Molecular Medicine

, Volume 17, Issue 5–6, pp 516–522 | Cite as

Insulin Protects against Hepatic Damage Postburn

  • Marc G JeschkeEmail author
  • Robert Kraft
  • Juquan Song
  • Gerd G Gauglitz
  • Robert A Cox
  • Natasha C Brooks
  • Celeste C Finnerty
  • Gabriela A Kulp
  • David N Herndon
  • Darren Boehning
Open Access
Research Article


Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.


A burn injury represents one of the most severe forms of trauma and occurs in over two million people in the United States of America per year (1). The liver, with its metabolic, inflammatory, immune and acute-phase functions, plays a pivotal role in patient outcome and recovery by modulating multiple pathways (2, 3, 4, 5, 6, 7). It has been suggested that because the liver modulates metabolic pathways, inflammatory processes and acute-phase responses, limiting hepatic damage after traumatic injury may improve patient outcomes significantly (7). In a recent study, Price and colleagues (8) looked at outcomes of 290 burned patients who suffered from liver disease prior to burn injury. They showed that preexisting liver disease increased mortality risk from 6% (total population) to 27%. The authors concluded that liver impairment worsens the prognosis in patients with thermal injury (8). This suggests that therapeutic agents, which protect against liver dysfunction after traumatic injury, may improve patient morbidity and mortality significantly.

Hepatic dysfunction after burn injury persists over a prolonged time period (3,7,9,10). At the molecular level, we recently have shown that burn injury leads to gross alterations in hepatocyte calcium homeostasis (7,11). Burn injury causes depletion of endoplasmic reticulum (ER) calcium stores and increased cytosolic calcium, which subsequently induces mitochondrial damage and cytochrome c release (11). Cytochrome c binds to the ER-resident inositol 1,4,5-trisphosphate receptor (IP3R) calcium channel, augmenting the depletion of ER calcium stores leading to ER stress and induction of the unfolded protein response (UPR) (7,11). ER stress/UPR due to calcium store depletion leads to activation of the JNK signaling pathway and ultimately hepatocyte apoptosis. Burn injury also induces the hepatic acute phase response and a concomitant decrease in the production of constitutive serum proteins such as albumin (3,7,9,12).

The introduction of insulin and the concept of tight euglycemic control represent a cornerstone of modern critical care medicine (13,14). Studies in severely burned patients conducted by our group indicated that insulin improves hypermetabolism by decreasing proinflammatory cytokines and hepatic acute-phase protein production (10,15,16). While insulin administration postburn is known to attenuate hepatic damage and improve liver function (5,17), the underlying mechanisms by which insulin exerts its effects on liver structure and function are not understood. The aim of this study was to determine the molecular mechanisms by which insulin administration improves hepatic structure and function postburn. We hypothesized that postburn insulin administration would improve hepatic function by decreasing ER stress and downstream mitochondrial dysfunction and apoptosis, leading to a marked reduction in acute phase protein production and activation of associated inflammatory pathways.

Material and Methods


All animal manipulations were approved by the Institutional Animal Care and Use Committee of the University of Texas Medical Branch at Galveston. The National Academy Press Guide for the Care and Use of Laboratory Animals (1996) were met. Sprague Dawley rats, 325 to 350 g, were used in these studies and were allowed to acclimate for 1 wk before experiments. Rats were housed in an institutional animal care facility and received a high-protein diet (Ensure, Abbott Laboratories, Waukegan, IL, USA) and water ad libitum throughout the study. Ensure (Abbott) was administered 7 d before the study to adjust the animals to the liquid diet.

