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Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat.

Lacraz G, Giroix MH, Kassis N, Coulaud J, Galinier A, Noll C, Cornut M, Schmidlin F, Paul JL, Janel N, Irminger JC, Kergoat M, Portha B, Donath MY, Ehses JA, Homo-Delarche F - PLoS ONE (2009)

Bottom Line: All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets.IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biology & Pathology of Endocrine Pancreas, Functional and Adaptive Biology Unit-CNRS EA 7059, University Paris-Diderot, Paris, France.

ABSTRACT

Background: Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra).

Methodology/principal findings: Gene expression was analyzed by quantitative RT-PCR on islets isolated from 10-week-old diabetic GK and control Wistar rats. Furthermore, GK rats were treated s.c twice daily with IL-1Ra (Kineret, Amgen, 100 mg/kg/day) or saline, from 4 weeks of age onwards (onset of diabetes). Four weeks later, islet gene analysis and pancreas immunochemistry were performed. Thirty-two genes were selected encoding molecules involved in endothelial cell activation, particularly fibrinolysis, vascular tone, OS, angiogenesis and also inflammation. All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets. After IL-1Ra treatment of GK rats in vivo, most selected genes implied in endothelium/OS/immune cells/fibrosis were significantly down-regulated. IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.

Conclusions/significance: GK rat islets have increased mRNA expression of markers of early islet endothelial cell activation, possibly triggered by several metabolic factors, and also some defense mechanisms. The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations. Thus, metabolically-altered islet endothelium might affect the beta-cell microenvironment and contribute to progressive type 2 diabetic beta-cell dysfunction in GK rats. Counteracting islet endothelial cell inflammation might be one way to ameliorate/prevent beta-cell dysfunction in type 2 diabetes.

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Proposed model illustrating the islet endothelial dysfunction and oxidative stress surrounding β cells in GK rats.Elevated glucose, FFA and possibly cytokines induce endothelial activation at the islet level by eliciting reactive oxygen species (ROS) production and cytokine/chemokine release by endothelial cells and vascular smooth muscle cells. Once released, chemokines (CXCL1, CCL2, CCL3) attract/retain immune cells (monocytes, neutrophils), which further induce ROS and cytokine production around β cells. In addition, cytokines as well as metabolic factors (high glucose and FFA) may act directly on β cells to increase intracellular cytokines and ROS production with consecutive antioxidant defense response. Antagonizing IL-1 by IL-1Ra may inhibit endothelial activation/dysfunction and subsequent immune cells attraction/activation. IL-1Ra may also blunt IL-1 signaling in β cells and subsequent ROS production and antioxidant defense response. CXCL1 (GRO1/KC, rodent equivalent of IL-8), CCL2 (MCP-1); CCL3 (MIP-1α); FFA (free fatty acids); IL-1β, interleukin-1β; IL-1Ra, interleukin-1 receptor antagonist; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.
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pone-0006963-g003: Proposed model illustrating the islet endothelial dysfunction and oxidative stress surrounding β cells in GK rats.Elevated glucose, FFA and possibly cytokines induce endothelial activation at the islet level by eliciting reactive oxygen species (ROS) production and cytokine/chemokine release by endothelial cells and vascular smooth muscle cells. Once released, chemokines (CXCL1, CCL2, CCL3) attract/retain immune cells (monocytes, neutrophils), which further induce ROS and cytokine production around β cells. In addition, cytokines as well as metabolic factors (high glucose and FFA) may act directly on β cells to increase intracellular cytokines and ROS production with consecutive antioxidant defense response. Antagonizing IL-1 by IL-1Ra may inhibit endothelial activation/dysfunction and subsequent immune cells attraction/activation. IL-1Ra may also blunt IL-1 signaling in β cells and subsequent ROS production and antioxidant defense response. CXCL1 (GRO1/KC, rodent equivalent of IL-8), CCL2 (MCP-1); CCL3 (MIP-1α); FFA (free fatty acids); IL-1β, interleukin-1β; IL-1Ra, interleukin-1 receptor antagonist; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.

Mentions: Molecular signs of GK islet endothelial activation and OS might not only derive from mild chronic hyperglycemia, but also from associated metabolic disorders, such as increased circulating FFA and cholesterol levels and/or insulin resistance, which can precede hyperglycemia [1]–[3], [12]–[14]. Hyperglycemia alone is recognized for a long time to be deleterious for EC [1], [2], [17], while it induces pro-inflammatory cytokine/chemokine expression in monocytes and increases their adhesion to EC [69], where hyperglycemia-induced ROS toxicity is dependent on paracrine factor release, like cytokines [70]. High levels of FFA signaling through TLR receptors, cholesterol, leptin and A-II are also able to stimulate cytokine/chemokine release from EC and/or vascular smooth muscle cells, consequently increasing vascular OS [63], [71], [72] (Fig. 3). Then, inflammatory cells migrate and produce cytokines/chemokines and ROS [73], which might alter β-cells. Also, β-cells are able to produce IL-1 and IL-Ra in the presence of glucose, FFA and/or leptin [74]. A vicious cycle is therefore initiated that will alter islet blood flow and β-cell function [7], unless the islets are able to mount defense mechanisms.


Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat.

