20 days postburn (44). Glycerol is a direct reflection of lipolysis, because it cannot be reutilized for TG synthesis within the adipocyte once it is released. This is because the adipocyte does not contain glycerol kinase, which is necessary to convert glycerol to glycerol phosphate, which is the backbone of newly produced TG. In trauma patients, increased glycerol concentrations, but not FFA concentrations, correlated with the severity of the injury (95). Glycerol concentrations and turnover were increased significantly 6 days following total hip replacement surgery (16). Decreased plasma albumin levels following trauma may contribute to increased reesterification of fatty acids within adipocytes (64, 115). FFA are hydrophobic and are therefore bound to albumin in plasma. Because of the decreased concentrations of albumin, the ratio of FFA to albumin was elevated three- to fourfold in burned adults compared with healthy controls (44). It may be that the decreased albumin concentration limits the release of FFA, whereas glycerol can freely enter the plasma.

Intracellular FFA turnover is part of the FFA flux that comprises the futile cycle involving the breakdown of adipose and muscle TGs into FFA, their subsequent reesterification into very low-density lipoprotein (VLDL) or TG in the liver, and their ultimate reincorporation into adipocytes or muscle TG. For each intracellular TG molecule, HSL facilitates the release of one glycerol and three FFA (80). When all FFA are released and not reesterified within the cell, three FFA will be released for each one glycerol molecule. β-Adrenergic stimulation of muscle strips from burned animals increased glycerol release threefold but did not affect FFA release, indicating increased breakdown of stored TG coupled with increased FFA recycling within muscle cells (31). In burn patients, the rate of FFA release far exceeds the amount needed for energy use, so that much of the FFA is recycled in the liver and resecreted as VLDL-TG (3, 112). In healthy adults, the reesterification of FFA accounts for 65% of VLDL-TG release after 96 h of hyperglycemia (1). After bariatric surgery, the clearance of infused TGs by the periphery in obese patients was increased twofold, and was accompanied by increased plasma glucose and insulin levels (101). Thus the futile cycling of FFA is related to hyperglycemia, yet the nature of the relationship is not clear.

Tissue-Specific Interactions Between Glucose and Fat Metabolism

The primary sites of glucose regulation are hepatic and muscle tissue. Both of these tissues also have important roles in fat metabolism, and it could be that understanding the interaction of glucose and fat in these tissues is key to understanding insulin resistance. Whereas adipose tissue also plays an important role in insulin resistance, very little research has been performed on this tissue in trauma. The only study of note is one in rats that found increased adipocyte apoptosis at days 3 and 7 post-scald injury and an overall decreased fat mass at day 7 (118). Thus we will focus our discussion on muscle and hepatic metabolism.

Hepatic metabolism. The liver is a complex organ with multiple metabolic roles. The primary action of the liver in glucose metabolism is to help maintain steady concentrations of plasma glucose, with gluconeogenesis and glycogenolysis in the fasted state and glyconeogenesis in the fed state. In terms of fat metabolism, the liver utilizes FFA for ATP generation and also secretes plasma TG, VLDL, and multiple apolipoproteins found on cholesterol molecules. Hepatic insulin resistance is manifest by insulin failing to suppress glucose release and lipolysis.

Hyperglycemia immediately following burn injury appears to be due to increased gluconeogenesis and glycogenolysis in the liver, mediated in part by increased catecholamines via different mechanisms (116). Increased gluconeogenesis may be induced by the stimulation of cAMP by catecholamines. cAMP-dependent protein kinase inactivates pyruvate kinase, preventing glycolysis and causing a shift in liver metabolism toward gluconeogenesis (17). Furthermore, glucose release is not increased in isolated perfused livers from burned animals, indicating that the increased glucose output is secondary to extrahepatic signaling such as via catecholamines (18, 62). Catecholamines also stimulate p38 mitogen-activated protein kinase, causing the release of tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-1 (IL-1), which activate nuclear factor-{kappa}B (NF-{kappa}B) via IKK (19). NF-{kappa}B is also activated by saturated plasma FFA, elevated secondary to the catecholamines, via toll-like receptor-4 (57, 61). Once activated, NF-{kappa}B can cause apoptosis, and hepatocyte damage has been documented following burn trauma and serious illness (19, 53, 105). NF-{kappa}B also induces the production of IL-6, and this can cause increased hepatic glucose release and hepatic insulin resistance (54, 102). It may be that a combination of factors is necessary for increased hepatic metabolic rate in vivo, as glucagon and free radicals were necessary to induce metabolic rates similar to those seen in injury compared with either substance alone, and there are multiple pathways that could occur immediately following burn (63).

During the second phase of injury, the liver continues to release glucose at an increased rate because of increased gluconeogenesis, with amino acids from protein breakdown assuming an increased role as precursors (110). Hyperglycemia fails to suppress hepatic glucose release during this time (113). Furthermore, the suppressive effect of insulin on glucose release is attenuated, so that even high concentrations of insulin fail to suppress hepatic glucose release (27, 113). We found that hepatic glucose release was only suppressed 48% during hyperinsulinemia (27). The increased glucose release during this time contributes significantly to posttrauma hyperglycemia.

The increased delivery of FFA to the liver tissue can be shunted via several different metabolic pathways. FFA can be reesterified into VLDL and TG for secretion, oxidized for energy, or stored within hepatocytes as TG. This is due in part to decreased β-oxidation of FFA and decreased VLDL-TG secretion (74). In the presence of hyperglycemia, hepatic FFA uptake is increased, and FFA appear to be secreted in the form of TG and VLDL, since these increase and β-oxidation decreases (92). When these defects are coupled with the increased FFA release, hepatomegaly due to increased storage of TGs within the liver ensues. In healthy volunteers, large increases in carbohydrate feeding lead to increased fat accumulation in adipocytes, but in the liver, VLDL-TG synthesis increases, and there is no significant de novo fat synthesis in the liver (2). Pigs with 40% burns had increased liver fat due to decreased VLDL secretion and not to decreased oxidation or changes in FFA uptake (69).

By using spectroscopy, we found that hepatic TG (HTG) in burned children was similar to the amount we previously found in elderly subjects with insulin resistance (25, 26). Although we have not measured HTG in healthy children, it should be similar to that found in young adults, since the diagnostic criteria of steatohepatitis are the same for both ages. Thus measured HTG was likely increased three- to fourfold in children at week 1 postburn. It is possible HTG was elevated even before that time, as liver fat in pigs doubled within 4 days postburn (69). Liver size was found to nearly double in children postburn, but ultrasound was unable to determine whether this was due to fat deposition or venous congestion (11). These are the only studies performed on living children, although many autopsy studies have long documented increased hepatic TG postburn (9, 10, 67). The hepatic TG may be related to increased mortality, underlying the importance of documenting its presence in patients who recover from their injuries (72).

It may be that the increased TG within the liver is related to the inability of the liver to respond to insulin, since these two processes occur within the same time period following injury. It is likely that the mechanism is similar to that described below for muscle.

