Severe injury is associated with insulin resistance, endoplasmic reticulum stress response, and unfolded protein response

Abstract

Objective: We determined whether postburn hyperglycemia and insulin resistance are associated with endoplasmic reticulum (ER) stress/unfolded protein response (UPR) activation leading to impaired insulin receptor signaling.

Background: Inflammation and cellular stress, hallmarks of severely burned and critically ill patients, have been causally linked to insulin resistance in type 2 diabetes via induction of ER stress and the UPR.

Methods: Twenty severely burned pediatric patients were compared with 36 nonburned children. Clinical markers, protein, and GeneChip analysis were used to identify transcriptional changes in ER stress and UPR and insulin resistance-related signaling cascades in peripheral blood leukocytes, fat, and muscle at admission and up to 466 days postburn.

Results: Burn-induced inflammatory and stress responses are accompanied by profound insulin resistance and hyperglycemia. Genomic and protein analysis revealed that burn injury was associated with alterations in the signaling pathways that affect insulin resistance, ER/sarcoplasmic reticulum stress, inflammation, and cell growth/apoptosis up to 466 days postburn.

Conclusion: Burn-induced insulin resistance is associated with persistent ER/sarcoplasmic reticulum stress/UPR and subsequent suppressed insulin receptor signaling over a prolonged period of time.

Figures

FIGURE 1

Severe burn injury leads to vast inflammatory stress responses, hyperglycemia, and hyperinsulinemia. Levels of urinary cortisol (A), epinephrine (B), serum MCP-1 (C), serum IL-6 (D), and REE% predicted (E), fasting serum of glucose (F), and insulin (G) were determined at various time points postburn and compared with nonburned children. Bars represent mean; error bars correspond to SEM. *Statistical difference between burned children versus non-burned children, P < 0.05.

FIGURE 2

Burn injury induces ER/SR stress and the UPR in muscle. Western blot analysis of muscle from normal, unburned patients, and burned patients taken at various time points postburn (0–10, 11–49, and 50–250 days postburn, respectively). Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) and actin served as control loading proteins (A). Quantitative analysis of proteomic alterations in muscle. Expression of proteins involved in ER/SR stress, the UPR, inflammation, and insulin signaling–related pathways were measured at the respective time periods (B–P). Histograms depict intensities of the phosphorylated protein bands divided by the intensity of the total form of the respective protein band or in the case of nonphosphorylated proteins, by the intensity of the respective actin or glyceraldehyde-3-phosphate-dehydrogenase band. Results are presented as fold change from unburned controls and represent 6 to 8 different patients per group, as indicated in the main text. Bars represent mean; error bars correspond to SEM. *Statistical significance: P < 0.05 for every comparison between groups and compared with controls.