Burn Injury

A well-established method was used to induce a full-thickness scald burn in our model (18). Animals were anesthetized with general anesthesia (keta-mine 40 mg/kg body weight and xylazine 5 mg/kg body weight, both injected intraperitoneally [i.p.]) and received analgesia (buprenorphine 0.05 mg/kg body weight, injected subcutaneously). The dorsum of the trunk and the abdomen were shaved, and a 60% total body surface area (TBSA) burn was administered by placing the animals in a mold exposing defined areas of the skin of the back and abdomen under general anesthesia and analgesia. The mold was placed in 96–98°C water, scalding the back for 10 sec and the abdomen for 2 sec. Lactated Ringer’s solution (40 mL/kg body weight) was administered i.p. immediately after the burn for resuscitation. After burn and resuscitation, animals were observed, received oxygen and were then placed into cages. Unburned (sham) animals received the same treatment except for the scald burn.

Animals were pair-fed with a liquid high-protein high-amino acid nutrition (Ensure, Abbott Laboratories) and water ad libitum. Ensure has a caloric distribution of 24% protein, 21% fat and 55% carbohydrate. All rats were pair-fed according to the caloric intake. The feeding protocol was as follows: 25 calories on the day of burn or sham, 51 calories on the first day postburn, 76 calories on the second, and 101 calories from the third day postburn on, to the end of the study. Nutritional intake was the same in all groups.

Treatment Groups

Animals received a 60% total body surface area (TBSA) burn and animals were injected once daily with either 2.5 IU/kg body weight of insulin glargine (Insulin Lantus, Sanofi Aventis, Kansas City, MO, USA; insulin group), or an equal amount of saline subcutaneous (control group, n = 10). Animals were killed by decapitation 24 and 48 h after burn injury and blood and liver was collected immediately thereafter (n = 10 for each group and time point). No animals were excluded from the study, and there were no significant differences in mortality rate between the groups.

Serum Markers

Serum was separated by centrifugation at 3,000g for 3 min at 4°C and stored at −80°C until analyzed. The levels of IL-6, cytokine-induced neutrophil chemoattractant (CINC)-1 and monocyte chemotactic protein (MCP)-1 as markers of systemic inflammation were determined by enzyme-linked immunosorbent assay (ELISA) (R&D Systems Inc., Minneapolis, MN, USA) according to the protocol of the manufacturer. Absolute cytokine concentrations were determined by comparison to a standard curve.

SDS-Polyacrylamide Gel Electrophoresis and Immunoblotting

Liver tissue was homogenized and solubilized in 150 mmol/L NaCl, 50 mmol/L Tris-HCl, pH 7.8, 1% (w/v) Triton X-100, 1 mmol/L EDTA, 0.5 mmol/L phenylmethanesulfonyl fluoride and 1 × protease inhibitor cocktail (Roche Molecular Biochemicals, Basel, Switzerland) for 5 min on ice and spun at 12,000g, and 20 µg of the resultant supernatant was run on a 4% to 20% gradient SDS-polyacrylamide gel and subsequently electrotransferred to nitrocellulose membranes (Bio-Rad Laboratories, Hercules, CA, USA). Nitrocellulose sheets then were probed with primary antibody against phosphorylated inositol requiring enzyme-1 (IRE1), c-Jun N-terminal Kinase (JNK), Thr183/185-phosphorylated-JNK, Thr980 phosphorylated PKR-like endoplasmic reticulum kinase (PERK), ATF6, Grp78/ Bip, and actin. Blots were developed with chemiluminescent substrates (Pierce Biotechnology, Rockford, IL, USA) and were quantified by densitometry (GENE GENIUS, Bio Imaging System, Syngene, Frederick, MD, USA). After quantification, the intensities of the phosphorylated protein bands were divided by the total form of the respective protein or by the intensity of the respective actin band. In those cases where a single blot was probed sequentially with more than one antibody, the nitrocellulose was stripped at 60°C for 30 min in stripping buffer (2% SDS, 100 mmol/L β-mercaptoethanol, 62.5 mmol/L Tris-HCl) before probing with the next antibody.

Liver Apoptosis

Terminal deoxyuridine nick end labeling (TUNEL) (Apoptag, Oncogene, Baltimore, MD, USA) staining to identify apoptotic hepatocytes in situ was performed as suggested by the manufacturer. Six sections of each liver block were obtained at 40- to 50-µm intervals. Within each section, a blinded observer selected five fields for counting TUNEL-positive cells. Three blinded observers counted TUNEL-positive cells and the data pooled. The data were quantified as the percentage of apoptotic cells per hundred hepatocytes.