Myocyte metabolism. Muscle is one of the major sites of insulin resistance in T2DM. Glucose is normally transported from plasma to within the cell via glucose transporter-4 (GLUT-4). This protein relocates to the cell surface after insulin binds to the insulin receptor (IR), causing phosphorylation of the protein and initiating a signal cascade involving, but not limited to, tyrosine phosphorylation of insulin signaling receptor-1 (IRS-1), association of phosphatidylinositol 3-kinase with IRS-1, activation of AKT, and, eventually, mobilization of intracellular GLUT-4 stores. Patients with T2DM have decreased phosphorylation of the IR, decreased tyrosine phosphorylation of IRS-1, and decreased association of Akt with IRS-1 (39). Studies have shown that the IRS-1 protein becomes phosphorylated at a serine-307 site, by atypical protein kinase C (PKC), preventing tyrosine phosphorylation and decreasing the activity of IRS-1 (122). There are several PKC isoforms in muscle, and the atypical ones, named {alpha}, {varepsilon}, and {theta}, are thought to be metabolically active in relation to insulin resistance (88).

The alterations in the insulin signaling pathway following burn are similar to those seen in T2DM and are shown in Table 2 and Fig. 1. We found that, in children 7 days postburn, there is no increase in IR or IRS-1 phosphorylation in muscle after insulin stimulation, or IRS-1-associated AKT (27). These findings are similar to those in burned animals. For example, 3 days after a scald injury, rats injected with insulin and killed had no insulin stimulation of IR tyrosine phosphorylation, IRS-1 tyrosine phosphorylation, or phosphatidylinositol 3-kinase activation compared with controls (52). These animals also had a 30% decrease in glucose uptake in the basal state and no insulin-stimulated glucose uptake compared with controls. A similar study by the same investigators found that AKT activity also was attenuated by burns (97). Serine phosphorylation of IRS-1 was increased in rat muscle 7 days postburn (123). During fasting, there is little tyrosine phosphorylation in the absence of insulin stimulation. However, rats undergoing abdominal surgery have increased fasting basal phosphorylation of the signaling cascade, despite a decrease in insulin signaling (96). The authors speculate that an increased basal level of tyrosine phosphorylation could perhaps lead to a decreased effect of insulin compared with the basal state, because of a smaller change in phosphorylation state with new phosphorylation of proteins.


View this table:
[in this window]
[in a new window]

  		Table 2. Muscle cell signaling after insulin stimulation in T2DM vs. postburn trauma

 

Figure 1
View larger version (46K):
[in this window]
[in a new window]

  		Fig. 1. Proposed pathways of insulin resistance in the first (ebb) and second (flow) stages of burn. Several hormones released in the initial stages of burn have direct effects on muscle downstream intracellular signaling molecules such as PKC and AKT in muscle tissue. Additionally, glucagon and catecholamines cause gluconeogenesis and glycolysis and increase plasma glucose concentrations. As time progresses from the moment of injury, mitochondrial damage and insufficient fat oxidation in relation to metabolic need may further exacerbate alterations in the muscle signaling cascade through fatty acid intermediates. Cytokines such as TNF-{alpha} can activate NF-{kappa}B and cause similar alterations in hepatic insulin sensitivity. DAG, diacylglycerol; EPI, epinephrine; FFA, free fatty acids; GLUT-4, glucose transporter-4; TG, triglyceride; HTG, hepatic TG; IL-6, interleukin-6; IMTG, intramyocellular TG; IR, insulin receptor; IRS-1, insulin receptor substrate-1; NE, norepinephrine; TNF-{alpha}, tumor necrosis factor-{alpha}; NF-{kappa}B, nuclear factor-{kappa}B; PKC, protein kinase C.

 
Insulin resistance is sometimes, but not always, associated with the ectopic storage of TG within myocytes. We found that concentrations of intramyocellular TG (IMTG) in pediatric burn patients were similar to those measured in the healthy elderly (25, 26). However, Astrakas et al. (8) found that IMTG in rats increased at days 1 and 3 postinjury. Animals with increased muscle lipoprotein lipase and muscle FFA delivery have increased IMTG and decreased intracellular insulin signaling, as well as decreased whole body glucose uptake (56). On the other hand, when myotubes overexpressed carnitine transporter-1 (CPT-1) and had increased β-oxidation and insulin sensitivity, the concentrations of IMTG were unchanged compared with control cells (82).

Studies have found close associations among intracellular lipid species such as IMTG, diacylglycerol (DAG), and fatty acyl-CoA and insulin sensitivity (91). These various fatty acid metabolites are thought to influence insulin signaling either directly or by increasing PKC, which inactivates IR and IRS-1 (87, 91). However, we found that when in vivo muscle insulin sensitivity in patients with severe burns was improved in association with increased palmitate oxidation, concentrations of intramyocyte DAG, IMTG, and fatty acyl-CoA did not change, whereas PKC-{theta} decreased with increasing insulin sensitivity (25). Similar results were reported in rats fed a high-fat diet that had overexpression of hepatic malonyl-CoA dehydrogenase (6). Malonyl-CoA dehydrogenase breaks down malonyl-CoA and presumably increases β-oxidation of fat. Muscle, fat, and whole body insulin sensitivity improved in these animals, but IMTG did not change, and there was a trend for increased fatty acyl-CoA production. The only metabolite that did change in these animals was short chain β-hydroxybutyrylcarnitine, a mitochondrial derivative of the ketone β-hyroxybutarate. Furthermore, in rats fed a high-fat diet, treatment with Wy-14643, a potent peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) agonist, increased long chain fatty acyl-CoAs and insulin-mediated glucose uptake and decreased intramuscular TG (121). A similar study found that chronic Wy-14643 administration in rats did not lower palmitoyl-CoA (120). These conflicting results indicate that the association between intracellular lipids and insulin sensitivity is perhaps not as clear as previously thought, and the relationships as speculated are shown in Fig. 1. A comparison of tissue lipids in burn vs. T2DM patients is shown in Table 3.


View this table:
[in this window]
[in a new window]

  		Table 3. Muscle cell lipid concentrations in T2DM vs. postburn trauma

 
The increased concentrations of intracellular lipids are due to two primary factors, increased delivery of FFA and/or decreased β-oxidation. As has already been discussed, whereas the overall plasma concentrations of FFA are varied, the FFA flux is increased, so that the absolute delivery of FFA is increased to muscle cells. It has been demonstrated in multiple studies that the absolute rate of β-oxidation of FFA within muscle is increased in burn patients, yet the rate of oxidation is inadequate to meet energy needs (25, 114, 115). Furthermore, the rate of whole body palmitate oxidation correlates with the degree of insulin sensitivity in burned children (25). We have recently shown that, when the rate of palmitate oxidation was increased (by ingestion of the PPAR-{alpha} agonist fenofibrate), insulin sensitivity was improved in burned patients (25).

