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    Analysis of inflammatory cytokine and TLR expression levels in Type 2 Diabetes with complications. Gupta Saket,Maratha Ashwini,Siednienko Jakub,Natarajan Anandan,Gajanayake Thusitha,Hoashi Shu,Miggin Sinéad Scientific reports The pathogenesis and complications of type 2 diabetes (T2DM) are closely linked with defective glucose metabolism, obesity, cardiovascular disease and an inability to mount an effective immune response to certain pathogenic organisms. Perturbations in key innate immune receptors known as Toll-like receptors (TLRs) and inflammatory mediators such as IL-6, TNFα and IL-1β have been linked with T2DM. Herein, we sought to establish whether patients with T2DM and underlying complications exhibit perturbations in cytokine and TLR expression. Serum cytokine and mRNA levels of cytokines/TLRs in monocytes (M) and neutrophils (N) were measured in a cohort of 112 diabetic patients: good glycaemic control without complications (GC), good glycaemic control with complications (GCC), poor glycaemic control without complications (PC) and poor glycaemic control with complications (PCC) and compared them with 34 non-diabetic volunteers (NGT). Serum cytokine levels were normal in all study participants. In the GC group, cytokine and TLR gene expression were enhanced compared to NGT. In contrast, suppressed cytokine and TLR gene expression were evident in PC, GCC & PCC groups when compared to the GC. In conclusion, whereas serum pro-inflammatory cytokine levels are unaltered in T2DM patients, differences in inflammatory gene profiles exist among the T2DM patient groups. 10.1038/s41598-017-07230-8
    Glycated LDL increase VCAM-1 expression and secretion in endothelial cells and promote monocyte adhesion through mechanisms involving endoplasmic reticulum stress. Toma Laura,Sanda Gabriela M,Deleanu Mariana,Stancu Camelia S,Sima Anca V Molecular and cellular biochemistry Type 2 Diabetes Mellitus is a worldwide epidemic, and its atherosclerotic complications produce morbidity and mortality in affected patients. It is known that the vascular cell adhesion molecule-1 (VCAM-1) levels are increased in the sera of diabetic patients. Our aim was to investigate the impact of the endoplasmic reticulum stress (ERS) in VCAM-1 expression and secretion in human endothelial cells (HEC) exposed to glycated low-density lipoproteins (gLDL). The results showed that 24 h incubation of HEC with gLDL induces (i) stimulation of VCAM-1 expression and secretion, determining increased monocyte adhesion to HEC; (ii) RAGE up-regulation and free cholesterol loading; (iii) ERS activation (increased eIF2α phosphorylation and CHOP mRNA levels, and decreased GRP78 protein expression); and (iv) oxidative stress [increased levels of reactive oxygen species (ROS) and glutamate cysteine ligase catalytic unit gene expression]. Treatment of gLDL-exposed HEC with ERS inhibitors, salubrinal (Sal) and sodium phenylbutyrate (PBA), decreased intracellular ROS. Incubation of gLDL-exposed cells with the anti-oxidant N-acetyl-cysteine (NAC) reduced ERS, revealed by decreased eIF2α phosphorylation and CHOP gene expression and increased GRP78 expression, thus validating the interconnection between ERS and oxidative stress. Sal, PBA, NAC and inhibitors of p38 MAP kinase and NF-kB induced the decrease of VCAM-1 expression and of the ensuing monocyte adhesion induced by gLDL. In conclusion, in HEC, gLDL stimulate the expression of cellular VCAM-1, the secretion of soluble VCAM-1, and the adhesion of monocytes through mechanisms involving p38 MAP kinase and NF-kB signalling pathways activated by RAGE, ERS and oxidative stress, thus contributing to diabetic atherosclerosis. 10.1007/s11010-016-2724-z
    Toll-like receptor 2 expression on monocytes and microvascular complications in type 2 diabetic patients. Badr Rasha Emad,Salama Mona Ibrahim,Abd-Elmaogood Asmaa Kamal,Eldeib Abd El-Raouf Mohamed Diabetes & metabolic syndrome Diabetes mellitus (DM) is a chronic debilitating illness, and atherosclerotic changes are inevitable and usually neglected during the follow-up of diabetic patients. Toll-like receptor 2 (TLR2) is under trial in many studies to hold responsibility for atherosclerosis process progression as they suggest a malfunction of these receptors expressed on monocytes in diabetic patients. This study aimed to assess the association between the TLR2 and type 2 diabetes mellitus (T2DM) in Egyptian diabetic patients and to investigate its relationship with some diabetic complications. METHODS:This study included a 60 diabetic patients group 1 (diabetic complicated), group 2 (diabetic non-complicated) and 30 age-matched normal healthy blood donors. RESULTS:Toll-like receptors (TLRs) expression was significantly associated with T2DM. In this study, the mean fluorescent intensity (MFI) of TLR2 was 596.9 ± 84.78 in group 1, 326.23 ± 62.98 in group 2 while in group 3 it was 208.47 ± 156.73. There was a significant correlation between MFI of TLR2 and random blood sugar (RBS) and glycated haemoglobin (HbA1c) (p < 0.05). CONCLUSION:TLR2 was overexpressed in diabetic patients with microvascular complications compared to diabetic non-complicated patients and normal healthy controls. 10.1016/j.dsx.2019.01.038
    TLR2 and TLR4 expression on CD14(++) and CD14(+) monocyte subtypes in adult-onset autoimmune diabetes. Cejkova Pavlina,Nemeckova Iva,Broz Jan,Cerna Marie Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia BACKGROUND:Peripheral blood monocytes are key effectors of innate immunity. Dysfunction, changes in their counts or altered expression of cytokines and pattern-recognition receptors on monocytes may contribute to the development of the autoimmune type of diabetes mellitus (AD). AIMS:We aimed to analyze the counts and proportions of the two main subtypes of monocyte cells, CD14(++) and CD14(+), and to look for potential changes in the expression of toll-like receptors 2 (TLR2) and 4 (TLR4) as well as cytokine prolactin (PRL) in adult-onset AD, including diabetes mellitus type 1 (T1DM) and latent autoimmune diabetes in adults (LADA). METHODS:We examined 21 T1DM patients, 9 patients with LADA, 16 control patients with type 2 diabetes mellitus (T2DM) and 24 healthy individuals. All diabetic patients were diagnosed after the age of 18 years. Expression at the mRNA level was determined by quantitative PCR. Flow cytometry was used to ascertain membrane expression and cell counts. RESULTS:T1DM patients had fewer CD14(++) (P < 0.01) and CD14(+) (P < 0.0001) monocytes whereas T2DM subjects showed decreased counts of CD14(+) monocytes compared to healthy controls (P < 0.001). TLR2 protein expression was significantly increased in T1DM CD14(+) monocytes compared to healthy controls (P < 0.05), while TLR4 expression in T1DM CD14(++) cells was significantly lower (P < 0.0001). There was no significant difference between the groups in terms of PRL mRNA expression in monocytes. CONCLUSIONS:The observed changes in the proportions of both immune cell types and in the expression of functional pattern-recognition receptors on monocytes in the subjects examined may arise as a consequence of chronic inflammation that accompanies long-term diabetes. 10.5507/bp.2015.016
    Changes in CDKN2A/2B expression associate with T-cell phenotype modulation in atherosclerosis and type 2 diabetes mellitus. VinuÉ Ángela,MartÍnez-HervÁs Sergio,Herrero-Cervera Andrea,SÁnchez-GarcÍa Verónica,AndrÉs-Blasco Irene,Piqueras Laura,Sanz MarÍa JesÚs,Real JosÉ TomÁs,Ascaso Juan F,Burks Deborah Jane,GonzÁlez-Navarro Herminia Translational research : the journal of laboratory and clinical medicine Previous studies indicate a role of CDKN2A/2B/2BAS genes in atherosclerosis and type 2 diabetes mellitus (T2DM). Progression of these diseases is accompanied by T-cell imbalance and chronic inflammation. Our main objective was to investigate a potential association between CDKN2A/2B/2BAS gene expression and T cell phenotype in T2DM and coronary artery disease (CAD) in humans, and to explore the therapeutic potential of these genes to restore immune cell homeostasis and disease progression. Reduced mRNA levels of CDKN2A (p16), CDKN2B (p15), and CDKN2BAS were observed in human T2DM and T2DM-CAD subjects compared with controls. Protein levels of p16 and p15 were also diminished in T2DM-CAD patients while CDK4 levels, the main target of p16 and p15, were augmented in T2DM and T2DM-CAD subjects. Both patient groups displayed higher activated CD3+CD69+ T cells and proatherogenic CD14++CD16+ monocytes, while CD4+CD25+CD127 regulatory T (Treg cells) cells were decreased. Treatment of primary human lymphocytes with PD0332991, a p16/p15 mimetic drug and a proven CDK4 inhibitor, increased Treg cells and the levels of activated transcription factor phosphoSTAT5. In vivo PD0332991 treatment of atherosclerotic apoE-/- mice and insulin resistant apoE-/-Irs2+/- mice augmented Foxp3-expressing Treg cells and decreased lesion size. Thus, atherosclerosis complications in T2DM associate with altered immune cell homeostasis, diminished CDKN2A/2B/2BAS expression, and increased CDK4 levels. The present study also suggests that the treatment with drugs that mimic CDKN2A/2B genes could potential be considered as a promising therapy to delay atherosclerosis. 10.1016/j.trsl.2018.08.003
    Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes. Szpigel Anaïs,Hainault Isabelle,Carlier Aurélie,Venteclef Nicolas,Batto Anne-Françoise,Hajduch Eric,Bernard Catherine,Ktorza Alain,Gautier Jean-François,Ferré Pascal,Bourron Olivier,Foufelle Fabienne Diabetologia AIMS/HYPOTHESIS:Obesity and type 2 diabetes are concomitant with low-grade inflammation affecting insulin sensitivity and insulin secretion. Recently, the thioredoxin interacting protein (TXNIP) has been implicated in the activation process of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. In this study, we aim to determine whether the expression of TXNIP is altered in the circulating immune cells of individuals with type 2 vs type 1 diabetes and whether this can be related to specific causes and consequences of inflammation. METHODS:The expression of TXNIP, inflammatory markers, markers of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress and enzymes involved in sphingolipid metabolism was quantified by quantitative reverse transcription real-time PCR (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) of 13 non-diabetic individuals, 23 individuals with type 1 diabetes and 81 with type 2 diabetes. A lipidomic analysis on the plasma of 13 non-diabetic individuals, 35 individuals with type 1 diabetes and 94 with type 2 diabetes was performed. The effects of ER stress or of specific lipids on TXNIP and inflammatory marker expression were analysed in human monocyte-derived macrophages (HMDMs) and THP-1 cells. RESULTS:The expression of TXNIP and inflammatory and UPR markers was increased in the PBMCs of individuals with type 2 diabetes when compared with non-diabetic individuals or individuals with type 1 diabetes. TXNIP expression was significantly correlated with plasma fasting glucose, plasma triacylglycerol concentrations and specific UPR markers. Induction of ER stress in THP-1 cells or cultured HMDMs led to increased expression of UPR markers, TXNIP, NLRP3 and IL-1β. Conversely, a chemical chaperone reduced the expression of UPR markers and TXNIP in PBMCs of individuals with type 2 diabetes. The lipidomic plasma analysis revealed an increased concentration of saturated dihydroceramide and sphingomyelin in individuals with type 2 diabetes when compared with non-diabetic individuals and individuals with type 1 diabetes. In addition, the expression of specific enzymes of sphingolipid metabolism, dihydroceramide desaturase 1 and sphingomyelin synthase 1, was increased in the PBMCs of individuals with type 2 diabetes. Palmitate or C2 ceramide induced ER stress in macrophages as well as increased expression of TXNIP, NLRP3 and IL-1β. CONCLUSIONS/INTERPRETATION:In individuals with type 2 diabetes, circulating immune cells display an inflammatory phenotype that can be linked to ER stress and TXNIP expression. Immune cell ER stress can in turn be linked to the specific exogenous and endogenous lipid environment found in type 2 diabetes. 10.1007/s00125-017-4462-5