Mitochondrial Isolation and Respiration

Liver tissue (400 mg) was minced on ice and transferred (10% w/v) to isolation buffer (250 mmol/L sucrose, 10 mmol/L HEPES, 0.5 mmol/L EGTA, 0.1% bovine serum albumin [BSA], pH 7.4). The sample was homogenized gently by 3 to 4 strokes with a Dounce homogenizer with a loose fitting pestle. The homogenate was centrifuged at 500g for 5 min at 4°C. The supernatant fraction was retained, whereas the pellet was washed with isolation buffer and centrifuged again (500g for 5 min at 4°C). The combined supernatant fractions were centrifuged at 7800g for 10 min at 4°C to obtain a crude mitochondria pellet. The mitochondria pellet was resuspended in isolation buffer without EGTA and BSA and centrifuged again at 7800g for 10 min. Oxygen consumption of isolated mitochondria was measured at 25°C by using a model 782 oxygen meter system and model 1302 Microcathode oxygen electrode (Strathkelvin, Glasgow, UK).

Statistical Analysis

All data is presented as the mean ± the standard error of the mean. Statistical significance between two groups was examined with a Student t test. A P value < 0.05 was determined to be significant. All data were analyzed by using Graph-Pad Prism software (GraphPad Software, Inc, San Diego, CA, USA).


We first determined whether insulin at a dose of 2.5 units/kg body weight alter serum glucose levels postburn. We found that insulin significantly decreased glucose levels at 24 h and 48 h postburn when compared with burn, P < 0.05 (Table 1).
Table 1

Blood glucose levels postburn in mg/dL.a




Burn + insulin

24 h

95 ± 5

145 ± 11

105 ± 6b

48 h

98 ± 6

138 ± 12

103 ± 7b

aData presented as mean ± SD.

bSignificant difference between burn versus burn + insulin, P < 0.05.

We next examined whether insulin administration would improve hepatic apoptosis postburn. As shown in Figure 1A, we found that burn induces a 5- to 7-fold increase in hepatic caspase-3 activation. Insulin significantly attenuated caspase-3 activation compared with burn (Figure 1A). Consistent with burn-induced activation of hepatocyte apoptosis, we found a 5- to 6-fold increase in the number of TUNEL-positive hepatocytes after burn injury, which was inhibited significantly by insulin administration (Figure 1B). Burn-induced hepatic apoptosis was associated with activation of the acute phase response as indicated by a drop in production of the constitutive protein albumin (Figure 1C). Importantly, insulin administration increased serum albumin levels significantly post-burn (see Figure 1C).
Figure 1

Insulin decreases hepatic apoptosis and increases albumin production after burn injury. (A) Caspase-3 activity in liver lysates from control (white bars), burn (black bars), and burn + insulin (hatch bars) animals 24 and 48 h after burn injury. (B) Percent of apoptotic hepatocytes as determined by TUNEL staining in control, burn and burn + insulin animals 24 and 48 h after burn injury. (C) Serum albumin levels in control, burn, and burn + insulin animals 24 and 48 h after burn injury. *P < 0.05 relative to control. **P < 0.05 relative to burn.

We next asked whether insulin protects against burn-induced induction of the hepatic ER stress response. Confirming previous studies (11,19), we found that burn injury is a potent inducer of the hepatic ER stress response 24 h after injury (Figure 2A). Burn increased levels of phospho-PERK significantly, cleaved ATF-6, phospho-IRE-1 and phospho-JNK (Figure 2CF). These effects were significantly inhibited in all cases by insulin administration. At 48 h postburn, similar changes persisted, and we also found significant upregulation of the ERresident chaperone Grp78/Bip, which is a transcriptional target of ATF6 (Figure 3AF).
Figure 2

Insulin decreases hepatic ER stress 24 h after burn injury. (A) Representative Western blots from control (C), burn (B), and burn + insulin (B + I) liver lysates 24 h after burn injury. Two separate animals from each group are shown. (B) Densitometric ratio of Grp78/Bip to actin. (C) Ratio of phospho (active) PERK to actin. (D) Ratio of cleaved (active) ATF6 to actin. (E) Ratio of phospho (active) IRE1 to actin. (F) Ratio of phospho (active) JNK to total JNK. *P< 0.05 relative to control. **P< 0.05 relative to burn.