Burns produce significant mitochondrial damage in multiple tissues. We recently found that 7 days posttrauma, children had a substantial decrease in the maximal mitochondrial oxidative capacity of both pyruvate and palmitate compared with healthy children (24). In rats, substantial burn caused a 43% decrease in ATP production in skeletal muscle (81). Furthermore, gene expression of many mitochondrial genes was downregulated in these animals, including cytochrome c, citrate synthase, and CPT-1 (81). Genes involved in mitochondrial protein production and activation within skeletal muscle were downregulated at 1 and 3 days postburn in rats (8). The mitochondrial dysfunction seen within 1 h postinjury was associated with increased skeletal muscle apoptosis up to 7 days after the original injury (119). Taken together, these data clearly demonstrate that the burn injury rapidly induced damage to the muscle mitochondria.

Mitochondrial damage may not be the only cause of decreased β-oxidation in trauma patients. Hyperglycemia has been shown to inhibit muscle β-oxidation of FFA, perhaps via inhibition of the CPT-1 transporter via malonyl-CoA (93). This system has not been evaluated in muscle from trauma patients.

The cause of mitochondrial damage after burns or trauma is unclear. The damage could partially arise secondary to reactive oxygen species (ROS). Liang et al. (66) found that following burn, cardiac muscle cells experienced a large influx of calcium that was associated with mitochondrial nitric oxide synthase, although it is unclear whether a similar mechanism occurs in skeletal muscle. Nitric oxide has been shown to directly block cytochrome c activity and also causes oxidative damage to the mitochondrial membrane (13). Alternatively, the chronic damage may be induced by lipid products, as Chen et al. (20–22) found that a lipid isolated from burn eschar was able to induce the characteristic alterations in mitochondrial function seen in burn injury, decreased ATP synthesis and state 3 oxidation and decreased cytochrome b and c activity. The increased calcium flux within cardiomyocytes postburn also induced increases in phospholipase A2 concentrations (66). Phospholipase A2 has been documented to release FFA that alter the mitochondrial membrane and cytochrome c activity (65). Alternatively, FFA can activate NF-{kappa}B within myocytes, leading to further release of ROS (107). These studies indicate that ROS may induce alterations in the mitochondrial membrane and/or changes in the activity of specific mitochondrial enzymes.

Future Potential Treatments for Posttrauma Insulin Resistance

Small studies have been conducted trying various means to control plasma hyperglycemia directly, influence fatty acid metabolism, or improve mitochondrial function with varied success. The simplest treatment approach has been to control glucose via chronic insulin infusions. Metformin and losartan, an angiotensin receptor blocker (ARB), have been used to improve insulin sensitivity of the muscle in humans and animals, respectively (41–43, 55). PPAR-{alpha} agonists have been used to increase fat oxidation and mitochondrial function (25, 27). Finally, antioxidants such as ascorbic acid (vitamin C) or topherol (vitamin E) or anti-inflammatory agents such as TNF-{alpha} inhibitors or cyclooxygenase-2 (COX-2) inhibitors have been given in an attempt to counteract the ROS that may induce mitochondrial damage and thus insulin resistance. All of these treatments have had varied success.

Recently, much attention has been given to controlling hyperglycemia via insulin infusion, as such treatment has been shown to significantly lower both morbidity and mortality of multiple types of critically ill patients (104). In burn patients, time spent in intensive care is dependent on the severity of the burn and the covering of burned areas with donor skin through autografting or from cadavers. Very high-level exogenous insulin administration in burn patients to maintain a plasma insulin level of 400–900 µU/ml was shown to improve the donor site wound healing from 6.5 ± 1.0 to 4.2 ± 1.2 days (85). In burned children, moderate-dose insulin therapy decreased acute-phase proteins and cytokines such as TNF-{alpha}, IL-1, and IL-6 from week 1 to week 4 postburn, whereas there was no decrease in these measures in placebo-treated burned children (117).

Although there are documented benefits, insulin therapy is not without risk. The administration of insulin requires intensive monitoring to avoid hypoglycemia. Furthermore, to meet the glucose demands during exogenous insulin administration, caloric intake must be increased far beyond the metabolic need of the patient, contributing to increased adiposity and thus increased plasma FFA due to fat deposition (14, 45). Additionally, although insulin lowers plasma glucose levels, studies have shown that insulin resistance still exists in terms of fat metabolism. High levels of exogenous insulin given for 7 days to severely burned patients (63 ± 8% total body surface area) did not suppress the release of endogenous FFA from adipocytes (4). The combination of increased calories and high plasma FFA can lead to increases in liver size (14). Indeed, 3 days of insulin infusion in type 2 diabetics leads to decreased plasma glucose in conjunction with increased muscle and liver fat (7). Insulin also prevents the transcription of CPT-1 in the liver, which would have the potential of decreasing fat oxidation and increasing fat accumulation (75).

Given the limitations of high-dose insulin therapy, approaches that would improve insulin sensitivity are appealing. In that regard, PPAR-{alpha} agonists have been demonstrated to increase the mitochondrial oxidation of fats and improve glucose homeostasis in animals and certain human populations (35, 77). We recently studied this medication in burned patients and found that 2 wk of treatment with the PPAR-{alpha} agonist fenofibrate significantly improved insulin-stimulated glucose uptake and hepatic insulin sensitivity, in conjunction with improved insulin signaling within the muscle (27). Furthermore, fenofibrate significantly increased maximal mitochondrial pyruvate and palmitate oxidation as well as the function of cytochrome c and COX enzymes (25, 27). Finally, the whole body β-oxidation of palmitate was increased significantly following treatment (25).

Metformin has been shown to decrease hepatic glucose release as well as improve peripheral insulin sensitivity. In burn trauma patients, metformin treatment lowered plasma glucose concentrations at 24–26 h postinjury in the fasted and in the fed state (42). Decreased plasma glucose was mediated by lower rates of hepatic glucose release and increased peripheral clearance of glucose (42, 43). Plasma insulin concentrations were also higher, indicating that metformin either increased the secretion of insulin or decreased the breakdown of insulin (42). Furthermore, metformin treatment was found to increase the synthetic rate of muscle protein, and, when combined with exogenous insulin, protein synthesis was further increased (41). These promising results in a small cohort of patients need to be followed by larger studies.

Insulin resistance is often accompanied by hypertension. Kasper et al. (55) studied the effects of ARBs on postburn trauma insulin sensitivity. They found that at day 3 postburn, the burned animals treated with ARBs had similar area under the curve (AUC) measurements of glucose and insulin during an oral glucose tolerance test as sham burn animals, whereas the burn-only animals had a significantly higher AUC of glucose and insulin (55). The authors speculate that the ARBs may work by decreasing serine phosphorylation of IR and IRS-1 via decreasing PKC. More studies on the mechanism of action and studies in humans are needed to determine whether the ARBs will be a potential therapeutic drug.

