Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: Role of glycogen synthase kinase-3β inhibition*

Dugo, Laura; Collin, Marika; Allen, David A.; Murch, Oliver; Foster, Simon J.; Yaqoob, Muhammad; Thiemermann, Christoph

doi:10.1097/01.ccm.0000215457.83953.e3

Cited by 53 publications

(49 citation statements)

References 42 publications

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“…For instance, insulin has been shown to increase the expression of mitogen-activated protein kinase phosphatase (MKP-1) in a PI3K-dependent manner (Desbois-Mouthon et al, 2000;Takehara et al, 2000), and this phosphatase negatively regulates IL-6 and TNF-␣ production in endotoxemic mice (Chi et al, 2006). Furthermore, a recent study showed that insulin and a glycogen synthase kinase 3␤ inhibitor had similar anti-inflammatory effects in a rat model of sepsis (Dugo et al, 2006). It is noteworthy that Akt-dependent phosphorylation decreases the activity of glycogen synthase kinase 3␤ (Guha and Mackman, 2002;Martin et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Insulin Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase B (Akt) Pathway Reduces Lipopolysaccharide-Induced Inflammation in Mice

Kidd

Schabbauer

Luyendyk

et al. 2008

J Pharmacol Exp Ther

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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-␣, 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.

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Section: Discussionmentioning

confidence: 99%

Insulin Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase B (Akt) Pathway Reduces Lipopolysaccharide-Induced Inflammation in Mice

Kidd

Schabbauer

Luyendyk

et al. 2008

J Pharmacol Exp Ther

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“…23,24 To date, TDZD-8 has been evaluated primarily as a cytoprotective agent in multiple rodent models for maladies such as septic and nonseptic shock, lung injury, arthritis, spinal cord injury, colitis, and Alzheimer disease. [25][26][27][28][29][30][31][32][33] However, in the present study we describe an entirely new activity for TDZD-8, which thus far appears to be restricted to cells derived from hematologic malignancies. We show that this compound is strongly cytotoxic to multiple types of primary leukemia cells, as well as phenotypically and functionally defined LSCs.…”

Section: Introductionmentioning

confidence: 87%

Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8)

Guzmán

Corbett

et al. 2007

Blood

100

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Leukemia is thought to arise from malignant stem cells, which have been described for acute and chronic myeloid leukemia (AML and CML) and for acute lymphoblastic leukemia (ALL). Leukemia stem cells (LSCs) are relatively resistant to current chemotherapy and likely contribute to disease relapse and progression. Consequently, the identification of drugs that can efficiently eradicate LSCs is an important priority. In the present study, we investigated the antileukemia activity of the compound TDZD-8. Analysis of primary AML, blast crisis CML (bcCML), ALL, and chronic lymphoblastic leukemia (CLL) specimens showed rapid induction of cell death upon treatment with TDZD-8. In addition, for myeloid leukemias, cytotoxicity was observed for phenotypically primitive cells, in vitro colony-forming progenitors, and LSCs as defined by xenotransplantation assays. In contrast, no significant toxicity was observed for normal hematopoietic stem and progenitor cells. Notably, cell death was frequently evident within 2 hours or less of TDZD-8 exposure. Cellular and molecular studies indicate that the mechanism by which TDZD-8 induces cell death involves rapid loss of membrane integrity, depletion of free thiols, and inhibition of both the PKC and FLT3 signaling pathways. We conclude that TDZD-8 uses a unique and previously unknown mechanism to rapidly target leukemia cells, including malignant stem and progenitor populations. (Blood. 2007;110: [4436][4437][4438][4439][4440][4441][4442][4443][4444]

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“…In addition, the reduction of endotoxin and peptidoglycan-induced pathologic conditions in rats by insulin, independent of blood glucose changes, has been demonstrated to involve GSK-3 inhibition (Dugo et al, 2006). Others reported that the insulin resistance and associated increase in GSK-3␤ activity in brains of a mouse model of T2DM, as well as what the authors noted were learning difficulties parallel to those seen in AD, were corrected by administering insulin (Jolivalt et al, 2008).…”

mentioning

confidence: 88%

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

et al. 2012

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Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: Role of glycogen synthase kinase-3β inhibition*

Cited by 53 publications

References 42 publications

Insulin Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase B (Akt) Pathway Reduces Lipopolysaccharide-Induced Inflammation in Mice

Insulin Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase B (Akt) Pathway Reduces Lipopolysaccharide-Induced Inflammation in Mice

Rapid and selective death of leukemia stem and progenitor cells induced by the compound 4-benzyl, 2-methyl, 1,2,4-thiadiazolidine, 3,5 dione (TDZD-8)

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

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