title: Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice.
abstract: Insulin is used to control pro-inflammatory hyperglycemia in critically ill patients. However, recent studies suggest that insulin-induced hypoglycemia may negate its beneficial effects in these patients. It is noteworthy that recent evidence indicates that insulin has anti-inflammatory effects that are independent of controlling hyperglycemia. To date, the mechanism by which insulin directly reduces inflammation has not been elucidated. It is well established that insulin activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling in many cell types. We and others have shown that this pathway negatively regulates LPS-induced signaling and pro-inflammatory cytokine production in monocytic cells. We hypothesized that insulin inhibits inflammation during endotoxemia by activation of the PI3K/Akt pathway. We used a nonhyperglycemic mouse model of endotoxemia to determine the effect of continuous administration of a low dose of human insulin on inflammation and survival. It is noteworthy that insulin treatment induced phosphorylation of Akt in muscle and adipose tissues but did not exacerbate lipopolysaccharide (LPS)-induced hypoglycemia. Insulin decreased plasma levels of interleukin-6, tumor necrosis factor-alpha, monocyte chemotactic protein 1 (MCP1)/JE, and keratinocyte chemoattractant, and decreased mortality. The PI3K inhibitor wortmannin abolished the insulin-mediated activation of Akt and the reduction of chemokine and interleukin-6 levels. We conclude that insulin reduces LPS-induced inflammation in mice in a PI3K/Akt-dependent manner without affecting blood glucose levels.
authors.affiliation: The Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Linda B
authors.initials: LB
authors.lastname: Kidd
authors.forename: Gernot A
authors.initials: GA
authors.lastname: Schabbauer
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.forename: Todd D
authors.initials: TD
authors.lastname: Holscher
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Tilley
authors.forename: Michael
authors.initials: M
authors.lastname: Tencati
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D018836:Inflammation Mediators; D007328:Insulin; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt