Elsevier

Metabolism

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

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

https://doi.org/10.1016/S0026-0495(03)00057-XGet 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

References (35)

  • D.K. Rosmarin et al.

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

    Nutr Clin Pract

    (1996)
  • G. van den Berghe et al.

    Intensive insulin therapy in critically ill patients

    N Engl J Med

    (2001)
  • T. Nishikawa et al.

    Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage

    Nature

    (2000)
  • K.K. Yerneni et al.

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

    Diabetes

    (1999)
  • P. Pozzilli et al.

    Infections and diabetesMechanisms and prospects for prevention

    Diabet Med

    (1994)
  • M.O. Kwoun et al.

    Immunologic effects of acute hyperglycemia in nondiabetic rats

    JPEN J Parenter Enteral Nutr

    (1997)
  • P.R. Ling et al.

    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

    (2002)
  • Cited by (64)

    • Hyperglycemia induces embryopathy, even in the absence of systemic maternal diabetes: An in vivo test of the fuel mediated teratogenesis hypothesis

      2014, Reproductive Toxicology
      Citation Excerpt :

      There are two conventional in vivo approaches to testing the fuel mediated teratogenesis hypothesis: (i) induction of diabetes in the pregnant rodent by various means such as streptozotocin [47], (ii) systemic administration of glucose [24,48]. However, neither of these approaches allows analysis of the isolated local effects of individual fuels on diabetic embryopathy because (i) systemic diabetes induces multifaceted irregularities in the maternal circulation, including abnormal energy fuels, inflammation, and oxidative stress, as noted in the introduction, and (ii) systemic induction of hyperglycemia by glucose administration produces a myriad of rapid (within hours) systemic aberrations including increased plasma triglycerides [25], oxidative stress and systemic inflammation [28–30], altered insulinemia [49], altered gene expression in tissues [50], and altered lipid and amino acid metabolism [26,27]. One elegant in vivo study tested whether hyperglycemia is necessary to induce diabetes-related embryopathy by treating diabetic pregnant rodents with phlorizin to selectively ameliorate the hyperglycemia but not the insulinopenic state [24].

    • The manner of the inflammation-boosting effect caused by acute hyperglycemia secondary to overfeeding and the effects of insulin therapy in a rat model of sepsis

      2013, Journal of Surgical Research
      Citation Excerpt :

      The second key question is whether insulin therapy can inhibit such an inflammation-boosting effect caused by acute hyperglycemia. The third key question is whether insulin therapy also improves metabolic stress associated with acute hyperglycemia induced by overfeeding, such as the oxidative stress [9,11]. To examine these issues, we designed a rat model of acute hyperglycemia obtained by adjusting intravenous glucose loading under septic conditions induced by cecal ligation and puncture (CLP).

    • Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats

      2012, Journal of Diabetes and its Complications
      Citation Excerpt :

      Liver is the focal organ of oxidative and detoxifying processes as well as free radical reactions and the biomarkers of oxidative stress are elevated in the liver at an early stage in many diseases, including diabetes mellitus (Stadler, Jenei, von Bölcsházy, Somogyi, & Jakus, 2003). In experimental diabetes, STZ exerts its toxic effect on liver and other organs in addition to pancreatic β-cells (Ling, Mueller, Smith, & Bistrian, 2003). The insulin insufficiency and hyperglycemia that result from β-cell necrosis further augment liver damage through ROS-mediated lipid peroxidation of hepatocellular membrane (Kume et al., 2004).

    View all citing articles on Scopus

    Supported in part by National Institutes of Health Grant No. DK 50411 (R.J.S., P.R.L. and B.R.S.)

    View full text