    Role of the JAK2/STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications. Yang Mengxue,Tian Mei,Zhang Xuan,Xu Jie,Yang Bo,Yu Jie,Li Fengping,Li Ya,Li Sicheng,Li Xianwen Oncotarget This study investigated the role of the JAK2/STAT3/SOCS pathway in type 2 diabetes mellitus (T2DM) and macrovascular complications (DV) (T2DM+DV) conditions. Human umbilical vein endothelial cells (HUVECs) were co-cultured with human monocytes (THP-1) and exposed to peripheral blood sera from 30 T2DM patients, 30 patients with T2DM+DV and 30 healthy controls; the groups were divided into the control, T2DM, DV, T2DM+AG490 and DV+AG490 groups. Chemotaxis of treated HUVECs toward THP-1 cells was assessed using Transwell migration. The mRNA expression of JAK2, STAT3, VEGF and FLT1 was evaluated using RT-PCR, whereas the protein levels of ICAM-1, p-JAK2, JAK2, STAT3, p-STAT3, SOCS1 and SOCS3 were determined using western blotting. p-STAT3 was observed using immunofluorescence. The IL-1β concentrations were assessed by ELISA. AG90 was used as a specific inhibitor of JAK2/STAT3 signaling. The chemotaxis assays revealed a migratory order of DV>DM>control, and AG490 treatment decreased chemotaxis. Additionally, p-STAT3 fluorescence was noticeably increased in the DM group and more so in the DV group. The mRNA expression of JAK2, STAT3, VEGF and FLT1 and the protein levels of ICAM-1, p-JAK2, p-STAT3, SOCS1 and SOCS3 were significantly higher in the T2DM and DV groups than in the control group and in the AG490-treated groups than in the untreated groups. The supernatant concentrations of IL-1β in the DV and T2DM groups were higher than those in the control group, and treatment with AG490 decreased the IL-1β concentration. The JAK2/STAT3/SOCS axis contributes to the development of DV by mediating inflammation associated with vascular endothelial cells and/or monocytes. 10.18632/oncotarget.18555
    p16INK4a deficiency promotes IL-4-induced polarization and inhibits proinflammatory signaling in macrophages. Cudejko Céline,Wouters Kristiaan,Fuentes Lucía,Hannou Sarah Anissa,Paquet Charlotte,Bantubungi Kadiombo,Bouchaert Emmanuel,Vanhoutte Jonathan,Fleury Sébastien,Remy Patrick,Tailleux Anne,Chinetti-Gbaguidi Giulia,Dombrowicz David,Staels Bart,Paumelle Réjane Blood The CDKN2A locus, which contains the tumor suppressor gene p16(INK4a), is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMϕ) or alternatively (AAMϕ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16(INK4a) deficiency (p16(-/-)) modulates the macrophage phenotype. Transcriptome analysis revealed that p16(-/-) BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4-induced macrophage polarization. In line with this observation, p16(-/-) BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16(-/-) BM displayed higher hepatic AAMϕ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMϕ phenotype skewing. Surprisingly, p16(-/-) BMDMs did not display increased IL-4-induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)-induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16(INK4a) as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases. 10.1182/blood-2010-10-313106
    Glucose enhances human macrophage LOX-1 expression: role for LOX-1 in glucose-induced macrophage foam cell formation. Li Ling,Sawamura Tatsuya,Renier Geneviève Circulation research Lectin-like oxidized LDL receptor-1 (LOX-1) is a newly identified receptor for oxidized LDL that is expressed by vascular cells. LOX-1 is upregulated in aortas of diabetic rats and thus may contribute to the pathogenesis of human diabetic atherosclerosis. In this study, we examined the regulation of human monocyte-derived macrophage (MDM) LOX-1 expression by high glucose and the role of LOX-1 in glucose-induced foam cell formation. Incubation of human MDMs with glucose (5.6 to 30 mmol/L) enhanced, in a dose- and time-dependent manner, LOX-1 gene and protein expression. Induction of LOX-1 gene expression by high glucose was abolished by antioxidants, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), and activated protein-1 (AP-1) inhibitors. In human MDMs cultured with high glucose, increased expression of PKCbeta2 and enhanced phosphorylation of extracellular signal-regulated protein kinase 1/2 was observed. Activation of these kinases was inhibited by the antioxidant N-acetyl-L-cysteine (NAC) and by the PKCbeta inhibitor LY379196. High glucose also enhanced the binding of nuclear proteins extracted from human MDMs to the NF-kappaB and AP-1 regulatory elements of the LOX-1 gene promoter. This effect was abrogated by NAC and PKC/MAPK inhibitors. Finally, high glucose induced human macrophage-derived foam cell formation through a LOX-1-dependent pathway. Overall, these results demonstrate that high glucose concentrations enhance LOX-1 expression in human MDMs and that this effect is associated with foam cell formation. Pilot data showing that MDMs of patients with type 2 diabetes overexpress LOX-1 support the relevance of this work to human diabetic atherosclerosis. 10.1161/01.RES.0000124920.09738.26
    Suppressive effect of insulin infusion on chemokines and chemokine receptors. Ghanim Husam,Korzeniewski Kelly,Sia Chang Ling,Abuaysheh Sanaa,Lohano Teekam,Chaudhuri Ajay,Dandona Paresh Diabetes care OBJECTIVE:In view of the previously described anti-inflammatory effects of insulin, we investigated the potential suppressive effect of insulin on plasma concentrations and expression of the chemokines, monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normal T-cell expressed and secreted (RANTES) and their receptors, chemokine receptor (CCR)-2 and CCR-5, in mononuclear cells (MNCs). We also investigated the effect of insulin on other chemokines. RESEARCH DESIGN AND METHODS:Ten obese type 2 diabetic patients were infused with insulin (2 units/h with 100 ml of 5% dextrose/h) for 4 h. Another 8 and 6 type 2 diabetic patients were infused with 100 ml of 5% dextrose/h or saline for 4 h, respectively, and served as control subjects. Blood samples were obtained at 0, 2, 4, and 6 h. RESULTS:Insulin infusion significantly suppressed the plasma concentrations of MCP-1, eotaxin, and RANTES and the expression of RANTES, macrophage inflammatory protein (MIP)-1beta, CCR-2, and CCR-5 in MNCs at 2 and 4 h. Dextrose and saline infusions did not alter these indexes. CONCLUSIONS:A low-dose infusion of insulin suppresses the plasma concentration of key chemokines, MCP-1, and RANTES, and the expression of their respective receptors, CCR-2 and CCR-5, in MNCs. Insulin also suppresses the expression of RANTES and MIP-1beta in MNCs. These actions probably contribute to the comprehensive anti-inflammatory effect of insulin. 10.2337/dc09-2193
    Fasting plasma leptin, tumor necrosis factor-alpha receptor 2, and monocyte chemoattracting protein 1 concentration in a population of glucose-tolerant and glucose-intolerant women: impact on cardiovascular mortality. Piemonti Lorenzo,Calori Giliola,Mercalli Alessia,Lattuada Guido,Monti Paolo,Garancini Maria Paola,Costantino Federica,Ruotolo Giacomo,Luzi Livio,Perseghin Gianluca Diabetes care OBJECTIVE:Leptin and tumor necrosis factor (TNF)-alpha are associated with insulin resistance and cardiovascular disease. In vitro studies suggested that these effects may be mediated via overproduction of monocyte chemoattracting protein (MCP)-1/CCL2, which is a chemokine involved in the pathogenesis of atherosclerosis. RESEARCH DESIGN AND METHODS:In this study, fasting plasma leptin, soluble TNF-alpha receptor 2 (TNF-alpha-R2), and MCP-1/CCL2 concentrations were measured in 207 middle-aged women (age 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2)), including 53 patients with type 2 diabetes, 42 with impaired glucose tolerance, and 112 with normal glucose tolerance, to assess cross-sectionally their relationship with markers of atherosclerosis and, longitudinally over 7 years, whether their circulating levels were associated with cardiovascular disease (CVD) mortality. RESULTS:At baseline, leptin and TNF-alpha-R2 were not different among groups; meanwhile, MCP-1/CCL2 was increased in type 2 diabetes (P < 0.05). All showed significant associations with biochemical risk markers of atherosclerosis. In a univariate analysis, age, fasting insulin, leptin, and MCP-1/CCL2 were associated with CVD mortality at 7 years. When a multivariate analysis was performed, only age, leptin, and insulin retained an independent association with CVD mortality, with leptin showing a protective effect (hazard ratio 0.88; P < 0.02). CONCLUSIONS:In middle-aged women, MCP-1/CCL2, leptin, and TNF-alpha-R2 were all related to biochemical risk markers of atherosclerosis. MCP-1/CCL2 concentration was the only one to be increased in type 2 diabetes with respect to nondiabetic women and the only one to be associated with increased risk of CVD mortality after a 7-year follow-up period in the univariate analysis. In the multivariate analysis, neither MCP-1/CCL2 nor TNF-alpha-R2 was associated with CVD mortality, and inspection of the data showed that leptin, in both the univariate and multivariate analysis, was associated with a protective effect. 10.2337/diacare.26.10.2883
    Chronic vascular inflammation in patients with type 2 diabetes: endothelial biopsy and RT-PCR analysis. Feng Lei,Matsumoto Carolyn,Schwartz Allan,Schmidt Ann Marie,Stern David M,Pile-Spellman John Diabetes care OBJECTIVE:Chronic vascular inflammation may play a role in the development of macrovascular complications in diabetic patients. In this study, we examine the association of endothelial expression of two inflammatory mediators, receptor for advanced glycation end product (RAGE) and monocyte chemoattractant protein-1 (MCP-1), with type 2 diabetes using novel endothelial biopsy and RT-PCR techniques. RESEARCH DESIGN AND METHODS:Endothelial samples are obtained from the aorta of 12 patients with type 2 diabetes and 23 control subjects who underwent cardiac catheterization for chest pain syndrome or heart transplant follow-up. Endothelial cells are purified using magnetic beads with adsorbed CD146 antibody and subjected to RT-PCR analysis of RAGE and MCP-1 transcripts. The association of RAGE and MCP-1 expression with type 2 diabetes is assessed with chi(2) test and confirmed with in vitro experiments on human aorta endothelial cells. RESULTS:RT-PCR reveals gene expression patterns in patient-derived endothelial cells. Strong associations are observed between induction of RAGE mRNA and diabetes (P < 0.01) and between induction of RAGE and MCP-1 transcripts (P < 0.05). Treatment of cultured human aortic endothelial cells with S100b induces the expression of MCP-1 and RAGE transcripts. CONCLUSIONS:Endothelial cells can be harvested during cardiac catheterization and can be characterized with respect to molecular phenotypes under the influence of both genetic and environmental factors. Induction of RAGE and MCP-1 transcripts in patients with diabetes supports a role of chronic vascular inflammation in macrovascular complications. 10.2337/diacare.28.2.379
    Inflammation, endoplasmic reticulum stress, autophagy, and the monocyte chemoattractant protein-1/CCR2 pathway. Kolattukudy Pappachan E,Niu Jianli Circulation research Numerous inflammatory cytokines have been implicated in the pathogenesis of cardiovascular diseases. Monocyte chemoattractant protein (MCP)-1/CCL2 is expressed by mainly inflammatory cells and stromal cells such as endothelial cells, and its expression is upregulated after proinflammatory stimuli and tissue injury. MCP-1 can function as a traditional chemotactic cytokine and also regulates gene transcription. The recently discovered novel zinc-finger protein, called MCPIP (MCP-1-induced protein), initiates a series of signaling events that causes oxidative and endoplasmic reticulum (ER) stress, leading to autophagy that can result in cell death or differentiation, depending on the cellular context. After a brief review of the basic processes involved in inflammation, ER stress, and autophagy, the recently elucidated role of MCP-1 and MCPIP in inflammatory diseases is reviewed. MCPIP was found to be able to control inflammatory response by inhibition of nuclear factor-κB activation through its deubiquitinase activity or by degradation of mRNA encoding a set of inflammatory cytokines through its RNase activity. The potential inclusion of such a novel deubiquitinase in the emerging anti-inflammatory strategies for the treatment of inflammation-related diseases such as cardiovascular diseases and type 2 diabetes is briefly discussed. 10.1161/CIRCRESAHA.111.243212
    Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type 2 diabetic patients with and without macrovascular complications: the effect of alpha-tocopherol supplementation. Devaraj S,Jialal I Circulation BACKGROUND:Although diabetes confers an increased propensity toward accelerated atherogenesis, data are lacking on monocyte activity in type 2 diabetic patients with (DM2-MV) and without (DM2) macrovascular disease compared with control subjects. Thus, we tested whether (1) postsecretory modifications of LDL (glycation and oxidation), monocyte proatherogenic activity, and circulating levels of soluble cell adhesion molecules (sCAMs) are more pronounced in DM2-MV than in DM2 and control subjects and (2) RRR-alpha-tocopherol (AT) therapy, 1200 IU/d for 3 months, has a similar effect in the 3 groups (n=25 per group). METHODS AND RESULTS:Although LDL glycation was increased in both diabetic groups compared with control subjects, AT therapy had no significant effect on glycation. AT therapy significantly decreased LDL oxidizability in all 3 groups. Diabetic monocytes released significantly more superoxide anion (O(2)(-)) and interleukin-1beta (IL-1beta) and exhibited greater adhesion to endothelium than control subjects. AT therapy significantly decreased the release of O(2)(-), IL-1beta, tumor necrosis factor-alpha, and monocyte-endothelium adhesion in all 3 groups. There was no significant difference between the 2 diabetic groups for any of the above parameters. sICAM levels were significantly elevated in both diabetic groups compared with controls. AT therapy resulted in a significant decrease in sCAMs. CONCLUSIONS:This is the first demonstration of increased IL-1beta secretion and increased adhesion of monocytes to endothelium from normotriglyceridemic diabetic subjects and of decreased monocyte activity and sCAMs with AT therapy in diabetic subjects with and without macrovasculopathy. 10.1161/01.cir.102.2.191