Lacraz G, Giroix MH, Kassis N, Coulaud J, Galinier A, Noll C, Cornut M, Schmidlin F, Paul JL, Janel N, Irminger JC, Kergoat M, Portha B, Donath MY, Ehses JA, Homo-Delarche F - PLoS ONE (2009)

Proposed model illustrating the islet endothelial dysfunction and oxidative stress surrounding β cells in GK rats.Elevated glucose, FFA and possibly cytokines induce endothelial activation at the islet level by eliciting reactive oxygen species (ROS) production and cytokine/chemokine release by endothelial cells and vascular smooth muscle cells. Once released, chemokines (CXCL1, CCL2, CCL3) attract/retain immune cells (monocytes, neutrophils), which further induce ROS and cytokine production around β cells. In addition, cytokines as well as metabolic factors (high glucose and FFA) may act directly on β cells to increase intracellular cytokines and ROS production with consecutive antioxidant defense response. Antagonizing IL-1 by IL-1Ra may inhibit endothelial activation/dysfunction and subsequent immune cells attraction/activation. IL-1Ra may also blunt IL-1 signaling in β cells and subsequent ROS production and antioxidant defense response. CXCL1 (GRO1/KC, rodent equivalent of IL-8), CCL2 (MCP-1); CCL3 (MIP-1α); FFA (free fatty acids); IL-1β, interleukin-1β; IL-1Ra, interleukin-1 receptor antagonist; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2737103&req=5

pone-0006963-g003: Proposed model illustrating the islet endothelial dysfunction and oxidative stress surrounding β cells in GK rats.Elevated glucose, FFA and possibly cytokines induce endothelial activation at the islet level by eliciting reactive oxygen species (ROS) production and cytokine/chemokine release by endothelial cells and vascular smooth muscle cells. Once released, chemokines (CXCL1, CCL2, CCL3) attract/retain immune cells (monocytes, neutrophils), which further induce ROS and cytokine production around β cells. In addition, cytokines as well as metabolic factors (high glucose and FFA) may act directly on β cells to increase intracellular cytokines and ROS production with consecutive antioxidant defense response. Antagonizing IL-1 by IL-1Ra may inhibit endothelial activation/dysfunction and subsequent immune cells attraction/activation. IL-1Ra may also blunt IL-1 signaling in β cells and subsequent ROS production and antioxidant defense response. CXCL1 (GRO1/KC, rodent equivalent of IL-8), CCL2 (MCP-1); CCL3 (MIP-1α); FFA (free fatty acids); IL-1β, interleukin-1β; IL-1Ra, interleukin-1 receptor antagonist; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.
Mentions: Molecular signs of GK islet endothelial activation and OS might not only derive from mild chronic hyperglycemia, but also from associated metabolic disorders, such as increased circulating FFA and cholesterol levels and/or insulin resistance, which can precede hyperglycemia [1]–[3], [12]–[14]. Hyperglycemia alone is recognized for a long time to be deleterious for EC [1], [2], [17], while it induces pro-inflammatory cytokine/chemokine expression in monocytes and increases their adhesion to EC [69], where hyperglycemia-induced ROS toxicity is dependent on paracrine factor release, like cytokines [70]. High levels of FFA signaling through TLR receptors, cholesterol, leptin and A-II are also able to stimulate cytokine/chemokine release from EC and/or vascular smooth muscle cells, consequently increasing vascular OS [63], [71], [72] (Fig. 3). Then, inflammatory cells migrate and produce cytokines/chemokines and ROS [73], which might alter β-cells. Also, β-cells are able to produce IL-1 and IL-Ra in the presence of glucose, FFA and/or leptin [74]. A vicious cycle is therefore initiated that will alter islet blood flow and β-cell function [7], unless the islets are able to mount defense mechanisms.

Bottom Line: All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets.IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biology & Pathology of Endocrine Pancreas, Functional and Adaptive Biology Unit-CNRS EA 7059, University Paris-Diderot, Paris, France.

ABSTRACT

Background: Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra).

Methodology/principal findings: Gene expression was analyzed by quantitative RT-PCR on islets isolated from 10-week-old diabetic GK and control Wistar rats. Furthermore, GK rats were treated s.c twice daily with IL-1Ra (Kineret, Amgen, 100 mg/kg/day) or saline, from 4 weeks of age onwards (onset of diabetes). Four weeks later, islet gene analysis and pancreas immunochemistry were performed. Thirty-two genes were selected encoding molecules involved in endothelial cell activation, particularly fibrinolysis, vascular tone, OS, angiogenesis and also inflammation. All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets. After IL-1Ra treatment of GK rats in vivo, most selected genes implied in endothelium/OS/immune cells/fibrosis were significantly down-regulated. IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.

Conclusions/significance: GK rat islets have increased mRNA expression of markers of early islet endothelial cell activation, possibly triggered by several metabolic factors, and also some defense mechanisms. The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations. Thus, metabolically-altered islet endothelium might affect the beta-cell microenvironment and contribute to progressive type 2 diabetic beta-cell dysfunction in GK rats. Counteracting islet endothelial cell inflammation might be one way to ameliorate/prevent beta-cell dysfunction in type 2 diabetes.

Show MeSH
Related in: MedlinePlus