Insulin therapy inhibits poly(ADP-ribose)polymerase activation in endotoxin shock

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated in various forms of circulatory shock. By triggering a cellular energetic dysfunction, and by promoting proinflammatory gene expression, PARP activation significantly contributes to the pathogenesis of shock. The activation of PARP is usually triggered by DNA strand breakage, which is typically the result of the overproduction of reactive oxidant species. In the present study we tested whether endotoxin-induced PARP activation and proinflammatory mediator production can be modified by insulin therapy. Rats subjected to bacterial lipopolysaccharide (LPS) with or without insulin pretreatment were studied. LPS-induced PARP activation in circulating leukocytes was measured by flow cytometry, and production of TNFα was measured by ELISA. LPS induced a significant hyperglycemic response, activated PARP in circulating leukocytes and induced the production of TNFα . Insulin treatment prevented the LPS-induced hyperglycemic response, blocked the activation of PARP and blunted the LPS-induced TNFα response. As hyperglycemia is known to induce the cellular formation of reactive species, we propose that PARP activation in endotoxin shock occurs as a result of hyperglycemia-induced reactive oxidant and free radical generation. The current findings may have significant implications in the context of the emerging concept of tight glycemic control for critically ill patients.