Several investigators have proposed that treatment with antioxidant substances, COX-2 inhibitors, or TNF-{alpha} inhibitors could counter the negative effects of ROS that may cause mitochondrial damage (49). Antioxidants are decreased in multiple tissues post-burn injury (59). Supplements of both ascorbic acid and glutathione attenuate the decrease in hepatic ATP production following burn trauma (58, 60). Others have found that high doses of ascorbic acid decreased lipid peroxidation products (70). Furthermore, cardiomyocyte ROS-associated activation of NF-{kappa}B, a molecule that induces cytokines such as TNF-{alpha} and IL-6, was reduced 24 h postburn in animals given a mixture of vitamins C, E, and A and zinc (49). However, TNF-{alpha} is an important signal in the inflammatory cascade and induces increases in several other proteins, such as fibrinogen. Thus burn patients who do not mount a robust response could be at risk for increased morbidity via hemorrhage because of an increased breakdown of fibrinogen (78). COX-2 inhibitors have been used in animal models of burn and have decreased morbidity (90). However, these studies need to be performed with glucose measurements to see whether there are any clinical implications to this work.

Alterations in operative patient care may also minimize insulin resistance. Since burn patients undergo multiple surgical procedures throughout their recovery, these studies may also be relevant to helping decrease hyperglycemia. Recent research has attempted to minimize surgical stress, and this has been shown to lower postoperative hyperglycemia (15). It may be that smaller operations will need to be balanced with the necessity for rapid coverage of open wounds. Other investigators have examined the effects of controlling intraoperative plasma glucose concentrations, administering caloric loads before surgery, and different routes of anesthesia with varied results in nontrauma patients (30, 37, 86). These approaches have yet to been investigated in trauma patients.

Overall, there are multiple approaches to increasing insulin sensitivity and decreasing hyperglycemia that may be available in the future. Further studies are needed on all of the above-mentioned medications. Furthermore, given the different mechanisms of the medications, it could be that the most beneficial treatment will be the combination of medications with complimentary actions. For example, it has already been shown that insulin and metformin increased protein synthesis more than either drug in isolation (41).

Conclusions

In conclusion, postburn insulin resistance, like the insulin resistance seen in T2DM, is complex and involves many tissues, cells, and metabolic pathways. It is clear that controlling insulin resistance is a high priority in the management of severely burned patients or patients with trauma. Understanding the mechanisms underlying the development of insulin resistance is central to formulating a rational clinical approach. Recent research indicates links among altered rates of lipolysis, impaired liver and muscle mitochondrial oxidative function, accumulation of tissue lipids, and alterations in the insulin signaling cascade that lead to insulin resistance, in terms of both the suppressive action on hepatic glucose production and stimulation of muscle glucose uptake. It is appealing to consider the stimulation of lipolysis in the absence of a corresponding increase in requirement for substrate metabolism as a starting point. Excess availability of fatty acids, coupled with impaired mitochondrial function, would lead to the accumulation of intracellular TG and other lipid products that in turn inhibit insulin signaling. This scenario would be similar to that proposed to apply in obesity and aging (51, 91). However, available evidence fails to completely support this scenario. For example, inhibition of lipolysis in burn patients with β-adrenergic blockade does not improve insulin sensitivity, and stimulation of fatty acid oxidation with fenofibrate improved insulin action without affecting intracellular or plasma lipids. Alternatively, it is possible that the initial derangement is a stimulation of hepatic glucose production and direct inhibition of insulin action peripherally by stress hormones. The decrease in fatty acid oxidation could primarily reflect inhibition of CPT-1 by glucose via malonyl-CoA. The limitation of this scenario is that insulin resistance persists long after the acute elevations in stress hormones have been resolved.

The failure of any simplistic explanation to completely unify available data indicates that the basis for insulin resistance after trauma and burns is multifactorial. We propose that there are perhaps different mechanisms occurring during the two phases following burn injury, as shown in Fig. 1 and illustrated above. Successful treatment will only be achieved after the interactions of pathways of lipid and glucose metabolism, in relation to the insulin signaling pathway, are understood.


   GRANTS
TOP
 ABSTRACT
 GRANTS
REFERENCES
 
This work was supported by Shriners Hospital Grant No. 8490 to R. R. Wolfe and National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-041317 (Substrate Cycling in Burns) to R. R. Wolfe.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. R. Wolfe, DWR Institute on Aging, 4301 W. Markham St., Slot 806, Little Rock, AR 72205 (e-mail: rwolfe2{at}uams.edu)


