PMID- 18445780
OWN - NLM
STAT- MEDLINE
DCOM- 20080730
LR  - 20211020
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 326
IP  - 1
DP  - 2008 Jul
TI  - Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) 
      pathway reduces lipopolysaccharide-induced inflammation in mice.
PG  - 348-53
LID - 10.1124/jpet.108.138891 [doi]
AB  - 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.
FAU - Kidd, Linda B
AU  - Kidd LB
AD  - The Department of Immunology, The Scripps Research Institute, La Jolla, 
      California, USA.
FAU - Schabbauer, Gernot A
AU  - Schabbauer GA
FAU - Luyendyk, James P
AU  - Luyendyk JP
FAU - Holscher, Todd D
AU  - Holscher TD
FAU - Tilley, Rachel E
AU  - Tilley RE
FAU - Tencati, Michael
AU  - Tencati M
FAU - Mackman, Nigel
AU  - Mackman N
LA  - eng
GR  - HL48872/HL/NHLBI NIH HHS/United States
GR  - T32 HL007195/HL/NHLBI NIH HHS/United States
GR  - T32 5 P32 HL007195-3/HL/NHLBI NIH HHS/United States
GR  - F32 HL085983/HL/NHLBI NIH HHS/United States
GR  - R01 HL048872/HL/NHLBI NIH HHS/United States
GR  - R01 HL048872-09/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080429
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Inflammation Mediators)
RN  - 0 (Insulin)
RN  - 0 (Lipopolysaccharides)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Endotoxemia/chemically induced/*enzymology/*prevention & control
MH  - Enzyme Activation/drug effects/physiology
MH  - Humans
MH  - Inflammation Mediators/*antagonists & inhibitors/toxicity
MH  - Insulin/*pharmacology/therapeutic use
MH  - Lipopolysaccharides/*antagonists & inhibitors/toxicity
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphatidylinositol 3-Kinases/*metabolism/physiology
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction/drug effects/*physiology
PMC - PMC2836781
MID - NIHMS181479
EDAT- 2008/05/01 09:00
MHDA- 2008/07/31 09:00
PMCR- 2010/03/11
CRDT- 2008/05/01 09:00
PHST- 2008/05/01 09:00 [pubmed]
PHST- 2008/07/31 09:00 [medline]
PHST- 2008/05/01 09:00 [entrez]
PHST- 2010/03/11 00:00 [pmc-release]
AID - jpet.108.138891 [pii]
AID - 10.1124/jpet.108.138891 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2008 Jul;326(1):348-53. doi: 10.1124/jpet.108.138891. Epub 
      2008 Apr 29.