Treatment with insulin inhibits poly(ADP-ribose)polymerase activation in a rat model of endotoxemia

In critically ill patients various conditions may lead to the activation of poly(ADP-ribose) polymerase (PARP). By promoting cellular energetic dysfunction, and by enhancing pro-inflammatory gene expression, PARP activation significantly contributes to the pathogenesis of shock. PARP activation is u...

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Bibliographic Details
Published in:Life sciences (1973) 2008-01, Vol.82 (3), p.205-209
Main Authors: Horváth, Eszter M., Benkő, Rita, Gerő, Domonkos, Kiss, Levente, Szabó, Csaba
Format: Article
Language:English
Subjects:
Animals
Blood Glucose - analysis
Blood Glucose - drug effects
Blotting, Western
Cell Line
Diabetes
Disease Models, Animal
Drug Therapy, Combination
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Endotoxemia - drug therapy
Endotoxemia - enzymology
Enzyme Activation - drug effects
Glycemic control
Humans
Hyperglycemia
Hypoglycemic Agents - therapeutic use
Inflammation
Insulin - therapeutic use
Lipopolysaccharides - pharmacology
Lymphocytes - drug effects
Lymphocytes - enzymology
Male
Oxidative stress
PARP
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - metabolism
Rats
Rats, Wistar
Sepsis
TNF-α
Tumor Necrosis Factor-alpha - metabolism
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Summary:In critically ill patients various conditions may lead to the activation of poly(ADP-ribose) polymerase (PARP). By promoting cellular energetic dysfunction, and by enhancing pro-inflammatory gene expression, PARP activation significantly contributes to the pathogenesis of shock. PARP activation is usually triggered by DNA strand breakage, which is typically the result of the overproduction of various reactive oxidant species. One of the pathophysiological conditions associated with PARP activation is hyperglycemia, where the reactive species are produced from the mitochondria and other cellular sources. In the present study we tested whether endotoxin-induced PARP activation and pro-inflammatory mediator production can be modified by insulin therapy. Rats subjected to bacterial lipopolysaccharide (LPS) with or without insulin co-treatment were studied. LPS-induced PARP activation in circulating lymphocytes was measured by flow cytometry, tumor necrosis factor alpha (TNF-α) production was measured by ELISA. The direct effect of insulin on the PARP activity of mononuclear leukocytes and human umbilical vein endothelial cells (HUVEC) in elevated glucose conditions was tested in vitro. LPS-induced significant hyperglycemic response activated PARP in circulating lymphocytes and induced TNF-α production. Insulin treatment prevented LPS-induced hyperglycemic response, blocked PARP activation and blunted LPS-induced TNF-α response. Insulin treatment caused a slight reduction in the PARP activity of mononuclear cells and HUVECs in vitro. We demonstrate that insulin treatment blocks LPS-induced PARP activation in vivo. We propose that this effect is mainly indirect, and occurs due to the prevention of stress induced hyperglycemia, with a direct cellular effect of insulin playing a potential minor supplemental role. The current findings may have significant implications in the context of the emerging concept of tight glycemic control and insulin treatment for critically ill patients.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2007.11.001