Figure 3

Insulin decreases hepatic ER stress 48 h after burn injury (A) Representative Western blots from control (C), burn (B), and burn + insulin (B + I) liver lysates 48 h after burn injury. Two separate animals from each group are shown. (B) Densitometric ratio of Grp78/Bip to actin. (C) Ratio of phospho (active) PERK to actin. (D) Ratio of cleaved (active) ATF6 to actin. (E) Ratio of phospho (active) IRE1 to actin. (F) Ratio of phospho (active) JNK to total JNK. *P< 0.05 relative to control. **P< 0.05 relative to burn.

Burn has been shown to cause profound calcium alterations in the ER by depleting ER stores and increasing cytosolic calcium (11). Increased cytosolic calcium has been shown to induce mitochondrial swelling, decrease respiratory capacity and release of mitochondrial apoptotic factors such as cytochrome c (20, 21, 22, 23). Previously we have shown that burn injury causes mitochondrial swelling and decreased state-3 respiration (11). Consistent with our previous studies, by using transmission electron microscopy we found marked alterations in mitochondrial morphology after burn injury (Figure 4AC). Mitochondrial swelling, loss of cristae (double asterisks; Figure 4B) and loss of matrix electron density (single asterisk, Figure 4B) were prominent in hepatocytes from burned animals. Furthermore, burn injury was associated with fragmentation of the tubular ER membrane structure (arrows; Figure 4B). Importantly, insulin administration reversed these ultrastructural changes in the mitochondria (Figure 4C). To examine mitochondrial function, we measured state-3 respiration in isolated hepatic mitochondria. We found that burn injury caused a marked impairment in hepatic mitochondria state-3 respiration, and this could be reversed significantly by insulin administration (Figure 4D).
Figure 4

Insulin reverses mitochondrial damage and associated respiratory dysfunction after burn injury. (A) Transmission electron microscopy of hepatocytes from normal liver, (B) hepatocytes from burned animals and (C) hepatocytes from burn-plus-insulin rats. A single asterisk highlights a mitochondrion with significant loss of matrix electron density. Two mitochondria with loss of cristae are highlighted with double asterisks. Arrows indicate fragmented ER. (D) State-3 respiration in isolated mitochondria from control, burn and burn + insulin rats. *P< 0.05 relative to control. **P< 0.05 relative to burn.

Burn injury induces the acute phase response and subsequent production of inflammatory mediators such as IL-6, CINC-1 and MCP-1. We found that burn increases the production of these cytokines 5- to 20-fold compared with control 24 and 48 h after burn injury (Figure 5). Importantly, insulin administration reduces IL-6, MCP-1, and CINC-1 significantly to almost normal levels, indicating that insulin suppresses the inflammatory response potently postburn.
Figure 5

Insulin decreases levels of inflammatory markers after burn injury. (A) IL-6, (B) MCP-1 and (C) CINC-1 levels in control, burn and burn + insulin rats 24 and 48 h after burn injury. *P< 0.05 relative to control. **P< 0.05 relative to burn.


The liver with a wide range of central physiologic, metabolic and immune functions is central for survival in critically ill patients or after a severe injury such as a burn injury (7,9,12). We have shown previously that a burn leads to marked alterations in liver integrity and function associated with gross alterations in ER calcium, with increased cytosolic calcium concentrations and hepatic apoptosis and ER stress/UPR that impact postburn morbidity and mortality (7,9,11,19,24). We now hypothesize that attenuation of hepatic apoptosis and ER stress will be associated with alleviated hypermetabolism and subsequent improved postburn outcome. To test this hypothesis we used an agent that is safe and widely used in the clinical setting, insulin (13,14,16). We found that insulin administration postburn attenuated hepatic ER stress, which was associated with an improved mitochondrial function, decreased apoptosis and decreased inflammation.

Intensive insulin therapy is beneficial in terms of postburn morbidity (16,25). In a recent prospective randomized trial, we found that intensive insulin therapy decreased the incidence of infections and sepsis significantly, along with dampened acute phase and inflammatory responses (15,16). We also showed that intensive insulin improved hepatic and renal function (15, 16, 17). The mechanisms by which insulin causes these effects are not determined, but based on this study and several other studies (5,25,26), all of which showed that insulin had antiinflammatory effects, improved organ function, and decreased incidence of infection and sepsis, we suggest that insulin exerts antiinflammatory effects and improves organ function by alleviating ER stress/UPR and exerting promitogenic effects in various organs, such as liver, heart and kidney (5,15,16). In the present study, we did not test the hypothesis that an alleviated ER stress/ UPR leads to an improved survival after a severe injury, but we speculate, based on a recent study in a burn-sepsis model in which it was demonstrated clearly that insulin improves survival, that a reduced ER stress response is associated with improved morbidity and mortality (26).

The ER, a membranous organelle that functions in the synthesis and processing of secretory and membrane proteins, is critical in the cellular stress response (27). Certain pathological stress conditions disrupt ER homeostasis and lead to accumulation of unfolded or misfolded proteins in the ER lumen (27, 28, 29). The ER stress response limits the unfolded protein burden in the ER lumen by inhibiting translation and inducing the nuclear transcription of additional chaperone proteins. If the unfolded protein burden cannot be reversed, apoptotic cell death ensues. To cope with this stress, cells activate a signal transduction system linking the ER lumen with the cytoplasm and nucleus, called the unfolded protein response (UPR) (28,29). ER stress is detected by transmembrane proteins that monitor the load of unfolded proteins in the ER lumen, and transmit this signal to the cytosol (27). Two of these proteins, inositol-requiring enzyme-1 and PKR-like ER kinase, undergo oligomerization and phosphorylation in response to increased ER stress (27). Work in our laboratory recently has demonstrated increased phosphorylation of IRE-1 and PERK in rodents and humans after burn injury, indicating postburn activation of ER-stress signaling pathways.

ER stress and UPR not only have been shown to affect inflammatory and stress responses, but also various metabolic responses (27,30,31). Specifically, several recent studies linked ER stress/UPR and JNK signaling to insulin resistance and hyperglycemia (11),12,19,32, 33, 34, 35). Upon binding to the α-subunit on the extracellular portion of its receptor, insulin induces autophosphorylation of the β-subunit, leading to conformational changes and phosphorylation of insulin receptor substrate (IRS)-1 at a critical tyrosine residue, which in turn leads to activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway (33,34). Recent work now suggests that stress-induced insulin resistance may in part be due to phosphorylation-based negative feedback, which may uncouple the insulin receptor or insulin receptor-associated proteins from their downstream signaling pathways, altering insulin action (34). Specifically, phosphorylation of IRS-1 at serine residues by various kinases may preclude its tyrosine phosphorylation by the insulin receptor tyrosine kinase, thus inhibiting insulin receptor trafficking (36).