    Transcriptional and epigenetic regulation of macrophages in atherosclerosis. Kuznetsova Tatyana,Prange Koen H M,Glass Christopher K,de Winther Menno P J Nature reviews. Cardiology Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation. 10.1038/s41569-019-0265-3
    Glucose regulates monocyte adhesion through endothelial production of interleukin-8. Srinivasan Suseela,Yeh Michael,Danziger Eric C,Hatley Melissa E,Riggan Anna E,Leitinger Norbert,Berliner Judith A,Hedrick Catherine C Circulation research We have shown that glucose increases monocyte adhesion to human aortic endothelial cells (HAECs) in vitro.1 In the present study, we examined mechanisms by which glucose stimulates monocyte:endothelial interactions. HAECs cultured for 7 days in 25 mmol/L glucose had a 2-fold elevation in interleukin-8 (IL-8) secretion over control cells cultured in 5.5 mmol/L glucose (P<0.001). Use of a neutralizing antibody to IL-8 prevented glucose-mediated monocyte adhesion. Both glucose and IL-8 activated beta1 integrin on the HAEC surface, suggesting that both activate the alpha5beta1 integrin complex on the endothelial surface. The alpha5beta1 integrin complex is important for anchoring connecting segment-1 fibronectin on the HAEC surface for monocyte adhesion. Analysis of the human IL-8 promoter revealed binding sites for NF-kappaB and AP-1 as well as several aligned carbohydrate response elements (also known as E-boxes). Glucose dramatically stimulated IL-8 promoter activity. Using mutated IL-8 promoter constructs and EMSA, we found that the AP-1 element and the glucose-response element were responsible for much of the glucose-mediated activation of IL-8 transcription. Interestingly, inhibition of reactive oxygen species (ROS) production through use of pharmacological uncouplers of the mitochondrial electron transport chain significantly reduced glucose-mediated induction of IL-8 expression. These data indicate that glucose regulates monocyte:endothelial interactions through stimulation of IL-8 and ROS production and activation of the alpha5beta1 integrin complex on HAECs. 10.1161/01.RES.0000061714.74668.5C
    Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Uribarri Jaime,Cai Weijing,Ramdas Maya,Goodman Susan,Pyzik Renata,Chen Xue,Zhu Li,Striker Gary E,Vlassara Helen Diabetes care OBJECTIVE:Increased oxidative stress (OS) and impaired anti-OS defenses are important in the development and persistence of insulin resistance (IR). Several anti-inflammatory and cell-protective mechanisms, including advanced glycation end product (AGE) receptor-1 (AGER1) and sirtuin (silent mating-type information regulation 2 homolog) 1 (SIRT1) are suppressed in diabetes. Because basal OS in type 2 diabetic patients is influenced by the consumption of AGEs, we examined whether AGE consumption also affects IR and whether AGER1 and SIRT1 are involved. RESEARCH DESIGN AND METHODS:The study randomly assigned 36 subjects, 18 type 2 diabetic patients (age 61±4 years) and 18 healthy subjects (age 67±1.4 years), to a standard diet (>20 AGE equivalents [Eq]/day) or an isocaloric AGE-restricted diet (<10 AGE Eq/day) for 4 months. Circulating metabolic and inflammatory markers were assessed. Expression and activities of AGER1 and SIRT1 were examined in patients' peripheral blood mononuclear cells (PMNC) and in AGE-stimulated, AGER1-transduced (AGER1+), or AGER1-silenced human monocyte-like THP-1 cells. RESULTS:Insulin and homeostasis model assessment, leptin, tumor necrosis factor-α and nuclear factor-κB p65 acetylation, serum AGEs, and 8-isoprostanes decreased in AGE-restricted type 2 diabetic patients, whereas PMNC AGER1 and SIRT1 mRNA, and protein levels normalized and adiponectin markedly increased. AGEs suppressed AGER1, SIRT-1, and NAD+ levels in THP-1 cells. These effects were inhibited in AGER1+ but were enhanced in AGER1-silenced cells. CONCLUSIONS:Food-derived pro-oxidant AGEs may contribute to IR in clinical type 2 diabetes and suppress protective mechanisms, AGER1 and SIRT1. AGE restriction may preserve native defenses and insulin sensitivity by maintaining lower basal OS. 10.2337/dc11-0091
    Association between plasma monocyte chemoattractant protein-1 concentration and cardiovascular disease mortality in middle-aged diabetic and nondiabetic individuals. Piemonti Lorenzo,Calori Giliola,Lattuada Guido,Mercalli Alessia,Ragogna Francesca,Garancini Maria Paola,Ruotolo Giacomo,Luzi Livio,Perseghin Gianluca Diabetes care OBJECTIVE:Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a chemokine involved into the pathogenesis of atherosclerosis and has prognostic value in the acute and chronic phases in patients with acute coronary syndromes. RESEARCH DESIGN AND METHODS:MCP-1/CCL2 concentration was measured in plasma fractions of 363 middle-aged overweight/obese individuals (aged 61 +/- 12 years, BMI 30.1 +/- 6.6 kg/m(2), 15% with type 2 diabetes, and 12% with impaired glucose tolerance) of a population survey carried out in 1990-1991 in Lombardy, Italy (Cremona Study), and cardiovascular disease (CVD) mortality was assessed in 2006 through Regional Health Registry files. RESULTS:At baseline MCP-1/CCL2 was increased in individuals with type 2 diabetes (P < 0.05) and showed significant correlations with biochemical risk markers of atherosclerosis. After 15 years, among the 363 subjects, there were 82 deaths due to CVD. In univariate analysis age, sex, fasting glucose and insulin, fibrinogen, glucose tolerance status, smoking habit, and MCP-1/CCL2 were associated with CVD mortality. Age, sex, fasting serum glucose, MCP-1/CCL2, and smoking habit maintained an independent association with CVD mortality in multiple regression analysis. In a subgroup of 113 subjects in whom data for C-reactive protein (CRP) were available, its level was not predictive of CVD mortality. CONCLUSIONS:In middle-aged overweight/obese individuals MCP-1/CCL2 was independently associated with CVD mortality. Further studies will be necessary to establish its role as a surrogate biomarker and as a potential therapeutic target. 10.2337/dc09-0763
    Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Dasu Mohan R,Devaraj Sridevi,Park Samuel,Jialal Ishwarlal Diabetes care OBJECTIVE:Individuals with type 2 diabetes have a myriad of metabolic aberrations including increased inflammation, increasing their cardiovascular risk. Toll-like receptors (TLRs) and their ligands play a key role in insulin resistance and atherosclerosis. However, there is a paucity of data examining the expression and activity of TLRs in type 2 diabetes. Thus, in the present study, we examined TLR2 and TLR4 mRNA and protein expression, their ligands, and signaling in monocytes of recently diagnosed type 2 diabetic patients. RESEARCH DESIGN AND METHODS:TLR mRNA, protein expression, TLR ligands, and TLR signaling were measured in freshly isolated monocytes from healthy human control subjects (n = 23) and type 2 diabetic subjects (n = 23) using real-time RT-PCR, Western blot, and flow cytometric assays. RESULTS:Type 2 diabetic subjects had significantly increased TLR2, TLR4 mRNA, and protein in monocytes compared with control subjects (P < 0.05). Increased TLR2 and TLR4 expression correlated with BMI, homeostasis model assessment-insulin resistance (HOMA-IR), glucose, A1C, N(epsilon)-(carboxymethyl) lysine (CML), and free fatty acid (FFA). Ligands of TLR2 and TLR4, namely, HSP60, HSP70, HMGB1, endotoxin, and hyaluronan levels, were elevated in type 2 diabetic subjects and positively correlated with TLR2 and TLR4. Type 2 diabetic subjects showed increased MyD88, phosphorylated IRAK-1, Trif, TICAM-1, IRF-3, and NF-kappaB p65 expression in monocytes compared with control subjects. Furthermore, TLR-MyD88-NF-kappaB signaling resulted in elevated levels of cytokines (P < 0.05), but increased interleukin (IL)-1beta, interferon (IFN)-gamma, and endotoxin were not significant when adjusted for BMI. CONCLUSIONS:In this comprehensive study, we make the novel observation that TLR2 and TLR4 expression and their ligands, signaling, and functional activation are increased in recently diagnosed type 2 diabetes and contribute to the proinflammatory state. 10.2337/dc09-1799
    Fructose reprogrammes glutamine-dependent oxidative metabolism to support LPS-induced inflammation. Jones Nicholas,Blagih Julianna,Zani Fabio,Rees April,Hill David G,Jenkins Benjamin J,Bull Caroline J,Moreira Diana,Bantan Azari I M,Cronin James G,Avancini Daniele,Jones Gareth W,Finlay David K,Vousden Karen H,Vincent Emma E,Thornton Catherine A Nature communications Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility. 10.1038/s41467-021-21461-4
    Profile of the Immune and Inflammatory Response in Individuals With Prediabetes and Type 2 Diabetes. Grossmann Vera,Schmitt Volker H,Zeller Tanja,Panova-Noeva Marina,Schulz Andreas,Laubert-Reh Dagmar,Juenger Claus,Schnabel Renate B,Abt Tobias G J,Laskowski Rafael,Wiltink Jörg,Schulz Eberhard,Blankenberg Stefan,Lackner Karl J,Münzel Thomas,Wild Philipp S Diabetes care OBJECTIVE:The inflammatory and immune systems are altered in type 2 diabetes. Here, the aim was to profile the immune and inflammatory response in subjects with prediabetes and diabetes in a large population-representative sample. RESEARCH DESIGN AND METHODS:In total, 15,010 individuals were analyzed from the population-based Gutenberg Health Study. Glucose status was classified according to HbA1c concentration and history of diagnosis. All samples were analyzed for white blood cells (WBCs), granulocytes, lymphocytes, monocytes, platelets, C-reactive protein (CRP), albumin, fibrinogen, and hematocrit. Interleukin-18 (IL-18), IL-1 receptor antagonist (IL-1RA), and neopterin concentrations were determined in a subcohort. RESULTS:In total, 7,584 men and 7,426 women were analyzed (range 35-74 years), with 1,425 and 1,299 having prediabetes and diabetes, respectively. Biomarkers showed varying dynamics from normoglycemic via subjects with prediabetes to subjects with diabetes: 1) gradual increase (WBCs, granulocytes, monocytes, IL-1RA, IL-18, and fibrinogen), 2) increase with subclinical disease only (lymphocytes and CRP), 3) increase from prediabetes to diabetes only (neopterin), and 4) no variation with glucose status (hematocrit). The strongest relative differences were found for CRP, IL-1RA, and fibrinogen concentrations. Several inflammatory and immune markers were associated with the glucose status independent from cardiovascular risk factors and comorbidities, varied with disease severity and the presence of disease-specific complications in the diabetes subcohort. CONCLUSIONS:The inflammatory and immune biomarker profile varies with the development and progression of type 2 diabetes. Markers of inflammation and immunity enable differentiation between the early preclinical and clinical phases of the disease, disease complications, and progression. 10.2337/dc14-3008
    Leukocyte profiles differ between type 1 and type 2 diabetes and are associated with metabolic phenotypes: results from the German Diabetes Study (GDS). Menart-Houtermans Barbara,Rütter Ruth,Nowotny Bettina,Rosenbauer Joachim,Koliaki Chrysi,Kahl Sabine,Simon Marie-Christine,Szendroedi Julia,Schloot Nanette C,Roden Michael, Diabetes care OBJECTIVE:Altered immune reactivity precedes and accompanies type 1 and type 2 diabetes. We hypothesized that the metabolic phenotype relates to the systemic cellular immune status. RESEARCH DESIGN AND METHODS:A total of 194 metabolically well-controlled patients with type 1 diabetes (n = 62, mean diabetes duration 1.29 years) or type 2 diabetes (n = 132, 1.98 years) and 60 normoglycemic persons underwent blood sampling for automated white blood cell counting (WBC) and flow cytometry. Whole-body insulin sensitivity was measured with hyperinsulinemic-euglycemic clamp tests. RESULTS:Patients with type 2 diabetes had higher WBC counts than control subjects along with a higher percentage of T cells and activated T helper (Th) and cytotoxic T (Tc) cells but lower proportions of natural killer (NK) cells. In type 1 diabetes, the percentage of activated Th and Tc cells was also higher compared with control subjects, whereas the ratio of regulatory T (Treg) cells to activated Th cells was lower, suggesting diminished regulatory capacity. Parameters of glycemic control related positively to Treg cells only in type 2 diabetes. Upon age, sex, and body mass adjustments, insulin sensitivity correlated positively with monocytes, while circulating lipids correlated positively with T cell subsets in type 1 diabetes. CONCLUSIONS:Immune cell phenotypes showed distinct frequencies of occurrence in both diabetes types and associate with insulin sensitivity, glycemia, and lipidemia. 10.2337/dc14-0316
    Functional variants of the HMGA1 gene and type 2 diabetes mellitus. Chiefari Eusebio,Tanyolaç Sinan,Paonessa Francesco,Pullinger Clive R,Capula Carmelo,Iiritano Stefania,Mazza Tommaso,Forlin Michele,Fusco Alfredo,Durlach Vincent,Durlach Anne,Malloy Mary J,Kane John P,Heiner Steven W,Filocamo Mirella,Foti Daniela P,Goldfine Ira D,Brunetti Antonio JAMA CONTEXT:High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM). OBJECTIVE:To examine the association of HMGA1 gene variants with type 2 DM. DESIGN, SETTINGS, AND PARTICIPANTS:Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls. MAIN OUTCOME MEASURES:The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis. RESULTS:The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P < .001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P < .001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P = .03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls. In addition to the IVS5 C-insertion, the c.310G>T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA. CONCLUSIONS:Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM. 10.1001/jama.2011.207
    Increased CD36 expression signals monocyte activation among patients with type 2 diabetes. Sun Yijuan,Scavini Marina,Orlando Robert A,Murata Glen H,Servilla Karen S,Tzamaloukas Antonios H,Schrader Ronald,Bedrick Edward J,Burge Mark R,Abumrad Nada A,Zager Philip G Diabetes care OBJECTIVE:To explore the hypothesis that CD36, a scavenger receptor and fatty acid translocase, is upregulated in peripheral blood mononuclear cells (PBMCs) among patients with type 2 diabetes and is a biomarker of PBMC activation and inflammation. RESEARCH DESIGN AND METHODS:We used a cross-sectional observational design to study a multi-racial/ethnic population sample consisting of Caucasians, Hispanics, and Native Americans with type 2 diabetes (n = 33) and nondiabetic control subjects (n = 27). PBMC CD36 mRNA/protein and plasma high sensitivity (hs) C-reactive protein (hsCRP), hs-interleukin-6 (hsIL-6), and adiponectin were measured. RESULTS:Unadjusted PBMC CD36 mRNA and protein were 1.56- and 1.63-fold higher, respectively, among type 2 diabetic subjects versus control subjects. PBMC CD36 protein was directly associated with CD36 mRNA, plasma hsCRP, and hsIL-6 and inversely associated with plasma adiponectin in both groups. CONCLUSIONS:Increased CD36 expression is a biomarker of PBMC activation and inflammation and may become a useful tool in cardiovascular disease risk stratification. 10.2337/dc10-0460
    The association between depressive symptoms and systemic inflammation in people with type 2 diabetes: findings from the South London Diabetes Study. Laake Jean-Pierre S,Stahl Daniel,Amiel Stephanie A,Petrak Frank,Sherwood Roy A,Pickup John C,Ismail Khalida Diabetes care OBJECTIVE:The prevalence of depression and depressive symptoms is increased twofold in people with type 2 diabetes compared with the general population and is associated with worse biomedical outcomes and increased mortality. Type 2 diabetes, cardiovascular disease, and depression in nondiabetes subjects are independently associated with raised concentrations of circulating inflammatory markers, but it is not known if a similar association is observed in type 2 diabetes. We tested the hypothesis that higher depressive symptom scores in newly diagnosed type 2 diabetes patients were associated with higher concentrations of inflammatory markers. RESEARCH DESIGN AND METHODS:Depressive symptoms in adults with newly diagnosed type 2 diabetes recruited from primary care were assessed using the Patient Health Questionnaire-9. Twelve markers of inflammation (C-reactive protein [hs-CRP], interleukin-4 [IL-4], IL-6, IL-10, vascular endothelial growth factor [VEGF], tumor necrosis factor-α [TNF-α], IL-1β, IL-1 receptor antagonist [IL-1RA], monocyte chemotactic protein-1 [MCP-1], white blood cell count [WBC], adiponectin, and triglyceride [TG]) were measured. Covariates included sociodemographic factors, adiposity, macrovascular disease, HbA1c, and prescribed medication. The association between each inflammatory marker and depressive symptom score was estimated by multiple linear regression. RESULTS:The baseline cohort consisted of 1,790 participants. After adjusting for covariates, CRP (B = 0.13, P < 0.001), IL-1β (B = 0.06, P = 0.047), IL-1RA (B = 0.13, P < 0.001), MCP-1 (B = 0.11, P = 0.001), WBC (B = 0.13, P < 0.001), and TG (B = 0.10, P < 0.001) were associated with depressive symptoms. CONCLUSIONS:Increased inflammation may be involved in the pathogenesis of depressive symptoms in type 2 diabetes and contribute to the increased risk of complications and mortality in this group. 10.2337/dc13-2522
    Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Sampson Mike J,Winterbone Mark S,Hughes Jackie C,Dozio Nicoletta,Hughes David A Diabetes care OBJECTIVE:Telomeres are DNA sequences necessary for DNA replication, which shorten at cell division at a rate related to levels of oxidative stress. Once shortened to a critical length, cells are triggered into replicative senescence. Type 2 diabetes is associated with oxidative DNA damage, and we hypothesized that telomere shortening would characterize type 2 diabetes. RESEARCH DESIGN AND METHODS:We studied 21 male type 2 diabetic subjects (mean age 61.2 years, mean HbA(1c) 7.9%) selected to limit confounding effects on telomere length and 29 matched control subjects. Telomere length was measured in peripheral venous monocyte and T-cells (naïve and memory) by fluorescent in situ hybridization and oxidative DNA damage by flow cytometry of oxidized DNA bases. Peripheral insulin resistance (homeostasis model assessment) and high-sensitivity C-reactive protein (hsCRP) were measured. RESULTS:Mean monocyte telomere length in the diabetic group was highly significantly lower than in control subjects (4.0 [1.1] vs. 5.5 [1.1]; P < 0.0001), without significant differences in lymphocyte telomere length. There was a trend toward increased oxidative DNA damage in all diabetes cell types examined and a significant inverse relationship between oxidative DNA damage and telomere length (r = -0.55; P = 0.018) in the diabetic group. Telomere length was unrelated to plasma CRP concentration or insulin resistance. CONCLUSIONS:Monocyte telomere shortening in type 2 diabetes could be due to increased oxidative DNA damage to monocyte precursors during cell division. This data suggests that monocytes adhering to vascular endothelium and entering the vessel wall in type 2 diabetes are from a population with shorter telomeres and at increased risk of replicative senescence within vascular plaque. 10.2337/diacare.29.02.06.dc05-1715
    Reduced expression of ATP-binding cassette transporter G1 increases cholesterol accumulation in macrophages of patients with type 2 diabetes mellitus. Mauldin Jeremy P,Nagelin Melissa H,Wojcik Allison J,Srinivasan Suseela,Skaflen Marcus D,Ayers Carlos R,McNamara Coleen A,Hedrick Catherine C Circulation BACKGROUND:Patients with type 2 diabetes mellitus are at increased risk for the development of atherosclerosis. A pivotal event in the development of atherosclerosis is macrophage foam cell formation. The ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 regulate macrophage cholesterol efflux and hence play a vital role in macrophage foam cell formation. We have previously found that chronic elevated glucose reduces ABCG1 expression. In the present study, we examined whether patients with type 2 diabetes mellitus had decreased ABCG1 and/or ABCA1, impaired cholesterol efflux, and increased macrophage foam cell formation. METHODS AND RESULTS:Blood was collected from patients with and without type 2 diabetes mellitus. Peripheral blood monocytes were differentiated into macrophages, and cholesterol efflux assays, immunoblots, histological analysis, and intracellular cholesteryl ester measurements were performed. Macrophages from patients with type 2 diabetes mellitus had a 30% reduction in cholesterol efflux with a corresponding 60% increase in cholesterol accumulation relative to control subjects. ABCG1 was present in macrophages from control subjects but was undetectable in macrophages from patients with type 2 diabetes mellitus. In contrast, ABCA1 expression in macrophages was similar in both control subjects and patients with type 2 diabetes mellitus. Macrophage expression of ABCG1 in both patients and control subjects was induced by treatment with the liver X receptor agonist TO-901317. Upregulation of liver X receptor dramatically reduced foam cell formation in macrophages from patients with type 2 diabetes mellitus. CONCLUSIONS:ABCG1 expression and cholesterol efflux are reduced in patients with type 2 diabetes mellitus. This impaired ABCG1-mediated cholesterol efflux significantly correlates with increased intracellular cholesterol accumulation. Strategies to upregulate ABCG1 expression and function in type 2 diabetes mellitus could have therapeutic potential for limiting the accelerated vascular disease observed in patients with type 2 diabetes mellitus. 10.1161/CIRCULATIONAHA.107.741314
    SGLT2 Inhibition with Empagliflozin Increases Circulating Provascular Progenitor Cells in People with Type 2 Diabetes Mellitus. Hess David A,Terenzi Daniella C,Trac Justin Z,Quan Adrian,Mason Tamique,Al-Omran Mohammed,Bhatt Deepak L,Dhingra Natasha,Rotstein Ori D,Leiter Lawrence A,Zinman Bernard,Sabongui Sandra,Yan Andrew T,Teoh Hwee,Mazer C David,Connelly Kim A,Verma Subodh Cell metabolism Hess et al. quantified circulating aldehyde dehydrogenase-expressing (ALDH) cell subsets in people with T2DM given either empagliflozin (EMPA) or placebo. EMPA treatment increased circulating pro-angiogenic CD133 progenitor cells, decreased pro-inflammatory ALDH granulocyte precursors, and increased ALDH monocytes with M2 polarization. EMPA treatment improved T2DM-associated "regenerative cell depletion" contributing to enhanced vascular health. 10.1016/j.cmet.2019.08.015
    Glucose-dependent leukocyte activation in patients with type 2 diabetes mellitus, familial combined hyperlipidemia and healthy controls. de Vries Marijke A,Alipour Arash,Klop Boudewijn,van de Geijn Gert-Jan M,Janssen Hans W,Njo Tjin L,van der Meulen Noëlle,Rietveld Arie P,Liem Anho H,Westerman Elsbeth M,de Herder Wouter W,Cabezas Manuel Castro Metabolism: clinical and experimental BACKGROUND:Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity. METHODS:Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC). RESULTS:51 Subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p=0.004 and p=0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearman's rho 0.481, p<0.001) and HbA1c (rho 0.433, p=0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p=0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p=0.022) and HbA1c (rho 0.319, p=0.023). CONCLUSIONS:These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions. 10.1016/j.metabol.2014.10.011
    Altered monocyte calcium-sensing receptor expression in patients with type 2 diabetes mellitus and atherosclerosis. Malecki R,Fiodorenko-Dumas Z,Jakobsche-Policht U,Malodobra M,Adamiec R Journal of physiology and pharmacology : an official journal of the Polish Physiological Society UNLABELLED:The increased cardiovascular risk in type 2 diabetes mellitus (DM2) is the result of disorders of the immune system, including the enhanced reactivity of monocytes and impaired secretion of inflammatory cytokines. The aim of this study was to analyze the expression of calcium-sensing receptor (CaR) in peripheral blood monocytes of individuals with DM2 and peripheral artery disease (PAD). The study included 88 individuals, among them 37 patients with PAD (group A--atherosclerosis), 27 individuals with DM2 and PAD (group AD--atherosclerosis and diabetes mellitus), and 24 controls (group C--controls). The expression of CaR on isolated peripheral blood monocytes was analyzed at the level of surface protein (CaR(surf)) and mRNA (CaR(mRNA)). Concentrations of pro-inflammatory cytokines were determined by means of ELISA, while the severity of PAD was assessed with Doppler and impedance plethysmography. The expression of CaR(surf) was the highest in the controls (mean 41.27%) and did not differ significantly as compared to individuals from group AD (35.66%); however it was significantly higher than in group A (24.49%). The expression of CaR(surf) was related to the severity of PAD, fasting concentration of glucose, and the concentration of monocyte chemotactic protein (MCP-1). Additionally, significant differences were observed with regards to CaR(mRNA) expression; although, no significant relationships were documented between CaR(mRNA) and laboratory or clinical variables. Different ways of CaR(surf) and CaR(mRNA) expression regulation were associated with the concentration of osteopontin. CONCLUSION:A nearly 1.5-fold higher expression of CaR(surf) on the peripheral blood monocytes of individuals with diabetes and PAD manifests during post-transcription stage and depends on fasting glucose concentration and MCP-1 concentration on one hand, and the severity of PAD on the other.