   REFERENCES
TOP
 ABSTRACT
 GRANTS
 REFERENCES
 

  1. AarslandA, Chinkes D, Wolfe RR. Contributions of de novo synthesis of fatty acids to total VLDL-triglyceride secretion during prolonged hyperglycemia/hyperinsulinemia in normal man. J Clin Invest 98: 2008–2017, 1996.[Web of Science][Medline]
  2. AarslandA, Chinkes D, Wolfe RR. Hepatic and whole-body fat synthesis in humans during carbohydrate overfeeding. Am J Clin Nutr 65: 1774–1782, 1997.[Abstract/Free Full Text]
  3. AarslandA, Chinkes D, Wolfe RR, Barrow RE, Nelson SO, Pierre E, Herndon DN. Beta-blockade lowers peripheral lipolysis in burn patients receiving growth hormone. Rate of hepatic very low density lipoprotein triglyceride secretion remains unchanged. Ann Surg 223: 777–787; discussion 787–779, 1996.[Web of Science]
  4. AarslandA, Chinkes DL, Sakurai Y, Nguyen TT, Herndon DN, Wolfe RR. Insulin therapy in burn patients does not contribute to hepatic triglyceride production. J Clin Invest 101: 2233–2239, 1998.[Web of Science][Medline]
  5. AllisonSP, Hinton P, Chamberlain MJ. Intravenous glucose-tolerance, insulin, and free-fatty-acid levels in burned patients. Lancet 2: 1113–1116, 1968.[CrossRef][Web of Science][Medline]
  6. AnJ, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI, Koves TR, Stevens R, Millington D, Newgard CB. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat Med 10: 268–274, 2004.[CrossRef][Web of Science][Medline]
  7. AnderwaldC, Bernroider E, Krssak M, Stingl H, Brehm A, Bischof MG, Nowotny P, Roden M, Waldhausl W. Effects of insulin treatment in type 2 diabetic patients on intracellular lipid content in liver and skeletal muscle. Diabetes 51: 3025–3032, 2002.[Abstract/Free Full Text]
  8. AstrakasLG, Goljer I, Yasuhara S, Padfield KE, Zhang Q, Gopalan S, Mindrinos MN, Dai G, Yu YM, Martyn JA, Tompkins RG, Rahme LG, Tzika AA. Proton NMR spectroscopy shows lipids accumulate in skeletal muscle in response to burn trauma-induced apoptosis. FASEB J 19: 1431–1440, 2005.[Abstract/Free Full Text]
  9. BarretJP, Jeschke MG, Herndon DN. Fatty infiltration of the liver in severely burned pediatric patients: autopsy findings and clinical implications. J Trauma 51: 736–739, 2001.[Web of Science][Medline]
  10. BarrowRE, Mlcak R, Barrow LN, Hawkins HK. Increased liver weights in severely burned children: comparison of ultrasound and autopsy measurements. Burns 30: 565–568, 2004.[CrossRef][Web of Science][Medline]
  11. BarrowRE, Wolfe RR, Dasu MR, Barrow LN, Herndon DN. The use of beta-adrenergic blockade in preventing trauma-induced hepatomegaly. Ann Surg 243: 115–120, 2006.[CrossRef][Web of Science][Medline]
  12. BlackPR, Brooks DC, Bessey PQ, Wolfe RR, Wilmore DW. Mechanisms of insulin resistance following injury. Ann Surg 196: 420–435, 1982.[Web of Science][Medline]
  13. BrookesPS, Bolanos JP, Heales SJ. The assumption that nitric oxide inhibits mitochondrial ATP synthesis is correct. FEBS Lett 446: 261–263, 1999.[CrossRef][Web of Science][Medline]
  14. BurkeJF, Wolfe RR, Mullany CJ, Mathews DE, Bier DM. Glucose requirements following burn injury. Parameters of optimal glucose infusion and possible hepatic and respiratory abnormalities following excessive glucose intake. Ann Surg 190: 274–285, 1979.[Web of Science][Medline]
  15. CarliF, Galeone M, Gzodzic B, Hong X, Fried GM, Wykes L, Eberhart L, Schricker T. Effect of laparoscopic colon resection on postoperative glucose utilization and protein sparing: an integrated analysis of glucose and protein metabolism during the fasted and fed states using stable isotopes. Arch Surg 140: 593–597, 2005.[Abstract/Free Full Text]
  16. CarpentierYA, Burr RE, Askanazi J, Gump FE, Stinchfield FE, Kinney JM. Effect of operative injury on rate of fat mobilization. Surg Forum 29: 90–92, 1978.[Web of Science][Medline]
  17. ChampeP, Harvey R. Lippincott's Illustrated Reviews. Philadelphia: Lippincott Williams and Wilkins, 1994.
  18. ChanC, Berthiaume F, Lee K, Yarmush ML. Metabolic flux analysis of cultured hepatocytes exposed to plasma. Biotechnol Bioeng 81: 33–49, 2003.[CrossRef][Web of Science][Medline]
  19. ChenXL, Xia ZF, Yu YX, Wei D, Wang CR, Ben DF. p38 mitogen-activated protein kinase inhibition attenuates burn-induced liver injury in rats. Burns 31: 320–330, 2005.[CrossRef][Web of Science][Medline]
  20. ChenZ, Xiong Y, Lou S, Shu C. Lipid peroxidation of mitochondrial membrane induced by D1: an organic solvent extractable component isolated from a crude extract of burn eschar. Burns 22: 369–375, 1996.[CrossRef][Web of Science][Medline]
  21. ChenZR, Lou SF. Sites of inhibition of mitochondrial electron transport by D1, an organic solvent extractable component from burn eschar. Burns 20: 311–315, 1994.[CrossRef][Web of Science][Medline]
  22. ChenZR, Xiong Y, Wang SB, Dong Y. Inhibition of mitochondrial respiratory function by an organic solvent extractable component from an extract of burn eschar. Burns 17: 282–287, 1991.[CrossRef][Web of Science][Medline]
  23. ChildsC, Heath DF, Little RA, Brotherston M. Glucose metabolism in children during the first day after burn injury. Arch Emerg Med 7: 135–147, 1990.[Web of Science][Medline]
  24. CreeMG, Fram RY, Herndon DN, Qian T, Angel CA, Green JM, Mlcak RP, Aarsland A, Wolfe RR. Human mitochondrial oxidative capacity is acutely impaired following burn trauma (Abstract). FASEB J 21: A839, 2007.
  25. CreeMG, Newcomer BR, Herndon DN, Qian T, Sun D, Morio B, Zwetsloot JJ, Dohm GL, Fram RY, Mlcak RP, Aarsland A, Wolfe RR. PPAR-alpha agonism improves whole body and muscle mitochondrial fat oxidation, but does not alter intracellular fat concentrations in burn trauma children in a randomized controlled trial. Nutr Metab (Lond) 4: 9, 2007.[CrossRef][Medline]
  26. CreeMG, Newcomer BR, Katsanos CS, Sheffield-Moore M, Chinkes D, Aarsland A, Urban R, Wolfe RR. Intramuscular and liver triglycerides are increased in the elderly. J Clin Endocrinol Metab 89: 3864–3871, 2004.[Abstract/Free Full Text]
  27. CreeMG, Zwetsloot JJ, Herndon DN, Qian T, Morio B, Fram R, Sanford AP, Aarsland A, Wolfe RR. Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate. Ann Surg 245: 214–221, 2007.[CrossRef][Web of Science][Medline]
  28. CuthbertsonD. Post-shock metabolic response. Lancet 1: 433–436, 1942.[CrossRef]
  29. DeFronzoRA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30: 1000–1007, 1981.[Web of Science][Medline]