We did not evaluate the effect of insulin administration on insulin resistance in the present study. The reason being that the study approach would have been to give the animals a peritoneal glucose tolerance test (PGTT) and therefore have the variable of PGTT stress altering our primary outcomes. Therefore, a PGTT was not within our outcome measures. However, in a recent clinical trial, we found that insulin administration improves insulin resistance (16) thus indicating that insulin not only alters glucose levels but also improves insulin resistance. We found in the present study that insulin decreased JNK activation. Activated JNK phosphorylates the IRS-1 kinase, which blocks IRS-1 tyrosine phosphorylation by the insulin receptor, leading to impaired insulin receptor signaling (32, 33, 34). We propose that this is one of the underlying mechanisms by which burn injury induces insulin resistance and hyperglycemia. Insulin decreased JNK activation, and it is therefore possible that insulin administration improves insulin resistance through inhibiting the JNK pathway (and thus allowing IRS-1 activation by the insulin receptor). That a burn in fact induces major insulin resistance not only has been shown clinically, but also in a rodent burn study which was very similar to the present study (19). The authors found that burn induces marked hepatic insulin resistance 1 to 3 d postburn associated with IR, PI3K, Akt and JNK signaling (19). Therefore, we suggest that insulin has a dual effect, decreasing glucose levels by increasing cellular uptake and by restoring insulin receptor signaling.

To examine mitochondrial and ER structure in situ, we performed transmission electron microscopy of liver sections from control, burn and burn-plus-insulin treated animals. We observed a significant loss of mitochondrial electron density and cristae in liver sections of burned animals. In addition, our electron microscopy analysis revealed fragmentation of the rough ER after burn injury. Thus, physiological changes observed in isolated mitochondria in vitro (that is, decreased state-3 respiration) are associated with consistent morphological changes in mitochondrial and ER structures in situ. Furthermore, we found that insulin treatment reversed these changes and improved hepatic mitochondrial and ER structure. These results clearly indicate that insulin is beneficial by improving not only hepatic function, but also by alleviating hepatocyte damage.

It is currently not clear whether inflammation induces ER stress and apoptosis or whether ER stress and apoptosis induce the inflammatory response. In the present study, we found that burn induced key inflammatory mediators. Insulin administration reduced IL-6, MCP-1, and CINC-1 significantly to almost normal levels when compared with burn, indicating that insulin leads to a decreased inflammatory response. As insulin also attenuated ER stress/UPR, we cannot address the question whether decreased inflammation causally leads to an alleviated ER stress response or vice versa. However, it appears that both responses are linked, and that insulin has antiinflammatory effects and alleviates the hepatic stress response.

In the present study, we found that insulin decreased hepatocyte apoptosis after a burn injury. Insulin administration further decreased ER stress/UPR, and improved hepatic mitochondrial respiration. The underlying mechanisms by which insulin improves hepatocyte apoptosis are not known. We hypothesize that insulin activates PI3K/Akt leading to decreased IP3R activation, which will restore intracellular calcium signaling and storage. Restored calcium signaling will reduce ER stress/UPR, which, in turn, will decrease JNK expression, which will decrease insulin resistance. Therefore, we conclude that insulin administration is a beneficial adjunct in critical care medicine to improve hepatic function and structure.


The authors declare that they have no competing interests as defined by Molecular Medicine, or other interests that might be perceived to influence the results and discussion reported in this paper.



The authors wish to thank Hal K Hawkins for assistance with the transmission electron microscopy. We also like to thank Eileen Figueroa and Steven Schuenke for their assistance in editing the manuscript. This work was supported by the Shriners Hospitals for Children grants 8660 (MG Jeschke), 8640 (MG Jeschke), 8760 (DN Herndon), 9145 (DN Herndon), and National Institutes of Health grants GM081685 (DB Boehning), GM008256 (DN Herndon), R01 GM087285 (MG Jeschke) and GM60338 (DN Herndon).