    Augmented NADPH oxidase activity and p22phox expression in monocytes underlie oxidative stress of patients with type 2 diabetes mellitus. Huang Xiuqing,Sun Mingxiao,Li Dongxiao,Liu Jin,Guo Hanbang,Dong Yuan,Jiang Lei,Pan Qi,Man Yong,Wang Shu,Li Jian Diabetes research and clinical practice BACKGROUND:This study was to test the hypothesis that enhanced oxidative stress is induced in monocytes with over-activated NADPH oxidase during the development of type 2 diabetes mellitus. METHODS:Levels of glucose and lipids were analyzed in 73 diabetic patients and 36 controls. Superoxide dismutase (SOD), malondialdehyde (MDA), reactive oxygen species (ROS) and protein carbonylation were tested. Expression of NADPH oxidase was examined and p47phox translocation was assessed. RESULTS:With the abnormality of glucose and lipid metabolism, diabetic patients showed a higher oxidative stress state indicated by decreased SOD activity but elevated MDA and protein carbonylation level. Monocytes in diabetes also showed elevated ROS generation and protein carbonylation level. Furthermore, NADPH oxidase was highly activated in monocytes represented by p22phox up-regulation and p47phox translocation. Significant positive bivariate correlation was found between glucose and MDA level as well as p22phox expression. In vitro experiments also indicated that glucose could stimulate ROS generation in a NADPH oxidase dependent manner. Moreover, we carried out same measurement in 40 diabetic patients with anti-diabetic intervention and obtained the reinforced results. CONCLUSIONS:Hyperglycemia is the main factor which induces oxidative stress mainly by activation of NADPH oxidase in monocytes of diabetic patients. 10.1016/j.diabres.2010.12.026
    Modulation of human monocyte CD36 by type 2 diabetes mellitus and other atherosclerotic risk factors. Bernal-Lopez Rosa M,Llorente-Cortes Vicenta,López-Carmona Dolores,Mayas Dolores M,Gomez-Huelgas Ricardo,Tinahones Francisco J,Badimon Lina European journal of clinical investigation BACKGROUND:The pathophysiological role of CD36 in atherosclerosis seems to be largely dependent on its pro-inflammatory function and ability to take up oxidized low-density lipoprotein. Controversy exists concerning the potential beneficial/harmful effects of vascular CD36 inhibition in atherosclerosis. However, as atherosclerosis in murine models does not result in clinical end points such as plaque rupture and thrombotic ischaemia, typical of human disease, clinical studies are required to understand the functional role of CD36 in human atherosclerosis. MATERIALS AND METHODS:Our aim was to investigate whether CD36 expression in monocytes is modulated by the presence of an increasing number of atherosclerotic risk factors, and specifically by hyperglycaemia because of diabetes mellitus. The study included 33 patients with advanced atherosclerosis and eight healthy blood donors, as controls. The patients were classified according to the presence of atherosclerotic risk factors. Diabetes mellitus was classified as either well-controlled or poorly controlled. Monocytes were exposed in vitro to low (5·5mM) or high glucose (26mM) concentrations for increasing times. RESULTS:Our results demonstrated that protein levels of glycated CD36 were significantly higher in patients with 3-4 atherosclerotic risk factors than in those with 0-2 atherosclerotic risk factors or in subjects with no atherosclerotic symptoms (P=0·04, in both cases). However, when we analysed just the poorly controlled diabetic patients, their glycated CD36 levels were lower. These data were corroborated by in vitro studies demonstrating that increasing glucose concentrations reduced glycated protein levels (P<0·05). CONCLUSIONS:Our results demonstrate that CD36 expression is altered by hyperglycaemia in atherosclerotic patients. 10.1111/j.1365-2362.2011.02475.x
    The effect of very-low-calorie diet on mitochondrial dysfunction in subcutaneous adipose tissue and peripheral monocytes of obese subjects with type 2 diabetes mellitus. Urbanová M,Mráz M,Ďurovcová V,Trachta P,Kloučková J,Kaválková P,Haluzíková D,Lacinová Z,Hansíková H,Wenchich L,Kršek M,Haluzík M Physiological research Mitochondrial dysfunction is a potentially important player in the development of insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the changes of mRNA expression of genes encoding main enzymatic complexes of mitochondrial respiratory chain in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 11 subjects with simple obesity (OB), 16 obese patients with T2DM and 17 healthy lean subjects (C) before and after very low-calorie diet (VLCD) using quantitative real time PCR. At baseline in SCAT, both T2DM and OB group had decreased mRNA expression of all investigated mitochondrial genes with the exception of 2 complex I (NDUFA 12) and complex IV (COX 4/1) enzymes in OB subjects. In contrast, in PM only the expression of complex I enzymes NDUFA 12 and MT-ND5 was reduced in both T2DM and OB subjects along with decreased expression of citrate synthase (CS) in T2DM group. Additionally, T2DM subjects showed reduced activity of pyruvate dehydrogenase and complex IV in peripheral blood elements. VLCD further decreased mRNA expression of CS and complex I (NT-ND5) and II (SDHA) enzymes in SCAT and complex IV (COX4/1) and ATP synthase in PM of T2DM group, while increasing the activity of complex IV in their peripheral blood elements. We conclude that impaired mitochondrial biogenesis and decreased activity of respiratory chain enzymatic complexes was present in SCAT and PM of obese and diabetic patients. VLCD improved metabolic parameters and ameliorated mitochondrial oxidative function in peripheral blood elements of T2DM subjects but had only minor and inconsistent effect on mitochondrial gene mRNA expression in SCAT and PM. 10.33549/physiolres.933469
    Acute high-intensity interval exercise reduces human monocyte Toll-like receptor 2 expression in type 2 diabetes. Durrer Cody,Francois Monique,Neudorf Helena,Little Jonathan P American journal of physiology. Regulatory, integrative and comparative physiology Type 2 diabetes (T2D) is characterized by chronic low-grade inflammation that contributes to disease pathophysiology. Exercise has anti-inflammatory effects, but the impact of high-intensity interval training (HIIT) is not known. The purpose of this study was to determine the impact of a single session of HIIT on cellular, molecular, and circulating markers of inflammation in individuals with T2D. Participants with T2D ( = 10) and healthy age-matched controls (HC; = 9) completed an acute bout of HIIT (7 × 1 min at ~85% maximal aerobic power output, separated by 1 min of recovery) on a cycle ergometer with blood samples obtained before (Pre), immediately after (Post), and at 1 h of recovery (1-h Post). Inflammatory markers on leukocytes were measured by flow cytometry, and TNF-α was assessed in both LPS-stimulated whole blood cultures and plasma. A single session of HIIT had an overall anti-inflammatory effect, as evidenced by ) significantly lower levels of Toll-like receptor (TLR) 2 surface protein expression on both classical and CD16+ monocytes assessed at Post and 1-h Post compared with Pre ( < 0.05 for all); ) significantly lower LPS-stimulated TNF-α release in whole blood cultures at 1-h Post ( < 0.05 vs. Pre); and ) significantly lower levels of plasma TNF-α at 1-h Post ( < 0.05 vs. Pre). There were no differences between T2D and HC, except for a larger decrease in plasma TNF-α in HC vs. T2D (group × time interaction, < 0.05). One session of low-volume HIIT has immunomodulatory effects and provides potential anti-inflammatory benefits to people with, and without, T2D. 10.1152/ajpregu.00348.2016
    BMP-2 induces human mononuclear cell chemotaxis and adhesion and modulates monocyte-to-macrophage differentiation. Pardali Evangelia,Makowski Lena-Maria,Leffers Merle,Borgscheiper Andreas,Waltenberger Johannes Journal of cellular and molecular medicine Type 2 diabetes mellitus (T2DM) is a cardiovascular risk factor which leads to atherosclerosis, an inflammatory disease characterized by the infiltration of mononuclear cells in the vessel. Bone morphogenetic protein (BMP)-2 is a cytokine which has been recently shown to be elevated in atherosclerosis and T2DM and to contribute to vascular inflammation. However, the role of BMP-2 in the regulation of mononuclear cell function remains to be established. Herein, we demonstrate that BMP-2 induced human monocyte chemotaxis via phosphoinositide 3 kinase and mitogen-activated protein kinases. Inhibition of endogenous BMP-2 signalling, by Noggin or a BMP receptor inhibitor, interfered with monocyte migration. Although BMP-2 expression was increased in monocytes from T2DM patients, it could still stimulate their migration. Furthermore, BMP-2 interfered with their differentiation into M2 macrophages. Finally, BMP-2 both induced the adhesion of monocytes to fibronectin and endothelial cells (ECs), and promoted the adhesive properties of ECs, by increasing expression of adhesion and pro-inflammatory molecules. Our data demonstrate that BMP-2 could exert its pro-inflammatory effects by inducing monocyte migration and adhesiveness to ECs and by interfering with the monocyte differentiation into M2 macrophages. Our findings provide novel insights into the mechanisms by which BMP-2 may contribute to the development of atherosclerosis. 10.1111/jcmm.13814
    An unbalanced monocyte polarisation in peripheral blood and bone marrow of patients with type 2 diabetes has an impact on microangiopathy. Fadini G P,de Kreutzenberg S Vigili,Boscaro E,Albiero M,Cappellari R,Kränkel N,Landmesser U,Toniolo A,Bolego C,Cignarella A,Seeger F,Dimmeler S,Zeiher A,Agostini C,Avogaro A Diabetologia AIM/HYPOTHESIS:Monocytes/macrophages play important roles in adipose and vascular tissues and can be polarised as inflammatory M1 or anti-inflammatory M2. We sought to analyse monocyte polarisation status in type 2 diabetes, which is characterised by chronic inflammation. METHODS:We enrolled 60 individuals without diabetes and 53 patients with type 2 diabetes. We quantified standard monocyte subsets defined by cluster of differentiation (CD)14 and CD16. In addition, based on the phenotype of polarised macrophages in vitro, we characterised and quantified more definite M1 (CD68(+)CCR2(+)) and M2 (CX3CR1(+)CD206(+)/CD163(+)) monocytes. We also analysed bone marrow (BM) samples and the effects of granulocyte-colony stimulating factor (G-CSF) stimulation in diabetic and control individuals. RESULTS:We found no alterations in standard monocyte subsets (classical, intermediate and non-classical) when comparing groups. For validation of M1 and M2 phenotypes, we observed that M2 were enriched in non-classical monocytes and had lower TNF-α content, higher LDL scavenging and lower transendothelial migratory capacity than M1. Diabetic patients displayed an imbalanced M1/M2 ratio compared with the control group, attributable to a reduction in M2. The M1/M2 ratio was directly correlated with waist circumference and HbA1c and, among diabetic patients, M2 reduction and M1/M2 increase were associated with microangiopathy. A decrease in M2 was also found in the BM from diabetic patients, with a relative M2 excess compared with the bloodstream. BM stimulation with G-CSF mobilised M2 macrophages in diabetic but not in healthy individuals. CONCLUSIONS/INTERPRETATION:We show that type 2 diabetes markedly reduces anti-inflammatory M2 monocytes through a dysregulation in bone-marrow function. This defect may have a negative impact on microangiopathy. 10.1007/s00125-013-2918-9
    Human mesenchymal stem cells alter the gene profile of monocytes from patients with Type 2 diabetes and end-stage renal disease. Wise Andrea F,Williams Timothy M,Rudd Stephen,Wells Christine A,Kerr Peter G,Ricardo Sharon D Regenerative medicine AIM:Macrophage infiltration contributes to the pathogenesis of Type 2 diabetes. Mesenchymal stem cells (MSCs) possess immunomodulatory properties, making them an ideal candidate for therapeutic intervention. This study investigated whether MSCs can modulate the phenotype of monocytes isolated from Type 2 diabetic patients with end-stage renal disease. MATERIALS & METHODS:Monocytes from control (n = 4) and Type 2 diabetic patients with end-stage renal disease (n = 5) were assessed using flow cytometry and microarray profiling, following 48 h of co-culture with MSCs. RESULTS:Control subjects had a greater proportion of CD14(++)CD16(-) monocytes while diabetic patients had a higher proportion of CD14(++)CD16(+) and CD14(+)CD16(++) monocytes. MSCs promoted the proliferation of monocytes isolated from diabetic patients, reduced HLA-DR expression in both groups and promoted the expression of anti-inflammatory genes. CONCLUSION:MSC-derived factors alter the polarization of monocytes isolated from healthy and diabetic subjects toward an M2 phenotype. 10.2217/rme.15.74
    Proinflammatory CD14+CD16+ monocytes are associated with microinflammation in patients with type 2 diabetes mellitus and diabetic nephropathy uremia. Yang Mengxue,Gan Hua,Shen Qing,Tang Weixue,Du Xiaogang,Chen Danyan Inflammation Diabetic nephropathy (DN) is a major cause of type 2 diabetes mellitus (T2DM) mortality. Innate immunity has been shown to be closely associated with the occurrence and progression of T2DM-associated complications. In this study, we investigated the expression of Toll-like receptor 4 (TLR4) and CD14(+)CD16(+) monocytes in patients with T2DM and DN patients with uremia and TLR4 response to lipopolysaccharide (LPS), and to further explore the potential effects of inflammatory immune response in T2DM and DN uremia. Thirty DN patients with uremia, 28 T2DM patients, and 20 healthy volunteers were enrolled for the determination of CD14(+)CD16(+) fluorescence intensity and TLR4 expression on monocytes by using peripheral blood flow cytometry. Serum C-reactive protein (CRP) level was determined by using the immunoturbidimetry. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with LPS for 24 h. monocytes were collected to detect NF-κB p65 and phosphorylated STAT5(p-STAT5) expressions by using Western blotting. Supernatants were sampled for the determination of interleukin-6 (IL-6) concentration by using ELISA. Compared to normal control, T2DM patients and DN uremic patients had a significantly higher CD14(+)CD16(+) fluorescence intensity, TLR4 expression, serum IL-6 and CRP level, whilst these biomarkers were more upregulated in DN uremic patients than in T2DM patients. Following the exposure to LPS, PBMCs showed a significant upregulation in NF-κB-p65 and p-STAT5 expression and a remarked increase in Supernatants IL-6 level, in a positive correlation with disease severity. Our results suggest that the disturbance in proinflammatory CD14(+)CD16(+) monocytes occurs in T2DM and DN uremic patients. Such immunological dysfunction may be related to the activation of TLR4/NF-κB and STAT5 signaling pathways underlying the immune abnormalities of CD14(+)CD16(+) monocytes. 10.1007/s10753-011-9374-9
    Influence of high density lipoprotein cholesterol levels on circulating monocytic angiogenic cells functions in individuals with type 2 diabetes mellitus. Lucchesi Daniela,Popa Simona Georgiana,Sancho Veronica,Giusti Laura,Garofolo Monia,Daniele Giuseppe,Pucci Laura,Miccoli Roberto,Penno Giuseppe,Del Prato Stefano Cardiovascular diabetology BACKGROUND:High-density lipoproteins (HDLs) can exert anti-atherogenic effects. On top of removing excess cholesterol through reverse cholesterol transport, HDLs play beneficial actions on endothelial function and integrity. In particular, HDLs are strong determinant of endothelial progenitor cells (EPCs) number and function. To gain further insights into such an effect we characterized in vitro functionality of circulating "early" EPCs obtained from 60 type 2 diabetes individuals with low HDL-cholesterol (HDL-C) and 59 with high HDL-C levels. METHODS:After an overnight fast, venous blood was drawn in EDTA tubes and processed within 2-h from sampling. Peripheral blood mononuclear cells were isolated and plated on fibronectin coated culture dishes; after 3 days culture, adherent cells positive for Dil-ac-LDL/Lectin dual fluorescent staining were identified as monocytic angiogenic cells (MACs). After 5-7 days culture in EBM-2 medium, adherent cells were evaluated for viability/proliferation (MTT assay), senescence (beta-galactosidase activity detection), migration (modified Boyden chamber using VEGF as chemoattractant), adhesion capacity (on fibronectin-coated culture dishes) and ROS production (ROS-sensitive fluorescent probe CM-HDCFDA). RESULTS:MACs obtained from diabetic individuals with high HDL-C had 23% higher viability compared to low HDL-C (111.6 ± 32.7% vs. 90.5 ± 28.6% optical density; p = 0.002). HO exposure impaired MACs viability to a similar extent in both groups (109.2 ± 31.7% vs. 74.5 ± 40.8% in high HDL-C, p < 0.0001; 88.3 ± 25.5% vs. 72.3 ± 22.5% in low-HDL, p = 0.004). MACs senescence was comparable in the two groups (102.7 ± 29.8% vs. 99.2 ± 27.8%; p = 0.703) and was only slightly modified by exposure to HO. There was no difference in the MACs migration capacity between the two groups (91.3 ± 34.2% vs. 108.7 ± 39.5%; p = 0.111), as well as in MACs adhesion capacity (105.2 ± 32.7% vs. 94.1 ± 26.1%; p = 0.223). Finally, ROS production was slightly thought not significantly higher in MACs from type 2 diabetes individuals with low- than high-HDL. After stratification of HDL-C levels into quartiles, viability (p < 0.0001) and adhesion (p = 0.044) were higher in Q4 than in Q1-Q3. In logistic regression analysis, HDL-C was correlated to MACs viability and adhesion independently of HbA1c or BMI, respectively. CONCLUSIONS:Our data suggest that in type 2 diabetes subjects, HDL-cholesterol is an independent determinant of circulating MACs functional capacities-mainly viability, to a lesser extent adhesion-likely contributing also through this mechanism to cardiovascular protection even in type 2 diabetes. 10.1186/s12933-018-0720-1
    Perturbation of the Monocyte Compartment in Human Obesity. Friedrich Kathleen,Sommer Miriam,Strobel Sarah,Thrum Stephan,Blüher Matthias,Wagner Ulf,Rossol Manuela Frontiers in immunology Circulating monocytes can be divided into classical (CM), intermediate (IM), and non-classical monocytes (NCM), and the classical monocytes also contain CD56+ monocytes and monocytic myeloid-derived suppressor cells (M-MDSC). The aim of the study was to evaluate the occurrence of the monocyte subpopulations in human obesity. Twenty-seven normal, 23 overweight, and 60 obese individuals (including 17 obese individuals with normal glucose tolerance and 27 with type 2 diabetes) were included into this study. Peripheral blood mononuclear cells were isolated from human blood, and surface markers to identify monocyte subpopulations were analyzed by flow cytometry. Obese individuals had higher numbers of total monocytes, CM, IM, CD56+ monocytes, and M-MDSCs. The number of CM, IM, CD56+ monocytes, and M-MDSCs, correlated positively with body mass index, body fat, waist circumference, triglycerides, C-reactive protein, and HbA1c, and negatively with high-density lipoprotein cholesterol. Individuals with obesity and type 2 diabetes had higher numbers of IM, NCM, and M-MDSCs, whereas those with obesity and impaired glucose tolerance had higher numbers of CD56+ monocytes. In summary, the comprehensive analysis of blood monocytes in human obesity revealed a shift of the monocyte compartment toward pro-inflammatory monocytes which might contribute to the development of low-grade inflammation in obesity, and immune-suppressive monocytes which might contribute to the development of cancer in obesity. 10.3389/fimmu.2019.01874
    Type 2 Diabetes Monocyte MicroRNA and mRNA Expression: Dyslipidemia Associates with Increased Differentiation-Related Genes but Not Inflammatory Activation. Baldeón R Lucy,Weigelt Karin,de Wit Harm,Ozcan Behiye,van Oudenaren Adri,Sempértegui Fernando,Sijbrands Eric,Grosse Laura,van Zonneveld Anton-Jan,Drexhage Hemmo A,Leenen Pieter J M PloS one OBJECTIVE:To study the expression pattern of microRNAs and mRNAs related to inflammation in T2D monocytes. DESIGN:A microRNA finding study on monocytes of T2D patients and controls using array profiling was followed by a quantitative Real Time PCR (qPCR) study on monocytes of an Ecuadorian validation cohort testing the top over/under-expressed microRNAs. In addition, monocytes of the validation cohort were tested for 24 inflammation-related mRNAs and 2 microRNAs previously found deregulated in (auto)-inflammatory monocytes. RESULTS:In the finding study, 142 significantly differentially expressed microRNAs were identified, 15 having the strongest power to discriminate T2D patients from controls (sensitivity 66%, specificity 90%). However, differences in expression of these microRNAs between patients and controls were small. On the basis of >1.4 or <0.6-fold change expression 5 microRNAs were selected for further validation. One microRNA (miR-34c-5p) was validated as significantly over-expressed in T2D monocytes. In addition, we found over expression of 3 mRNAs (CD9, DHRS3 and PTPN7) in the validation cohort. These mRNAs are important for cell morphology, adhesion, shape change, and cell differentiation. Classical inflammatory genes (e.g. TNFAIP3) were only over-expressed in monocytes of patients with normal serum lipids. Remarkably, in dyslipidemia, there was a reduction in the expression of inflammatory genes (e.g. ATF3, DUSP2 and PTGS2). CONCLUSIONS:The expression profile of microRNAs/mRNAs in monocytes of T2D patients indicates an altered adhesion, differentiation, and shape change potential. Monocyte inflammatory activation was only found in patients with normal serum lipids. Abnormal lipid values coincided with a reduced monocyte inflammatory state. 10.1371/journal.pone.0129421
    Increased monocyte-derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress. Restaino Robert M,Deo Shekhar H,Parrish Alan R,Fadel Paul J,Padilla Jaume Experimental physiology NEW FINDINGS:What is the central question of this study? Patients with type 2 diabetes exhibit increased oxidative stress in peripheral blood mononuclear cells, including monocytes; however, the mechanisms remain unknown. What is the main finding and its importance? The main finding of this study is that factors contained within the plasma of patients with type 2 diabetes can contribute to increased oxidative stress in monocytes, making them more adherent to endothelial cells. We show that these effects are largely mediated by the interaction between endoplasmic reticulum stress and NADPH oxidase activity. Recent evidence suggests that exposure of human monocytes to glucolipotoxic media to mimic the composition of plasma of patients with type 2 diabetes (T2D) results in the induction of endoplasmic reticulum (ER) stress markers and formation of reactive oxygen species (ROS). The extent to which these findings translate to patients with T2D remains unclear. Thus, we first measured ROS (dihydroethidium fluorescence) in peripheral blood mononuclear cells (PBMCs) from whole blood of T2D patients (n = 8) and compared the values with age-matched healthy control subjects (n = 8). The T2D patients exhibited greater basal intracellular ROS (mean ± SD, +3.4 ± 1.4-fold; P < 0.05) compared with control subjects. Next, the increase in ROS in PBMCs isolated from T2D patients was partly recapitulated in cultured human monocytes (THP-1 cells) exposed to plasma from T2D patients for 36 h (+1.3 ± 0.08-fold versus plasma from control subjects; P < 0.05). In addition, we found that increased ROS formation in THP-1 cells treated with T2D plasma was NADPH oxidase derived and led to increased endothelial cell adhesion (+1.8 ± 0.5-fold; P < 0.05) and lipid uptake (+1.3 ± 0.3-fold; P < 0.05). Notably, we found that T2D plasma-induced monocyte ROS and downstream functional effects were abolished by treating cells with tauroursodeoxycholic acid, a chemical chaperone known to inhibit ER stress. Collectively, these data indicate that monocyte ROS production with T2D can be attributed, in part, to signals from the circulating environment. Furthermore, an interplay between ER stress and NADPH oxidase activity contributes to ROS production and may be a mechanism mediating endothelial cell adhesion and foam cell formation in T2D. 10.1113/EP085794
    Monocyte lymphocyte ratio As a predictor of Diabetic Kidney Injury in type 2 Diabetes mellitus; The MADKID Study. Kocak Mehmet Zahid,Aktas Gulali,Duman Tuba Taslamacioglu,Atak Burcin Meryem,Kurtkulagi Ozge,Tekce Hikmet,Bilgin Satilmis,Alaca Betül Journal of diabetes and metabolic disorders Aims:Inflammation is a cardinal pathogenetic mechanism in diabetic kidney injury (DKI). The detection of microalbuminuria (MA) is very important in preventing end-stage renal failure in diabetic subjects. A combination of high monocyte and low lymphocyte counts are used as a marker of inflammation. Monocyte to lymphocyte ratio (MLR) is considered as a marker in inflammatory diseases. We aimed to evaluate the MLR levels in diabetic subjects as a predictive marker in detecting MA. Methods:A total of 212 patients with type 2 diabetes mellitus (T2DM) were included in the study. Patients with T2DM were divided into two groups as MA and normoalbuminuria (NA). MLR of the groups were compared. Results:There were 72 patients in MA and 140 patients in NA group. MLR of the MA and NA groups were 0.247 (0.131-0.540) and 0.211 (0.052-0.390), respectively (p < 0.001). There was a statistically significant correlation between MLR and MA (r = 0.228, p = 0.001). In multivariate backward logistic regression analysis, MLR, fasting blood glucose, HbA1c and presence of comorbid clinical diseases were determined as independent predictors of DKI. Conclusions:We suggest that MLR could serve as a predictive and effective marker for DKI in diabetic subjects due to its strong correlation with MA and inexpensive and readily available nature. 10.1007/s40200-020-00595-0
