Hyperglycemia induced by glucose infusion causes hepatic oxidative stress and systemic inflammation, but not STAT3 or MAP kinase activation in liver in rats

doi:10.1016/S0026-0495(03)00057-X

Metabolism

Volume 52, Issue 7, July 2003, Pages 868-874

https://doi.org/10.1016/S0026-0495(03)00057-X Get rights and content

Abstract

The purpose of this study was to determine the effects of acute hyperglycemia induced by glucose infusion on oxidative stress, systemic inflammation, and several key signal intermediates in liver for the systemic inflammatory response in nonstressed rats. Rats received saline or glucose infusion (hyperglycemic clamp) for 3 hours. Rats without catheter insertion were included as an additional control for observing the effects of surgical stress. Levels of malondialdehyde (MDA) and total glutathione to assess oxidative stress were determined in liver and muscle. Proinflammatory cytokines including tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6, and alpha 1 acid glycoprotein (α1-AG) were determined in serum. The protein content and phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 stress-activated protein kinase (p38), and signal transducer and activator of transcription-3 (STAT-3) were examined in the liver tissue with or without IL-6 stimulation. The results showed that acute hyperglycemia significantly increased MDA release and depleted total glutathione in liver but not in muscle. Hyperglycemia also significantly elevated the production of TNF, IL-1, and α1-AG, but not IL-6 in serum. However, hyperglycemia for 3 hours in vivo did not activate ERK1/2, p38 and STAT3 in liver, and also did not alter the response of these signal proteins to IL-6 stimulation. These data suggest that acute (3 hours) hyperglycemia causes hepatic oxidative stress and activates a low-grade systemic inflammation but does not affect key components of the IL-6 signaling pathway in liver.

Section snippets

Animals

Male Sprague-Dawley rats (weight, 200 to 220 g; Taconic Farms, Germantown, NY) were acclimated in individual cages in a light-controlled room (12 hours on/12 hours off) at 22 to 24°C for 4 days in the animal facility of Beth Israel Deaconess Medical Center. During this period, animals were given free access to food and tap water. The laboratory diet contained 24 % protein, 6 % fat, and 4.5 % fiber with adequate minerals and vitamins (Rodent diet 8664, Harlan Teklad, Madison, WI).

After

Results

At the onset of the experiment, serum glucose was similar in all animals while insulin was not determined because of the limited blood sample from the tail vein. During the experiment, serum glucose concentrations were maintained at basal levels (110 ± 9 mg/dL) in both the Con and Surg − clamp groups. However, in the Surg + clamp group glucose level was significantly raised to 350 mg/dL and effectively maintained by glucose infusion. At the end of the study, serum insulin levels were

Discussion

In this study, the hyperglycemic clamp technique was used to achieve an elevated glucose (∼350 mg/dL) level for 3 hours, and the effects of this level of blood glucose on activation of systemic inflammation and development of oxidative stress were assessed. An average 0.09 g of glucose/kg/min was infused into animals, which would provide approximately 460 calories/kg/d if continued at this rate. This amount of energy intake is about 2.5 times the required energy for rats of this size (estimated

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BG level in all groups remained in the preestablished target range throughout the experiment. Plasma IL-6 level in all septic groups increased in a time-dependent manner, whereas that in the sham group with moderate hyperglycemia hardly increased. Nine hours after CLP, plasma IL-6 level in the HG group rose to 7407.5 ± 1987.3 pg/mL, which was three times higher than that in the other septic groups. There was no significant difference among moderate glucose, no glucose, and HI groups, in which BG level remained constant at <300 mg/dL. The HG group showed the worst consequences of lung injury and oxidative stress in the liver, which were completely stable in HI group.
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^☆: Supported in part by National Institutes of Health Grant No. DK 50411 (R.J.S., P.R.L. and B.R.S.)

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Hyperglycemia induced by glucose infusion causes hepatic oxidative stress and systemic inflammation, but not STAT3 or MAP kinase activation in liver in rats☆

Abstract

Section snippets

Animals

Results

Discussion

Am J Clin Nutr

Am J Clin Nutr

J Biol Chem

Free Radic Biol Med

J Biol Chem

Kidney Int

J Diabetes Compl

J Biol Chem

Nutrition

Resting energy expenditure in the critically illEstimations versus measurement

Br J Surg

Hyperglycemia associated with high, continuous infusion rates of total parenteral nutrition dextrose

Nutr Clin Pract

Intensive insulin therapy in critically ill patients

N Engl J Med

Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage

Nature

Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells

Diabetes

Infections and diabetesMechanisms and prospects for prevention

Diabet Med

Immunologic effects of acute hyperglycemia in nondiabetic rats

JPEN J Parenter Enteral Nutr

Inhibition of IL-6-activated janus/signal transducers and activators of transcription but not mitogen-activated protein kinase signaling in liver of endotoxin-teated rats

Crit Care Med