  1. 1.
    Bringham PA, McLoughlin E. (1996) Burn incidence and medical care use in the United States: estimates, trends and data sources. J. Burn Care Rehabil. 17:95–107.CrossRefGoogle Scholar
  2. 2.
    Jeschke MG, et al. (2001) Cell proliferation, apoptosis, NF-kappaB expression, enzyme, protein, and weight changes in livers of burned rats. Am. J. Physiol. Gastrointest. Liver Physiol. 280:G1314–20.CrossRefGoogle Scholar
  3. 3.
    Jeschke MG, Mlcak RP, Finnerty CC, Herndon DN. (2007) Changes in liver function and size after a severe thermal injury. Shock. 28:172–7.CrossRefGoogle Scholar
  4. 4.
    Jeschke MG, et al. (2005) Insulin prevents liver damage and preserves liver function in lipopolysaccharide-induced endotoxemic rats. J. Hepatol. 42:870–9.CrossRefGoogle Scholar
  5. 5.
    Klein D, Schubert T, Horch RE, Jauch KW, Jeschke MG. (2004) Insulin treatment improves hepatic morphology and function through modulation of hepatic signals after severe trauma. Ann. Surg. 240:340–9.CrossRefGoogle Scholar
  6. 6.
    Moshage H. (1997) Cytokines and the hepatic acute phase response. J. Pathol. 181:257–66.CrossRefGoogle Scholar
  7. 7.
    Jeschke MG. (2009) The hepatic response to thermal injury: is the liver important for postburn outcomes? Mol. Med. 15:337–51.CrossRefGoogle Scholar
  8. 8.
    Price LA, Thombs B, Chen CL, Milner SM. (2007) Liver disease in burn injury: evidence from a national sample of 31,338 adult patients. J. Burns Wounds. 7:e1.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Jeschke MG, Barrow RE, Herndon DN. (2004) Extended hypermetabolic response of the liver in severely burned pediatric patients. Arch. Surg. 139:641–7.CrossRefGoogle Scholar
  10. 10.
    Jeschke MG, Boehning DF, Finnerty CC, Herndon DN. (2007) Effect of insulin on the inflammatory and acute phase response after burn injury. Crit. Care Med. 35:S519–23.CrossRefGoogle Scholar
  11. 11.
    Jeschke MG, et al. (2009) Calcium and ER stress mediate hepatic apoptosis after burn injury. J. Cell Mol. Med. 13:1857–65.CrossRefGoogle Scholar
  12. 12.
    Jeschke MG, et al. (2008) Pathophysiologic response to severe burn injury. Ann. Surg. 248:387–401.CrossRefGoogle Scholar
  13. 13.
    Van den Berghe G, et al. (2006) Intensive insulin therapy in the medical ICU. N. Engl. J. Med. 354:449–61.CrossRefGoogle Scholar
  14. 14.
    van den Berghe G, et al. (2001) Intensive insulin therapy in the critically ill patients. N. Engl. J. Med. 345:1359–67.CrossRefGoogle Scholar
  15. 15.
    Jeschke MG, Klein D, Herndon DN. (2004) Insulin treatment improves the systemic inflammatory reaction to severe trauma. Ann. Surg. 239:553–60.CrossRefGoogle Scholar
  16. 16.
    Jeschke MG, et al. (2010) Intensive insulin therapy in severely burned pediatric patients: a prospective randomized trial. Am. J. Respir. Crit. Care Med. 182:351–9.CrossRefGoogle Scholar
  17. 17.
    Jeschke MG, Einspanier R, Klein D, Jauch KW. (2002) Insulin attenuates the systemic inflammatory response to thermal trauma. Mol. Med. 8:443–50.CrossRefGoogle Scholar
  18. 18.
    Herndon DN, Wilmore DW, Mason AD Jr. (1978) Development and analysis of a small animal model simulating the human postburn hypermetabolic response. J. Surg. Res. 25:394–403.CrossRefGoogle Scholar
  19. 19.
    Gauglitz GG, et al. (2009) Post-burn hepatic insulin resistance is associated with ER stress. Shock. 2009, June 18 [Epub ahead of print].Google Scholar
  20. 20.
    Boehning D, et al. (2003) Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat. Cell Biol. 5:1051–61.CrossRefGoogle Scholar
  21. 21.