    Resveratrol supplementation decreases blood glucose without changing the circulating CD14CD16 monocytes and inflammatory cytokines in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Khodabandehloo Hadi,Seyyedebrahimi ShadiSadat,Esfahani Ensieh Nasli,Razi Farideh,Meshkani Reza Nutrition research (New York, N.Y.) Chronic low-grade inflammation is the hallmark of type 2 diabetes (T2D). Although in vitro and animal studies have shown that resveratrol exerts anti-inflammatory effects, clinical trials addressing these effects in patients with T2D are limited. Therefore, in the present study, we hypothesized that supplementation of resveratrol might improve inflammatory markers in patients with T2D in a randomized, double-blind, placebo-controlled clinical trial. A total of 45 T2D patients were supplemented with either of 800 mg/d resveratrol or placebo capsules for 8 weeks. Percentage of CD14CD16 monocytes, plasma levels of inflammatory cytokines (tumor necrosis factor α, interleukin [IL] 1β, IL-6, and monocyte chemoattractant protein-1), the expression levels of genes involved in the inflammatory responses (toll-like receptor 2, toll-like receptor 4, and nuclear factor κB), lipopolysaccharide-stimulated cytokine (tumor necrosis factor α, IL-1β, and IL-6) secretion from peripheral blood mononuclear cells, and metabolic and anthropometric parameters were assessed at both the baseline level and the end of the study. Compared with the placebo group, we could not detect any significant difference in the percentage of CD14CD16 monocytes, lipopolysaccharide-induced cytokine secretion, plasma levels of inflammatory cytokines, and the expression of inflammatory genes in resveratrol group. Moreover, we did not find any significant change in the metabolic and anthropometric parameters except for a significant reduction in fasting blood glucose and blood pressure. In conclusion, 8-week supplementation of resveratrol reduces blood glucose level in patients with T2D without improving their inflammatory markers. 10.1016/j.nutres.2018.03.015
    The Role of Butyrate on Monocyte Migration and Inflammation Response in Patient with Type 2 Diabetes Mellitus. Larasati Rahma Ayu,Harbuwono Dante Saksono,Rahajeng Ekowati,Pradipta Saraswati,Nuraeni Hanny Siti,Susilowati Andi,Wibowo Heri Biomedicines Type 2 Diabetes Mellitus (T2DM) is a very serious global problem. In Indonesia, this disease attacks at the most productive age; consequently, it can reduce economic status and life expectancy. The pathogenesis of T2DM is very closely related to inflammation and macrophage accumulation. However, no anti-inflammatory agent has been proven to play a role in the management of T2DM. Butyrate is a short chain fatty acid produced from resistant starch fermentation in the intestinal lumen. It is able to bind to GPR41 and GPR43 receptors on monocytes, so that it can change the pattern of cytokine expression, activation, migration and cell differentiation. Hence, it is interesting to examine the anti-inflammation effect of butyrate and the effect on monocyte migration. A total of 37 subjects were examined in this study. They were divided into two groups, with and without butyrate treatment. We analyzed two pro-inflammatory cytokines (Tumor Necrosis Factor TNF-α and Interleukin IL-6) and one anti-inflammatory cytokine, IL 10. Monocytes were isolated in type 1 collagen gel for migration testing using the µ-slide chemotaxis IBIDI. Image analysis used ImageJ and Chemotaxis tool software. There was a significant difference in the TNFα/IL 10 ratio between healthy groups and T2DM. Butyrate also appears to suppress TNFα cytokine production and increase IL10 production. It also decreases the accumulation distance of monocyte migration in T2DM. 10.3390/biomedicines7040074
    5-Lipoxygenase (ALOX5): Genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes. Nejatian Nojan,Häfner Ann-Kathrin,Shoghi Firouzeh,Badenhoop Klaus,Penna-Martinez Marissa The Journal of steroid biochemistry and molecular biology The arachidonate 5-lipoxygenase (ALOX5) pathway has been implicated in chronic inflammatory disease which may be influenced by vitamin D due to vitamin D response elements (VDRE). We investigated an ALOX5 polymorphism (rs4987105) in patients with type 2 diabetes (T2D) and the in vitro effects of calcitriol (1,25(OH)D) on ALOX5 metabolism in monocytes of T2D patients and healthy controls (HC). 533 T2D and 473 HC were genotyped for the rs4987105 polymorphism. In addition, the 25(OH)D and 1,25(OH)D plasma levels were measured in both cohorts. Further C-reactive protein (CRP) was determined in T2D patients. Our results demonstrate, that genotype CC and the allele C of ALOX5 rs4987105 polymorphism were more frequent in T2D compared to HC (OR = 1.44; 95% CI: 1.12-1.84; p < 0.05). Lower levels of both vitamin D metabolites (p < 0.0001 respectively) were found in the CC genotyped T2D patients compared to CC genotyped HC. In addition, CC genotyped T2D patients had higher levels of CRP compared to CT and TT genotyped T2D patients, (p < 0.01). In order to evaluate the impact of calcitriol in primary isolated monocytes, we isolated monocytes of 20 T2D patients and 20 HC. The cells were treated with 1,25(OH)D and interleukin-1beta (IL-1β) for 24 h. The following genes were analysed for expression changes: ALOX5, leukotriene A4 hydrolase (LTA4H), leukotriene B4 receptor type 1 (LTB4R1) and CD14. Treatment with IL-1β+1,25(OH)D increased ALOX5, LTA4H and LTB4R1 and CD14 mRNA in both T2D patients and HC (p < 0.0001, respectively). In addition, IL-1β+1,25(OH)D treatment led to higher ALOX5, LTA4H and CD14 mRNA levels in T2D patients compared to HC (p < 0.001, p < 0.05, p ≤ 0.05, respectively). In conclusion, ALOX5 rs4987105 allele C confers susceptibility to T2D, lower vitamin D metabolites and higher CRP levels complement this association. Additionally, IL-1β+1,25(OH)D treatment on, ALOX5, LTA4H and CD14 mRNA indicate a diabetes specific modulation. These findings identify a novel pathway in T2D potentially amenable for individualized therapeutic targeting. 10.1016/j.jsbmb.2018.10.022
    Peripheral monocyte count is an independent predictor of all-cause mortality in type 2 diabetes with macro-vascular complications. Yang Lina,Hu Jinbo,Wang Zhihong,Chen Xiangjun,Wang Yue,Yang Shumin,Luo Ting,Mei Mei,Cheng Qingfeng,Xu Zhixin,Du Zhipeng,Gong Lilin,Luo Rong,Li Qifu Medicine The relationship between monocyte count and mortality seemed to be varied in different diseases, and it remains unclear in type 2 diabetes (T2D). We conducted a prospective study to investigate whether monocyte count predict all-cause mortality in patients with T2D.In this prospective study, a total of 1073 patients with T2D were enrolled at baseline and 880 patients completed the follow up. The median follow-up time was 47 months. At baseline, clinical characteristics including height, weight, waist circumference, blood pressure were recorded. Biochemical parameters including counts of white blood cells (WBCC), neutrophil (NC) and monocyte (MC), lipid profiles, glycated hemoglobin (HbA1c), serum creatinine were measured. Charlson comorbidity index (CCI) was calculated based on age and comorbidities. Participants were stratified into low, median, and high tertiles according to the baseline MC. Regression models were used to analyze the associations of peripheral MC and the all-cause mortality.Compared to the survived subjects, the baseline MC was significantly higher in patients who deceased during the follow-up (0.45 ± 0.16 vs 0.37 ± 0.15 × 10/L, P = .003). In the multivariate Cox hazard models, subjects in higher MC tertile showed higher risks of all-cause mortality (low tertile as the reference, hazard ratio [HR] 95%CI 2.65 [0.84,8.31] and 3.73 [1.14,12.24] for middle and high MC tertile, respectively) after adjusted for gender, body mass index, CCI, duration of T2D, history of hypertension and metabolic syndrome, drugs, levels of high-sensitivity C-reactive protein, systolic blood pressure, HbA1c, WBCC, and NC. In T2D patients with macro-vascular complications at baseline, 1-SD increment of MC resulted in 1.92-fold higher risk of all-cause mortality. However, the relationship disappeared in subjects without macro-vascular complications at baseline (1.13 [0.72, 1.78], P = .591).Peripheral monocyte count is an independent predictor of all-cause mortality in T2D, especially for subjects with macro-vascular complications. 10.1097/MD.0000000000018876
    The Association between Monocyte Surface CD163 and Insulin Resistance in Patients with Type 2 Diabetes. Kawarabayashi Reina,Motoyama Koka,Nakamura Miyuki,Yamazaki Yuko,Morioka Tomoaki,Mori Katsuhito,Fukumoto Shinya,Imanishi Yasuo,Shioi Atsushi,Shoji Tetsuo,Emoto Masanori,Inaba Masaaki Journal of diabetes research Aim:To investigate the association between monocyte CD163 and insulin resistance in patients with type 2 diabetes. Methods:One hundred sixty-six patients with type 2 diabetes without inflammatory or chronic kidney disease were recruited. The monocyte CD163 levels were measured by flow cytometry and soluble CD163 (sCD163) by ELISA. Insulin resistance was evaluated by the index of the homeostasis model assessment (HOMA-R). Results:The median sCD163 and monocyte CD163 expression levels were 582.9 (472.4-720.0) ng/ml and 6061 (4486-7876) mean fluorescent intensity (MFI), respectively. In a simple regression analysis, monocyte CD163 was inversely correlated with log [HOMA-R] ( = -0.257, = 0.010), and sCD163 was positively correlated with log [HOMA-R] ( = 0.198, = 0.042). In multiple regression analyses, monocyte CD163 was an independent contributor to log [HOMA-R] ( = -0.220, = 0.020) even after adjustment of various clinical factors for HOMA-R ( = 0.281, = 0.001), whereas sCD163 was not. Conclusions:Monocyte surface CD163 expression levels were more significantly associated with insulin resistance than sCD163 in patients with type 2 diabetes, suggesting a novel pathophysiological role of CD163. 10.1155/2017/6549242
    Proinflammatory (CD14+CD16++) monocytes in type 2 diabetes mellitus patients with/without chronic periodontitis. Jagannathan Raghunathan,Thayman Malini,Rao Suresh Ranga Dental research journal Background:Until date, the proportion of nonclassic monocytes in type 2 diabetic mellitus patients with and without chronic periodontitis has not been evaluated based on glycemic control. The objective of this study was to compare the proportion of CD14+CD16++ monocytes in type 2 diabetic patients with and without chronic periodontitis. Materials and Methods:In this cross sectional study A total of sixty individuals with type 2 diabetes mellitus ( = 15/group) were recruited. Individuals were grouped based on glycosylated hemoglobin A (HbA 1c) values and the presence of chronic periodontitis; Group 1 (diabetes mellitus with good glycemic control), Group 2 (diabetes mellitus with poor glycemic control), Group 3 (diabetic mellitus with chronic periodontitis and good glycemic control), Group 4 (diabetic mellitus with chronic periodontitis and poor glycemic control). Fluorochrome-conjugated monoclonal antibodies against CD14, CD16, and human leukocyte antigen-antigen D related was used to analyze the proportion of nonclassic monocytes by flow cytometry. One-way ANOVA with Tukey's test was used to assess the significant differences in monocyte subpopulations. The Pearson's correlation test was used to assess the relationship between hemoglobin A1c values and percentage of nonclassical monocytes. In both the above statistical tools, the value of < 0.05 is considered as significant level. Results:Group 4 had the highest percentage of CD14+CD16++ monocytes 14.67% + 4.70%, followed by Group 3-9.73% + 0.60%, Group 2-9.32% + 2.03% and Group 1-5.92% + 0.63% ( < 0.001). Further, a statistically significant positive correlation between HbA (1c) levels and the proportion of CD14+CD16++ monocytes was observed. Conclusion:In the present study, we observed type 2 diabetes mellitus patients with poor glycemic control and chronic periodontitis showed more than two-fold increase in the proportion of nonclassic monocytes compared to type 2 diabetes mellitus patients with good glycemic control.
