The protective role of insulin and PI3-kinase in sepsis

Sepsis is defined by the systemic inflammatory response to an infection with high morbidity and mortality. The patho-physiology of sepsis is complex and the molecular basis is still poorly understood. Recently it has been shown that high dose insulin therapy in septic intensive care unit patients showed improved survival. Here we are interested in the beneficial signaling properties of insulin in sepsis beyond its role in glucose metabolism. We believe that there are protective, anti-inflammatory signaling pathways, such as the phosphatidylinsositol-3 kinase (PI3K) pathway, regulating the host inflammatory response in mouse models of sepsis and endotoxemia. Hence, activation of PI3K by insulin may contribute to the beneficial effects observed in insulin-treated patients. The PI3K pathway has been shown in vitro and in vivo to suppress the activation of pro-inflammatory intracellular signaling pathways as well as the expression of pro-inflammatory cytokines and the pro-coagulant tissue factor (TF). In this study we want to investigate Insulin and the potentially protective properties of the PI3K signaling pathway in experimental sepsis applying a pharmacologic approach using the potent PI3K activator, insulin, and a genetic approach using insulin-sensitive PI3K gene modified mice. Results of these experiments could provide more insight into the protective signaling properties of insulin by activation of the PI3K pathway and may lead to a better understanding of sepsis on a molecular level.

Morbidity and mortality related to infectious diseases in humans still represent some of the major problems in our society. This is not only the case in the developing world but also in developed countries in Europe as well as North America. Infectious diseases which result in the development of sepsis cause a major burden for our health care system with high and yearly rising expenditures. Prevention of sepsis and the reduction of the number of septic patients are indispensable. Furthermore the precise understanding of "the septic disease" is of utmost importance, since clinical treatment options are still very limited to date. One clinically applied strategy is "intensive insulin therapy". However the molecular mechanism behind the beneficial effects of this treatment is still unresolved. We are interested in the decryption of beneficial signaling pathways, such as the Phosphatidylinositol-3 Kinase (PI3-K) pathway, in immune cells that might help to increase survival in animal models of acute inflammation and sepsis. We hypothesize that the PI3-K signaling pathway downmodulates pro-inflammatory signals leading to a significantly reduced "cytokine storm" in septic organisms. Among many others, Insulin is one of the most potent endogenous factors inducing PI3-K activity. That is the reason why we wanted to test whether Insulin effects observed in septic animals are indeed depending on the activation of PI3-K. We could clearly show that systemic inhibition of the PI3K using a fungal metabolite could substantially abrogate the protective properties of insulin in a mouse model of acute inflammation. Furthermore we could provide convincing evidence in number of published studies using genetically modified mouse models that the modulation of the PI3-K pathway activation directly interferes with relevant pro- inflammatory effector mechanisms in models of clinically relevant infectious diseases. In conclusion we hope that the results of our project help to gain more functional insight in sepsis and the molecular mechansism underlying the disease. Furthermore we believe that our studies strengthen the idea that currently developed PI3-K targeting therapeutics should be used with caution in patients with higher incidence of infectious diseases, since PI3-K is a central regulator of the host immune response.