    Boehning D, Patterson RL, Snyder SH. (2004) Apoptosis and calcium: new roles for cytochrome c and inositol 1,4,5-trisphosphate. Cell Cycle. 3:252–254.CrossRefGoogle Scholar
  22. 22.
    Boehning D, van Rossum DB, Patterson RL, Snyder SH. (2005) A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways. Proc. Natl. Acad. Sci. U. S. A. 102:1466–71.CrossRefGoogle Scholar
  23. 23.
    Wozniak AL, et al. (2006) Requirement of biphasic calcium release from the endoplasmic reticulum for Fas-mediated apoptosis. J. Cell Biol. 175:709–14.CrossRefGoogle Scholar
  24. 24.
    Song J, Finnerty CC, Herndon DN, Boehning D, Jeschke MG. (2009) Severe burn-induced endoplasmic reticulum stress and hepatic damage in mice. Mol. Med. 15:316–20.CrossRefGoogle Scholar
  25. 25.
    Hemmila MR, Taddonio MA, Arbabi S, Maggio PM, Wahl WL. (2008) Intensive insulin therapy is associated with reduced infectious complications in burn patients. Surgery. 144:629–37.CrossRefGoogle Scholar
  26. 26.
    Gauglitz GG, et al. (2009) Insulin increases resistance to burn wound infection-associated sepsis. Crit. Care Med. 38:202–8.CrossRefGoogle Scholar
  27. 27.
    Ron D, Walter P. (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol. Cell. Biol. 8:519–29.CrossRefGoogle Scholar
  28. 28.
    Hampton RY. (2000) ER stress response: getting the UPR hand on misfolded proteins. Curr. Biol. 10:R518–21.CrossRefGoogle Scholar
  29. 29.
    Mori K. (2000) Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell. 101:451–4.CrossRefGoogle Scholar
  30. 30.
    Ozcan U, et al. (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 306:457–61.CrossRefGoogle Scholar
  31. 31.
    Ozcan U, et al. (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 313:1137–40.CrossRefGoogle Scholar
  32. 32.
    White MF. (1997) The insulin signalling system and the IRS proteins. Diabetologia. 40 Suppl 2:S2–17.CrossRefGoogle Scholar
  33. 33.
    Kahn CR, et al. (1993) The insulin receptor and its substrate: molecular determinants of early events in insulin action. Recent Prog. Horm. Res. 48:291–339.CrossRefGoogle Scholar
  34. 34.
    Le Roith D, Zick Y. (2001) Recent advances in our understanding of insulin action and insulin resistance. Diabetes Care. 24:588–97.CrossRefGoogle Scholar
  35. 35.
    Gauglitz GG, Herndon DN, Jeschke MG. (2008) Insulin resistance postburn: underlying mechanisms and current therapeutic strategies. J. Burn Care Res. 29:683–94.CrossRefGoogle Scholar
  36. 36.
    Aguirre V, Uchida T, Yenush L, Davis R, White MF. (2000) The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J. Biol. Chem. 275:9047–54.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  • Marc G Jeschke
    • 1
    • 2
    • 3
    • 5
    Email author
  • Robert Kraft
    • 1
    • 2
  • Juquan Song
    • 1
    • 2
  • Gerd G Gauglitz
    • 1
    • 6
  • Robert A Cox
    • 1
  • Natasha C Brooks
    • 3
  • Celeste C Finnerty
    • 1
    • 2
  • Gabriela A Kulp
    • 1
  • David N Herndon
    • 1
    • 2
  • Darren Boehning
    • 4
  1. 1.Shriners Hospitals for ChildrenThe University of Texas Medical BranchGalvestonUSA
  2. 2.Department of SurgeryThe University of Texas Medical BranchGalvestonUSA
  3. 3.Department of Biochemistry and Molecular BiologyThe University of Texas Medical BranchGalvestonUSA
  4. 4.Department of Neuroscience and Cell BiologyThe University of Texas Medical BranchGalvestonUSA
  5. 5.Director Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Department of Surgery Division of Plastic SurgeryUniversity of Toronto Senior Scientist Sunnybrook Research InstituteTorontoCanada
  6. 6.Department of DermatologyLudwig-Maximilians University of MunichMunichGermany

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