    P2X7 Receptor Expression in Peripheral Blood Monocytes Is Correlated With Plasma C-Reactive Protein and Cytokine Levels in Patients With Type 2 Diabetes Mellitus: a Preliminary Report. Wu Hong,Nie Yijun,Xiong Huangui,Liu Shuangmei,Li Guilin,Huang An,Guo Lili,Wang Shouyu,Xue Yun,Wu Bing,Peng Lichao,Song Miaomiao,Li Guodong,Liang Shangdong Inflammation Chronic inflammation plays a major role in development of type 2 diabetes mellitus (T2DM). C-reactive protein (CRP) and inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) are directly involved in the occurrence of insulin resistance. Increased extracellular ATP levels can amplify the inflammatory response in vivo via the P2X7 receptor. The present study aimed to assess the relationship between P2X7 receptor expression in human peripheral blood monocytes and plasma levels of TNF-α, IL-1β, and CRP in T2DM patients. The results showed the association of increased P2X7 receptor expression of monocytes with high serum CRP, TNF-α, and IL-1β levels. TNF-α and IL-1β levels were lowest in healthy subjects; in T2DM patients, these inflammatory markers were less abundant in individuals with normal CRP levels compared to those with high CRP contents. In contrast, IL-10 levels in T2DM patients with high CRP levels were dramatically decreased. P2X7 receptor expression in monocytes from T2DM patients with high CRP levels was significantly increased in comparison with healthy individuals and T2DM patients with normal CRP levels. These findings indicated that P2X7 receptor in peripheral blood monocytes may be involved in the pathological changes of T2DM, particularly affecting patients with high CRP levels. 10.1007/s10753-015-0189-y
    T cell immunoglobulin and mucin domain-containing molecule 3 on CD14 monocytes serves as a novel biological marker for diabetes duration in type 2 diabetes mellitus. Yan Wen-Jiang,Sun Peng,Wei Dan-Dan,Wang Shuang-Xi,Yang Jing-Jing,Li Yi-Hui,Zhang Cheng Journal of diabetes investigation AIMS/INTRODUCTION:Type 2 diabetes is a worldwide disease that is associated with increased rates of obesity and reduced physical activity. Obesity-associated insulin resistance in type 2 diabetes is a disorder in the balance between pro-inflammatory and anti-inflammatory signals. T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) has been reported as an important regulatory inflammation molecule, and plays a pivotal role in several inflammation-related diseases. MATERIALS AND METHODS:Peripheral blood mononuclear cells were obtained from type 2 diabetes patients (n = 31) and healthy donors (n = 18), and Tim-3 expression on peripheral blood mononuclear cells was evaluated by flow cytometry. RESULTS:We showed the downregulated expression of Tim-3 on CD14 monocytes from type 2 diabetes patients. In addition, the upregulated expression of Tim-3 on peripheral CD4 T cells and CD8 T cells was observed in the present study. The correlation analysis between Tim-3 expression on CD14 monocytes and diabetes duration showed the longer diabetes duration time, the lower Tim-3 expression on CD14 monocytes. CONCLUSIONS:The present results suggest that Tim-3 might participate in the progression of type 2 diabetes by its negative regulation on these immune cells, and Tim-3 on CD14 monocytes serves as a novel biological marker for diabetes duration in type 2 diabetes patients. 10.1111/jdi.12523
    Relation of Monocyte/High-Density Lipoprotein Cholesterol Ratio with Coronary Artery Disease in Type 2 Diabetes Mellitus. Ya Gao,Qiu Zhang,Tianrong Pan Clinical laboratory BACKGROUND:Atherosclerotic cardiovascular disease is the leading cause of mortality of patients with type 2 diabetes mellitus, and both coronary artery disease (CAD) and diabetes mellitus are associated with inflammation. Emerging evidence suggests a relationship of the monocyte to high-density lipoprotein cholesterol ratio (MHR) with the incidence and severity of CAD. The aim of the present study was to examine the association of MHR with CAD in patients with type 2 diabetes mellitus. METHODS:A total of 458 consecutive individuals were enrolled, comprising 178 type 2 diabetic patients, 124 type 2 diabetes with CAD, and 156 healthy volunteers as the controls. A multivariable logistic regression model was used to evaluate the relationship between the MHR and CAD in type 2 diabetes, and the receiver operating characteristic (ROC) curve of MHR was used for predicting the presence of CAD in type 2 diabetic patients. RESULTS:Values of MHR were significantly higher in type 2 diabetic patients with CAD compared with those without CAD and the control group. Moreover, multivariate logistic regression analysis showed that MHR was an independent predictor of the presence of CAD in type 2 diabetic patients (OR = 1.361, 95% CI 1.245 - 1.487, p < 0.0001). Based on the receiver operating characteristic (ROC) curve, the cutoff value of MHR (> 8.2) in predicting the presence of CAD in type 2 diabetic patients yields a sensitivity and specificity of 83.74% and 62.15%, respectively, with an area under the curve of 0.795 (95% CI: 0.745 - 0.840). CONCLUSIONS:The MHR is strongly associated with CAD in type 2 diabetes and might be a potential biomarker to predict the presence of CAD in type 2 diabetic patients. 10.7754/Clin.Lab.2018.171022
    Monocyte-mediated inflammation and cardiovascular risk factors in type 2 diabetes mellitus: A systematic review and meta-analysis of pre-clinical and clinical studies. Mokgalaboni Kabelo,Dludla Phiwayinkosi V,Nyambuya Tawanda M,Yakobi Sinethemba H,Mxinwa Vuyolwethu,Nkambule Bongani B JRSM cardiovascular disease Background:Monocyte-mediated inflammation increases the risk of developing type 2 diabetes mellitus and cardiovascular disease. This is the first systematic review and meta-analysis of studies reporting on monocyte-mediated inflammation in type 2 diabetes mellitus. Methods:This systematic review and meta-analysis was registered in the international prospective register of a systematic review: CRD42019132902. The MEDLINE, EMBASE and Google scholar electronic databases were searched, and a random-effects model was used to generate pooled standardised mean differences between patients with type 2 diabetes mellitus and healthy controls. Results:The clinical studies (n = 20) comprised of 1065 patients with type 2 diabetes mellitus and 1103 healthy controls. Notably, the levels of monocyte activation were higher in patients with type 2 diabetes mellitus compared to healthy controls (standardised mean difference  = 0.47, 95% confidence interval (0.10, 0.84), p = 0.01) (χ = 65.72,  = 83%, p < 0.00001). Patients with type 2 diabetes mellitus had an increased risk of cardiovascular disease compared to healthy controls (standardised mean difference  = 0.37, 95% confidence interval (0.13, 0.61), p = 0.003) (χ = 958.77,  = 95%, p < 0.00001). All included pre-clinical studies reported on the C57BL/6 mice strain, with a majority of the studies 57% of reporting on high fat diet-induced C57BL/6 mice model. The overall quality of the studies was good with a median score and range of 16 (13-19). Conclusion:Our meta-analysis suggests that there is increased monocyte activation in patients with type 2 diabetes mellitus. 10.1177/2048004019900748
    Type 2 diabetes mellitus metabolic control correlates with the phenotype of human monocytes and monocyte-derived macrophages. Valtierra-Alvarado M A,Castañeda Delgado J E,Ramírez-Talavera S I,Lugo-Villarino G,Dueñas-Arteaga F,Lugo-Sánchez A,Adame-Villalpando M S,Rivas-Santiago B,Enciso-Moreno J,Serrano C J Journal of diabetes and its complications AIMS:Monocytes and macrophages express cell-surface markers indicative of their inflammatory and activation status. In this study, we investigated whether these markers are affected or correlated in non-obese T2D subjects, or glycemic/metabolic control variables. METHODS:Clinical data was recorded, and peripheral blood drawn from T2D patients (n = 28) and control subjects (n = 27). Isolated monocytes were evaluated by flow cytometry for the expression of CD14, CD16, and the phenotypic markers for the different states of activation spectrum, such as pro-inflammatory (M1) (HLA-DR, CD86), anti-inflammatory/pro-resolving (M2) (CD163, CD206, MERTK, PD-L1) and metabolically-activated (MMe) (CD36, ABCA-1). From a subset of individuals, monocytes-derived macrophages (MDM) were obtained and evaluated for phenotypic markers. A correlation analysis was performed between the clinical variables and the marker expression. RESULTS:The frequency of CD14CD16 monocytes was lower in T2D patients and it correlates negatively with poor control in glycemic and metabolic variables. T2D monocytes expressed lower levels of HLA-DR, CD86, PD-L1, and CD163, which correlated negatively with poor metabolic control. In MDM from T2D patients, HLA-DR, CD86 and CD163 expression was lower and it inversely correlated with deficient glycemic or metabolic control parameters. CONCLUSION:The glycemic/metabolic control associated with T2D influences monocyte and MDM phenotypes toward an immune-suppressive phenotype. 10.1016/j.jdiacomp.2020.107708