Insulin Activation of PI3K Reduces Inflammation in a Mouse Model of Endotoxemia.

A recent clinical study showed that intensive insulin treatment in patients in intensive care units reduced morbidity and mortality. Other studies indicate that insulin has anti-inflammatory properties beyond its regulation of glucose metabolism. We determined the effect of insulin on LPS-induced inflammation in vivo. Insulin was administered via miniosmotic pump at a low dose (2.5 mU/h) that did not affect plasma glucose levels. Insulin treatment significantly reduced levels of plasma TNFα and IL-6 and prolonged the survival of endotoxemic mice. Next, we determined the role of the phosphatidyl-inositol-3 kinase (PI3K) pathway in insulin protection. Insulin is a potent activator of PI3K signaling. We and others have shown that inhibition of PI3K in monocytes, endothelial cells and in a model of endotoxemia enhances inflammation, suggesting that the PI3K pathway suppresses LPS signaling. We determined if insulin reduced inflammation in a PI3K-dependent manner by blocking PI3K in endotoxemic mice using wortmannin. We found that wortmannin abolished the protective effect of insulin. Finally, we examined the effect of insulin on p85β^−/− mice, which have increased PI3K activity and are hyperresponsive to insulin. Endotoxemic p85β^−/− mice exhibited reduced plasma TNFα and IL-6 and had a prolonged survival compared with endotoxemic wild-type littermate controls. Taken together, these results indicate that insulin reduces LPS-induced inflammation in a PI3K-dependent manner.