  30. DonatelliF, Vavassori A, Bonfanti S, Parrella P, Lorini L, Fumagalli R, Carli F. Epidural anesthesia and analgesia decrease the postoperative incidence of insulin resistance in preoperative insulin-resistant subjects only. Anesth Analg 104: 1587–1593, table of contents, 2007.[Abstract/Free Full Text]
  31. EnokssonS, Hagstrom-Toft E, Nordahl J, Hultenby K, Pettersson N, Isaksson B, Permert J, Wibom R, Holm C, Bolinder J, Arner P. Marked reutilization of free fatty acids during activated lipolysis in human skeletal muscle. J Clin Endocrinol Metab 90: 1189–1195, 2005.[Abstract/Free Full Text]
  32. FraynKN. Effects of burn injury on insulin secretion and on sensitivity to insulin in the rat in vivo. Eur J Clin Invest 5: 331–337, 1975.[Web of Science][Medline]
  33. FraynKN, Little RA, Maycock PF, Stoner HB. The relationship of plasma catecholamines to acute metabolic and hormonal responses to injury in man. Circ Shock 16: 229–240, 1985.[Web of Science][Medline]
  34. FredholmBB. The effect of lactate in canine subcutaneous adipose tissue in situ. Acta Physiol Scand 81: 110–123, 1971.[Web of Science][Medline]
  35. FuruhashiM, Ura N, Murakami H, Hyakukoku M, Yamaguchi K, Higashiura K, Shimamoto K. Fenofibrate improves insulin sensitivity in connection with intramuscular lipid content, muscle fatty acid-binding protein, and beta-oxidation in skeletal muscle. J Endocrinol 174: 321–329, 2002.[Abstract]
  36. GalsterAD, Bier DM, Cryer PE, Monafo WW. Plasma palmitate turnover in subjects with thermal injury. J Trauma 24: 938–945, 1984.[Web of Science][Medline]
  37. GandhiGY, Nuttall GA, Abel MD, Mullany CJ, Schaff HV, Williams BA, Schrader LM, Rizza RA, McMahon MM. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. Mayo Clin Proc 80: 862–866, 2005.[Abstract/Free Full Text]
  38. Garcia-AvelloA, Lorente JA, Cesar-Perez J, Garcia-Frade LJ, Alvarado R, Arevalo JM, Navarro JL, Esteban A. Degree of hypercoagulability and hyperfibrinolysis is related to organ failure and prognosis after burn trauma. Thromb Res 89: 59–64, 1998.[CrossRef][Web of Science][Medline]
  39. GoodyearLJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 95: 2195–2204, 1995.[Web of Science][Medline]
  40. GoreDC, Chinkes D, Heggers J, Herndon DN, Wolf SE, Desai M. Association of hyperglycemia with increased mortality after severe burn injury. J Trauma 51: 540–544, 2001.[Web of Science][Medline]
  41. GoreDC, Herndon DN, Wolfe RR. Comparison of peripheral metabolic effects of insulin and metformin following severe burn injury. J Trauma 59: 316–322; discussion 322–313, 2005.[Web of Science][Medline]
  42. GoreDC, Wolf SE, Herndon DN, Wolfe RR. Metformin blunts stress-induced hyperglycemia after thermal injury. J Trauma 54: 555–561, 2003.[Web of Science][Medline]
  43. GoreDC, Wolf SE, Sanford A, Herndon DN, Wolfe RR. Influence of metformin on glucose intolerance and muscle catabolism following severe burn injury. Ann Surg 241: 334–342, 2005.[CrossRef][Web of Science][Medline]
  44. HarrisRL, Frenkel RA, Cottam GL, Baxter CR. Lipid mobilization and metabolism after thermal trauma. J Trauma 22: 194–198, 1982.[Web of Science][Medline]
  45. HartDW, Wolf SE, Herndon DN, Chinkes DL, Lal SO, Obeng MK, Beauford RB, Mlcak RR. Energy expenditure and caloric balance after burn: increased feeding leads to fat rather than lean mass accretion. Ann Surg 235: 152–161, 2002.[CrossRef][Web of Science][Medline]
  46. HartDW, Wolf SE, Mlcak R, Chinkes DL, Ramzy PI, Obeng MK, Ferrando AA, Wolfe RR, Herndon DN. Persistence of muscle catabolism after severe burn. Surgery 128: 312–319, 2000.[CrossRef][Web of Science][Medline]
  47. HerndonDN, Nguyen TT, Wolfe RR, Maggi SP, Biolo G, Muller M, Barrow RE. Lipolysis in burned patients is stimulated by the beta 2-receptor for catecholamines. Arch Surg 129: 1301–1304; discussion 1304–1305, 1994.[Abstract/Free Full Text]
  48. HolmC, Horbrand F, Mayr M, von Donnersmarck GH, Muhlbauer W. Acute hyperglycaemia following thermal injury: friend or foe? Resuscitation 60: 71–77, 2004.[CrossRef][Web of Science][Medline]
  49. HortonJW. Free radicals and lipid peroxidation mediated injury in burn trauma: the role of antioxidant therapy. Toxicology 189: 75–88, 2003.[CrossRef][Web of Science][Medline]
  50. HowardJM. Studies of the absorption and metabolism of glucose following injury; the systemic response to injury. Ann Surg 141: 321–326, 1955.[Web of Science][Medline]
  51. HulverMW, Dohm GL. The molecular mechanism linking muscle fat accumulation to insulin resistance. Proc Nutr Soc 63: 375–380, 2004.[CrossRef][Web of Science][Medline]
  52. IkezuT, Okamoto T, Yonezawa K, Tompkins RG, Martyn JA. Analysis of thermal injury-induced insulin resistance in rodents. Implication of postreceptor mechanisms. J Biol Chem 272: 25289–25295, 1997.[Abstract/Free Full Text]
  53. JeschkeMG, Low JF, Spies M, Vita R, Hawkins HK, Herndon DN, Barrow RE. Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats. Am J Physiol Gastrointest Liver Physiol 280: G1314–G1320, 2001.[Abstract/Free Full Text]
  54. KanemakiT, Kitade H, Kaibori M, Sakitani K, Hiramatsu Y, Kamiyama Y, Ito S, Okumura T. Interleukin 1beta and interleukin 6, but not tumor necrosis factor alpha, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes. Hepatology 27: 1296–1303, 1998.[CrossRef][Web of Science][Medline]
  55. KasperSO, Castle SM, Daley BJ, Enderson BL, Karlstad MD. Blockade of the renin-angiotensin system improves insulin sensitivity in thermal injury. Shock 26: 485–488, 2006.[CrossRef][Web of Science][Medline]
  56. KimJK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA 98: 7522–7527, 2001.[Abstract/Free Full Text]
  57. LainePS, Schwartz EA, Wang Y, Zhang WY, Karnik SK, Musi N, Reaven PD. Palmitic acid induces IP-10 expression in human macrophages via NF-kappaB activation. Biochem Biophys Res Commun 358: 150–155, 2007.[CrossRef][Web of Science][Medline]
  58. LaLondeC, Nayak U, Hennigan J, Demling R. Antioxidants prevent the cellular deficit produced in response to burn injury. J Burn Care Rehabil 17: 379–383, 1996.[Medline]
  59. LaLondeC, Nayak U, Hennigan J, Demling R. Plasma catalase and glutathione levels are decreased in response to inhalation injury. J Burn Care Rehabil 18: 515–519, 1997.[Medline]
  60. LaLondeC, Nayak U, Hennigan J, Demling RH. Excessive liver oxidant stress causes mortality in response to burn injury combined with endotoxin and is prevented with antioxidants. J Burn Care Rehabil 18: 187–192, 1997.[Medline]
