Functional and Metabolic Abnormalities of Diabetic Monocytes

Hill, Harry R.; Hogan, Nancy A.; Rallison, Marvin L.; Santos, José Ignacio; Charette, Richard P.; Kitahara, Mitsuo; Harkness, R. A.

doi:10.1007/978-1-4684-8088-7_61

Cited by 16 publications

(17 citation statements)

References 8 publications

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“…Because type 2 diabetes mellitus manifests obesity and hyperglycemia, it is conceived that the proinflammatory state is accentuated. Monocytes are classic phagocytes that are crucial and the most readily accessible cell in the artery wall, contributing substantially to diabetes and atherosclerosis (18). Here, we provide evidence that IL-1␤-to-IL-1␤/IL-1ra ratios are increased in the monocytes under HG conditions.…”

Section: Discussionmentioning

confidence: 60%

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High glucose induces IL-1β expression in human monocytes: mechanistic insights

Dasu¹,

Devaraj²,

Jialal³

2007

American Journal of Physiology-Endocrinology and Metabolism

149

116

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secretion from Type 2 diabetic patients has been shown to be increased compared with controls. In this study, we aimed to delineate the mechanism of IL-1␤ induction under high-glucose (HG) conditions in human monocytes. THP-1 cells cultured in normal glucose were treated with increasing concentrations of D-glucose (10 -25 mM) for 6 -72 h. IL-1␤ and IL-1 receptor antagonist levels were measured by ELISA and Western blots, whereas mRNA was quantitated by RT-PCR. Specific inhibitors and small interfering RNAs of PKC, p38, ERK1/2, NF-B, and NADPH oxidase were used to determine the mediators in parallel experiments under HG conditions. IL-1␤-secreted protein, cellular protein, and mRNA increase under HG conditions is time and dose dependent, with maximum increase at 15 mM (48 h; P Ͻ 0.05). IL-1 receptor antagonist release was time and dose dependent, similar to IL-1␤ expression pattern; however, the molar ratio of IL-1␤ to IL-1RA was increased. Data from inhibitor and small interfering RNA experiments indicate that IL-1␤ release under HG is mediated by PKC-␣, via phosphorylation of p38 MAPK, and ERK1/2 leading to NF-B activation, resulting in increased mRNA and protein for IL-1␤. At the same time, it appears that NADPH oxidase via p47phox activates NF-B, resulting in increased IL-1␤ secretion. Data suggest that, under HG conditions, monocytes release significantly higher amounts of IL-1␤ through multiple mechanisms, further compounding the disease progression. Targeting signaling pathways mediating IL-1␤ release could result in the amelioration of inflammation and possibly diabetic vasculopathies. protein kinase C; diabetes; p38 phosphorylation; interleukin-1␤

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Section: Discussionmentioning

confidence: 60%

“…The monocyte-macrophage is a crucial and the most readily accessible cell in the artery wall, secreting several proinflammatory, proatherogenic cytokines, such as IL-1␤, IL-6, and TNF-␣, which are increased in diabetes (18,19,25).…”

mentioning

confidence: 99%

High glucose induces IL-1β expression in human monocytes: mechanistic insights

Dasu¹,

Devaraj²,

Jialal³

2007

American Journal of Physiology-Endocrinology and Metabolism

149

116

View full text Add to dashboard Cite

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“…A likely common denominator in all these abnormalities is the dysfunction of the macrophage system. Numerous phenotypic abnormalities, including altered metabolism (9-13), aberrations in chemotactic response (12)(13)(14), phagocytosis (12,15,16), antigen presentation (17)(18)(19), receptor functions (20,21), and cytokine release (18,(22)(23)(24)(25)(26)(27) have indeed been found in peripheral blood mononuclear cells from both type 1 and type 2 diabetic patients. On the other hand, data on the function of tissue macrophages in human diabetes are not available.…”

Section: Discussionmentioning

confidence: 99%

Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice.

et al. 2000

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Macrophage dysfunction is a likely mechanism underlying common diabetic complications such as increased susceptibility to infection, accelerated atherosclerosis, and disturbed wound healing. There are no available studies on the function of tissue macrophages in diabetes in humans. We have therefore studied peritoneal macrophages from diabetic type 2-like db/db mice. We found that the release of tumor necrosis factor-␣ and interleukin-1␤ from lipopolysaccharide plus interferon-␥-stimulated macrophages and vascular endothelial growth factor from both stimulated and nonstimulated macrophages was significantly reduced in diabetic animals compared with nondiabetic controls. Nitric oxide production from the stimulated db/db macrophages was significantly higher than that in the db/+ cultures, whereas there was no difference in their ability to generate reactive oxygen species. When studied both at light and electron microscopic levels, macrophages in diabetic animals had an altered morphological appearance compared with those of normal controls. We conclude that the function and morphology of the macrophages are disturbed in db/db mice and that this disturbance is related to the mechanisms underlying common inflammatory and degenerative manifestations in diabetes.

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“…There are some controversial findings regarding O 2 generation by diabetic monocytes. Some studies [2][3][4] reported that O 2 -generation was elevated in diabetes, and another study found that it was decreased in Type 2 diabetes mellitus (DM) [5]. In this study, the oxidative burst from diabetic monocytes was evaluated thoroughly, and the effects of hyperglycemia were investigated.…”

Section: Introductionmentioning

confidence: 96%

Activation of RAGE induces elevated O2− generation by mononuclear phagocytes in diabetes

Ding

Kantarcı

Hastürk

et al. 2006

Journal of Leukocyte Biology

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Oxidative stress has been found to play a role in the pathogenesis of diabetic complications. The aim of this study was to define the oxidative burst of diabetic monocytes to characterize the phenotype associated with poor diabetic control. Superoxide (O 2 -) is the first molecule generated during the respiratory burst of phagocytes by NADPH oxidase, and its generation by monocytes from 26 controls and 34 diabetic subjects was evaluated in this study. Under resting states or stimulation by PMA or opsonized zymosan, diabetic monocytes produce significantly more O 2 -than nondiabetic cells. The increased O 2 -generation was found to be correlated with glycemic control (glycated hemoglobin) of patients. To clarify the effects of hyperglycemia on O 2 -generation, normal human monocytes were treated with receptor for advanced glycation endproducts (RAGE) ligands (AGE protein and S100B) or high glucose media before stimulation. RAGE ligands and high glucose concentration increased O 2 -generation from human mononuclear phagocytes. RAGE ligands, specifically and potently, increased O 2 -generation from mononuclear phagocytes, and high-glucose effects were associated with correspondingly increased osmotic pressure. Differentiated THP-1 cells, from a human monocytic cell line, were used as a model of human monocytes to study the effects of S100B, the RAGE ligand. It was confirmed that RAGE is involved in the priming of O 2 -generation by S100B. This study demonstrates that RAGE ligands can contribute significantly to the hyperresponsive phenotype of diabetic monocytes, which might be reversible by blocking the RAGE or controlling the presence of RAGE ligands by controlling hyperglycemia.

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Functional and Metabolic Abnormalities of Diabetic Monocytes

Cited by 16 publications

References 8 publications

High glucose induces IL-1β expression in human monocytes: mechanistic insights

High glucose induces IL-1β expression in human monocytes: mechanistic insights

Altered cytokine and nitric oxide secretion in vitro by macrophages from diabetic type II-like db/db mice.

Activation of RAGE induces elevated O2− generation by mononuclear phagocytes in diabetes

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