Effects of Hyperglycemia and Insulin Therapy on Outcome in a Hyperglycemic Septic Model of Critical Illness

Heuer, Josef G.; Sharma, Ganesh R.; Zhang, Tonghai; Ding, Chunjin; Bailey, Dianna L.; Stephens, Eddie J.; Holmes, Kimberly; Grubbs, Renee L.; Fynboe, Kelly A.; Chen, Yunfei; Jakubowski, Joseph A.

doi:10.1097/01.ta.0000215565.29846.ab

Cited by 20 publications

(16 citation statements)

References 47 publications

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“…Stressinduced hyperglycaemia frequently occurs in infection and is associated with an adverse outcome [14,48]. Elevated TNFα levels, increased MCP-1 production as well as low adiponectin may act in concert to induce and to maintain hyperglycaemia in critical illness.…”

Section: Discussionmentioning

confidence: 99%

Endotoxaemia leads to major increases in inflammatory adipokine gene expression in white adipose tissue of mice

Leuwer

Welters

Marx

et al. 2008

Pflugers Arch - Eur J Physiol

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The proposition that white adipose tissue is involved in the inflammatory response and metabolic dysregulation of endotoxaemia has been examined. Mice were injected with lipopolysaccharide (LPS; 25 mg/kg) and epididymal, perirenal and subcutaneous adipose tissue removed 4 or 24 h later. The expression of genes encoding key inflammation-related adipokines was measured by real-time polymerase chain reaction. At 24 h after the administration of LPS, there was no change in leptin mRNA level, and adiponectin mRNA fell. However, major increases in TNFalpha, MCP-1 (up to 40-fold) and IL-6 (up to 250-fold) mRNA levels were evident; a substantial elevation in these mRNAs occurred by 4 h, and adipose tissue IL-6 protein also increased (three- to eightfold). At 24 h, the responses in the subcutaneous depot were much lower than in epididymal and perirenal adipose tissue, but at 4 h, the subcutaneous tissue showed major increases in IL-6, MCP-1 and TNFalpha gene expression. In contrast to the inflammatory adipokines, the mRNA level of two macrophage markers, F4/80 and MAC-1, was unaltered in adipose tissue during endotoxaemia. Expression of the hypoxia-sensitive transcription factor, HIF-1alpha, gene was increased at both 4 and 24 h, and HIF-1alpha protein was elevated at 4 h, suggesting that the tissue was hypoxic. It is concluded that white adipose tissue may play an important role in the production of inflammatory mediators in endotoxaemia.

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Section: Discussionmentioning

confidence: 99%

Endotoxaemia leads to major increases in inflammatory adipokine gene expression in white adipose tissue of mice

Leuwer

Welters

Marx

et al. 2008

Pflugers Arch - Eur J Physiol

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“…Heuer et al (11) reported that hyperglycemic and septic rodents had higher levels of cytokines/chemokines, serum organ damage markers and reduced survival. In a rabbit model of critical illness, elevated blood glucose induced by alloxan administration evoked cellular glucose overload, inducing mitochondrial dysfunction (12).…”

Section: Introductionmentioning

confidence: 99%

Hyperglycemia Exacerbates Burn-Induced Liver Inflammation via Noncanonical Nuclear Factor-κB Pathway Activation

Kulp

Tilton

Herndon

et al. 2012

Mol Med

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Hyperglycemia and inflammation are hallmarks of burn injury. In this study, we used a rat model of hyperglycemia and burn injury to investigate the effects of hyperglycemia on inflammatory responses in the liver. Hyperglycemia was induced in male Sprague-Dawley rats with streptozotocin (STZ) (35-40 mg/kg), followed by a 60% third-degree scald burn injury. Cytokine levels (by multiplex, in cytosolic liver extracts), hormones (by enzyme-linked immunosorbent assay [ELISA], in serum), nuclear factor (NF)-κB protein deoxyribonucleic acid (DNA) binding (by ELISA, in nuclear liver extracts) and liver functional panel (using VetScan, in serum) were measured at different time points up to 7 d after burn injury. Blood glucose significantly increased after burn injury in both groups with different temporal patterns. Hyperglycemic rats were capable of endogenous insulin secretion, which was enhanced significantly versus controls 12 h after burn injury. DNA binding data of liver nuclear extracts showed a robust and significant activation of the noncanonical NF-κB pathway in the hyperglycemic versus control burn animals, including increased NF-κB-inducing kinase expression (p < 0.05). Liver acute-phase proteins and cytokine expression were increased, whereas secretion of constitutive proteins was decreased after burn injury in hyperglycemic versus control animals (p < 0.05). These results indicate that burn injury to the skin rapidly activated canonical and noncanonical NF-κB pathways in the liver. Robust activation of the NF-κB noncanonical pathway was associated with increased expression of inflammatory markers and acute-phase proteins, and impaired glucose metabolism. Hyperglycemia is detrimental to burn outcome by augmenting inflammation mediated by hepatic noncanonical NF-κB pathway activation.

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“…During a bout of sepsis, whole body metabolism is shifted into a catabolic state, the most marked features of which include increased resting energy expenditure, hyperglycemia, and rapid muscle loss (4). Attenuation of each of these features is associated with a reduction in associated mortality (5)(6)(7). A prime mediator of the response to sepsis is a rapid increase in catecholamine levels and sympathetic activation (8).…”

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confidence: 98%

Metabolism modulators in sepsis: Propranolol

Norbury

Jeschke

Herndon

2007

Critical Care Medicine

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Sepsis is accompanied by an enormous increase in catecholamine expression, leading to metabolism of lipids and glucose, changes in cardiovascular output, immunomodulatory effects, and changes in protein metabolism, all of which push the body into a catabolic state. Deleterious beta-adrenoceptor controlled responses to stress and sepsis are well documented; therefore, it would seem appropriate to use propranolol under such circumstances. There are arguments both for and against the use of beta-adrenoceptor blockade during episodes of stress and infection. The definition of sepsis itself is a clinical one in most cases. There are guidelines concerning the diagnosis of sepsis (systemic inflammatory response syndrome [SIRS] in the presence of significant infection). However, when the cause of SIRS is not infection, for example, in burn patients, is it not possible, and indeed preferable, to tackle the stress response in a more aggressive fashion? The effects of SIRS on the body are myriad and have been defined and illustrated in many fine reviews. The effects of sepsis on the body, as well, have been discussed in the world literature and are beyond the scope of this article. In this article we attempt to demonstrate the effects of sepsis (SIRS plus infection) on whole body metabolism, outline the mediators of these changes, and then show the ability of propranolol to attenuate the changes seen.

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Effects of Hyperglycemia and Insulin Therapy on Outcome in a Hyperglycemic Septic Model of Critical Illness

Abstract: Hyperglycemia is associated with greater morbidity and mortality in sepsis. Insulin therapy significantly improved survival suggesting that management of hyperglycemia with insulin may improve outcome in septic patients.

Cited by 20 publications

References 47 publications

Endotoxaemia leads to major increases in inflammatory adipokine gene expression in white adipose tissue of mice

Endotoxaemia leads to major increases in inflammatory adipokine gene expression in white adipose tissue of mice

Hyperglycemia Exacerbates Burn-Induced Liver Inflammation via Noncanonical Nuclear Factor-κB Pathway Activation

Metabolism modulators in sepsis: Propranolol

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