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

Eszter M. Horváth, Rita Benko, Domonkos Gero, Levente Kiss, Csaba Szabo

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)205-209
Number of pages5
JournalLife Sciences
Volume82
Issue number3-4
DOIs
StatePublished - Jan 16 2008
Externally publishedYes

Fingerprint

Endotoxemia
Poly(ADP-ribose) Polymerases
Rats
Chemical activation
Insulin
Lipopolysaccharides
Therapeutics
Lymphocytes
Tumor Necrosis Factor-alpha
Human Umbilical Vein Endothelial Cells
Critical Illness
Hyperglycemia
Mononuclear Leukocytes
Mitochondria
Flow cytometry
Endothelial cells
Oxidants
Gene expression
Endotoxins
Shock

Keywords

  • Diabetes
  • Glycemic control
  • Inflammation
  • Oxidative stress
  • PARP
  • Sepsis
  • TNF-α

ASJC Scopus subject areas

  • Pharmacology

Cite this

Treatment with insulin inhibits poly(ADP-ribose)polymerase activation in a rat model of endotoxemia. / Horváth, Eszter M.; Benko, Rita; Gero, Domonkos; Kiss, Levente; Szabo, Csaba.

In: Life Sciences, Vol. 82, No. 3-4, 16.01.2008, p. 205-209.

Research output: Contribution to journalArticle

Horváth, Eszter M. ; Benko, Rita ; Gero, Domonkos ; Kiss, Levente ; Szabo, Csaba. / Treatment with insulin inhibits poly(ADP-ribose)polymerase activation in a rat model of endotoxemia. In: Life Sciences. 2008 ; Vol. 82, No. 3-4. pp. 205-209.
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