  61. LeeJY, Sohn KH, Rhee SH, Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J Biol Chem 276: 16683–16689, 2001.[Abstract/Free Full Text]
  62. LeeK, Berthiaume F, Stephanopoulos GN, Yarmush DM, Yarmush ML. Metabolic flux analysis of postburn hepatic hypermetabolism. Metab Eng 2: 312–327, 2000.[CrossRef][Medline]
  63. LeeK, Berthiaume F, Stephanopoulos GN, Yarmush ML. Induction of a hypermetabolic state in cultured hepatocytes by glucagon and H2O2. Metab Eng 5: 221–229, 2003.[CrossRef][Web of Science][Medline]
  64. LehnhardtM, Jafari HJ, Druecke D, Steinstraesser L, Steinau HU, Klatte W, Schwake R, Homann HH. A qualitative and quantitative analysis of protein loss in human burn wounds. Burns 31: 159–167, 2005.[CrossRef][Web of Science][Medline]
  65. LevratC, Louisot P. Increase of mitochondrial PLA2-released fatty acids is an early event in tumor necrosis factor alpha-treated WEHI-164 cells. Biochem Biophys Res Commun 221: 531–538, 1996.[CrossRef][Web of Science][Medline]
  66. LiangWY, Tang LX, Yang ZC, Huang YS. Calcium induced the damage of myocardial mitochondrial respiratory function in the early stage after severe burns. Burns 28: 143–146, 2002.[CrossRef][Web of Science][Medline]
  67. LinaresHA. A report of 115 consecutive autopsies in burned children: 1966–80. Burns Incl Therm Inj 8: 263–270, 1982.[CrossRef][Web of Science][Medline]
  68. LittleRA, Henderson A, Frayn KN, Galasko CS, White RH. The disposal of intravenous glucose studied using glucose and insulin clamp techniques in sepsis and trauma in man. Acta Anaesthesiol Belg 38: 275–279, 1987.[Medline]
  69. MartiniWZ, Irtun O, Chinkes DL, Rasmussen B, Traber DL, Wolfe RR. Alteration of hepatic fatty acid metabolism after burn injury in pigs. JPEN J Parenter Enteral Nutr 25: 310–316, 2001.[Abstract/Free Full Text]
  70. MatsudaT, Tanaka H, Yuasa H, Forrest R, Matsuda H, Hanumadass M, Reyes H. The effects of high-dose vitamin C therapy on postburn lipid peroxidation. J Burn Care Rehabil 14: 624–629, 1993.[Medline]
  71. MatsuiM, Kudo T, Kudo M, Ishihara H, Matsuki A. The endocrine response after burns. Agressologie 32: 233–235, 1991.[Medline]
  72. MittendorferB, Jeschke MG, Wolf SE, Sidossis LS. Nutritional hepatic steatosis and mortality after burn injury in rats. Clin Nutr 17: 293–299, 1998.[CrossRef][Web of Science][Medline]
  73. MorioB, Irtun O, Herndon DN, Wolfe RR. Propranolol decreases splanchnic triacylglycerol storage in burn patients receiving a high-carbohydrate diet. Ann Surg 236: 218–225, 2002.[CrossRef][Web of Science][Medline]
  74. MorioB, Irtun O, Herndon DN, Wolfe RR. Propranolol decreases splanchnic triacylglycerol storage in burn patients receiving a high-carbohydrate diet. Ann Surg 236: 218–225, 2002.[CrossRef][Web of Science][Medline]
  75. MorioB, Yeckel C, Wolfe R. Fatty acid oxidation. In: Encyclopedia of Life Sciences. Chichester, UK: John Wiley and Sons, 2003, p. 1–13.
  76. MowlaviA, Andrews K, Milner S, Herndon DN, Heggers JP. The effects of hyperglycemia on skin graft survival in the burn patient. Ann Plast Surg 45: 629–632, 2000.[Web of Science][Medline]
  77. MuoioDM, Way JM, Tanner CJ, Winegar DA, Kliewer SA, Houmard JA, Kraus WE, Dohm GL. Peroxisome proliferator-activated receptor-alpha regulates fatty acid utilization in primary human skeletal muscle cells. Diabetes 51: 901–909, 2002.[Abstract/Free Full Text]
  78. NiemiT, Svartling N, Syrjala M, Asko-Seljavaara S, Rosenberg P. Haemostatic disturbances in burned patients during early excision and skin grafting. Blood Coagul Fibrinolysis 9: 19–28, 1998.[Web of Science][Medline]
  79. NygrenJ, Thorell A, Efendic S, Nair KS, Ljungqvist O. Site of insulin resistance after surgery: the contribution of hypocaloric nutrition and bed rest. Clin Sci (Lond) 93: 137–146, 1997.[Medline]
  80. OscaiLB, Essig DA, Palmer WK. Lipase regulation of muscle triglyceride hydrolysis. J Appl Physiol 69: 1571–1577, 1990.[Abstract/Free Full Text]
  81. PadfieldKE, Astrakas LG, Zhang Q, Gopalan S, Dai G, Mindrinos MN, Tompkins RG, Rahme LG, Tzika AA. Burn injury causes mitochondrial dysfunction in skeletal muscle. Proc Natl Acad Sci USA 102: 5368–5373, 2005.[Abstract/Free Full Text]
  82. PerdomoG, Commerford SR, Richard AM, Adams SH, Corkey BE, O'Doherty RM, Brown NF. Increased beta-oxidation in muscle cells enhances insulin-stimulated glucose metabolism and protects against fatty acid-induced insulin resistance despite intramyocellular lipid accumulation. J Biol Chem 279: 27177–27186, 2004.[Abstract/Free Full Text]
  83. PetersenKF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL, DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300: 1140–1142, 2003.[Abstract/Free Full Text]
  84. PetersenKF, Hendler R, Price T, Perseghin G, Rothman DL, Held N, Amatruda JM, Shulman GI. 13C/31P NMR studies on the mechanism of insulin resistance in obesity. Diabetes 47: 381–386, 1998.[Abstract]
  85. PierreEJ, Barrow RE, Hawkins HK, Nguyen TT, Sakurai Y, Desai M, Wolfe RR, Herndon DN. Effects of insulin on wound healing. J Trauma 44: 342–345, 1998.[Web of Science][Medline]
  86. Rapp-KesekD, Stridsberg M, Andersson LG, Berne C, Karlsson T. Insulin resistance after cardiopulmonary bypass in the elderly patient. Scand Cardiovasc J 41: 102–108, 2007.[CrossRef][Web of Science][Medline]
  87. Schmitz-PeifferC. Protein kinase C and lipid-induced insulin resistance in skeletal muscle. Ann NY Acad Sci 967: 146–157, 2002.[Web of Science][Medline]
  88. Schmitz-PeifferC, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ. Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 46: 169–178, 1997.[Abstract]
  89. ShangrawRE, Stuart CA, Prince MJ, Peters EJ, Wolfe RR. Insulin responsiveness of protein metabolism in vivo following bedrest in humans. Am J Physiol Endocrinol Metab 255: E548–E558, 1988.[Abstract/Free Full Text]
  90. ShoupM, He LK, Liu H, Shankar R, Gamelli R. Cyclooxygenase-2 inhibitor NS-398 improves survival and restores leukocyte counts in burn infection. J Trauma 45: 215–220; discussion 220–211, 1998.[Web of Science][Medline]
  91. ShulmanGI. Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology Bethesda 19: 183–190, 2004.[CrossRef][Medline]
  92. SidossisLS, Mittendorfer B, Walser E, Chinkes D, Wolfe RR. Hyperglycemia-induced inhibition of splanchnic fatty acid oxidation increases hepatic triacylglycerol secretion. Am J Physiol Endocrinol Metab 275: E798–E805, 1998.[Abstract/Free Full Text]
  93. SidossisLS, Wolfe RR. Glucose and insulin-induced inhibition of fatty acid oxidation: the glucose-fatty acid cycle reversed. Am J Physiol Endocrinol Metab 270: E733–E738, 1996.[Abstract/Free Full Text]
  94. SmithA, Barclay C, Quaba A, Sedowofia K, Stephen R, Thompson M, Watson A, McIntosh N. The bigger the burn, the greater the stress. Burns 23: 291–294, 1997.[CrossRef][Web of Science][Medline]
  95. StonerHB, Frayn KN, Barton RN, Threlfall CJ, Little RA. The relationships between plasma substrates and hormones and the severity of injury in 277 recently injured patients. Clin Sci (Lond) 56: 563–573, 1979.[Medline]
  96. StrommerL, Permert J, Arnelo U, Koehler C, Isaksson B, Larsson J, Lundkvist I, Bjornholm M, Kawano Y, Wallberg-Henriksson H, Zierath JR. Skeletal muscle insulin resistance after trauma: insulin signaling and glucose transport. Am J Physiol Endocrinol Metab 275: E351–E358, 1998.[Abstract/Free Full Text]
  97. SugitaH, Kaneki M, Sugita M, Yasukawa T, Yasuhara S, Martyn JA. Burn injury impairs insulin-stimulated Akt/PKB activation in skeletal muscle. Am J Physiol Endocrinol Metab 288: E585–E591, 2005.[Abstract/Free Full Text]
  98. ThorellA, Efendic S, Gutniak M, Haggmark T, Ljungqvist O. Development of postoperative insulin resistance is associated with the magnitude of operation. Eur J Surg 159: 593–599, 1993.[Web of Science][Medline]
  99. ThorellA, Efendic S, Gutniak M, Haggmark T, Ljungqvist O. Insulin resistance after abdominal surgery. Br J Surg 81: 59–63, 1994.[Web of Science][Medline]
  100. ThorellA, Nygren J, Essen P, Gutniak M, Loftenius A, Andersson B, Ljungqvist O. The metabolic response to cholecystectomy: insulin resistance after open compared with laparoscopic operation. Eur J Surg 162: 187–191, 1996.[Web of Science][Medline]
  101. ThorneA, Aberg W, Carneheim C, Olivecrona T, Nordenstrom J. Influence of trauma on plasma elimination of exogenous fat and on lipoprotein lipase activity and mass. Clin Nutr 24: 66–74, 2005.[CrossRef][Web of Science][Medline]
  102. TsigosC, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab 82: 4167–4170, 1997.[Abstract/Free Full Text]
  103. TurinskyJ, Saba TM, Scovill WA, Chesnut T. Dynamics of insulin secretion and resistance after burns. J Trauma 17: 344–350, 1977.[Web of Science][Medline]
  104. van den BergheG, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 345: 1359–1367, 2001.[Abstract/Free Full Text]
  105. VanhorebeekI, De Vos R, Mesotten D, Wouters PJ, De Wolf-Peeters C, Van den Berghe G. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 365: 53–59, 2005.[CrossRef][Web of Science][Medline]
  106. WachtelTL, Shuck JM, Schade D, Eaton RP, Shuck LW. Hyperglucagonemia and hepatic ketogenesis in burned swine. J Trauma 18: 248–253, 1978.[Web of Science][Medline]
  107. WeigertC, Brodbeck K, Staiger H, Kausch C, Machicao F, Haring HU, Schleicher ED. Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-kappaB. J Biol Chem 279: 23942–23952, 2004.[Abstract/Free Full Text]
  108. WilmoreDW, Mason AD Jr, Pruitt BA Jr. Insulin response to glucose in hypermetabolic burn patients. Ann Surg 183: 314–320, 1976.[Web of Science][Medline]
  109. WolfeRR. Glucose metabolism in burn injury: a review. J Burn Care Rehabil 6: 408–418, 1985.[CrossRef][Medline]
  110. WolfeRR. Regulation of skeletal muscle protein metabolism in catabolic states. Curr Opin Clin Nutr Metab Care 8: 61–65, 2005.[Web of Science][Medline]
  111. WolfeRR. Review: acute versus chronic response to burn injury. Circ Shock 8: 105–115, 1981.[Web of Science][Medline]
  112. WolfeRR. Substrate utilization/insulin resistance in sepsis/trauma. Baillieres Clin Endocrinol Metab 11: 645–657, 1997.[CrossRef][Web of Science][Medline]
  113. WolfeRR, Durkot MJ, Allsop JR, Burke JF. Glucose metabolism in severely burned patients. Metabolism 28: 1031–1039, 1979.[CrossRef][Web of Science][Medline]
  114. WolfeRR, Herndon DN, Jahoor F, Miyoshi H, Wolfe M. Effect of severe burn injury on substrate cycling by glucose and fatty acids. N Engl J Med 317: 403–408, 1987.[Abstract]
  115. WolfeRR, Herndon DN, Peters EJ, Jahoor F, Desai MH, Holland OB. Regulation of lipolysis in severely burned children. Ann Surg 206: 214–221, 1987.[Web of Science][Medline]
  116. WolfeRR, Miller HI, Spitzer JJ. Glucose and lactate kinetics in burn shock. Am J Physiol Endocrinol Metab Gastrointest Physiol 232: E415–E418, 1977.[Abstract/Free Full Text]
  117. WuX, Thomas SJ, Herndon DN, Sanford AP, Wolf SE. Insulin decreases hepatic acute phase protein levels in severely burned children. Surgery 135: 196–202, 2004.[CrossRef][Web of Science][Medline]
  118. YasuharaS, Kaneki M, Sugita H, Sugita M, Asai A, Sahani N, Chon JY, Tompkins RG, Martyn JA. Adipocyte apoptosis after burn injury is associated with altered fat metabolism. J Burn Care Res 27: 367–376, 2006.[Web of Science][Medline]
  119. YasuharaS, Perez ME, Kanakubo E, Yasuhara Y, Shin YS, Kaneki M, Fujita T, Martyn JA. Skeletal muscle apoptosis after burns is associated with activation of proapoptotic signals. Am J Physiol Endocrinol Metab 279: E1114–E1121, 2000.[Abstract/Free Full Text]
  120. YeJM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EW. Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes 50: 411–417, 2001.[Abstract/Free Full Text]
  121. YeJM, Iglesias MA, Watson DG, Ellis B, Wood L, Jensen PB, Sorensen RV, Larsen PJ, Cooney GJ, Wassermann K, Kraegen EW. PPAR-alpha/gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly. Am J Physiol Endocrinol Metab 284: E531–E540, 2003.[Abstract/Free Full Text]
  122. YuC, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277: 50230–50236, 2002.[Abstract/Free Full Text]
  123. ZhangQ, Carter EA, Ma BY, White M, Fischman AJ, Tompkins RG. Molecular mechanism(s) of burn-induced insulin resistance in murine skeletal muscle: role of IRS phosphorylation. Life Sci 77: 3068–3077, 2005.[CrossRef][Web of Science][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/1/E1    most recent
00562.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cree, M. G.
Right arrow Articles by Wolfe, R. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cree, M. G.
Right arrow Articles by Wolfe, R. R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.