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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
    Neutrophil surface expression of CD11b and CD62L in diabetic microangiopathy. Mastej K,Adamiec R Acta diabetologica The aims of the study are (1) assessment of cell surface expression of adhesion molecules CD11b and CD62L on peripheral blood neutrophils in patients with type 2 diabetes and microangiopathy; (2) analysis of serum levels of soluble adhesion molecules: E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1) and von Willebrand factor (vWF) and; (3) evaluation of systemic inflammatory markers like interleukin-6 (IL-6), soluble interleukin-6 receptor (IL-6Rs), high sensitivity C-reactive protein (hsCRP) and fibrinogen. Thirty patients with type 2 diabetes and microangiopathy were enrolled in the study. The study group was compared to 22 patients with type 2 diabetes without microangiopathic compliations. The control group included 20 healthy volunteers. Flow cytometry was used to analyse surface expression of adhesion molecules. Both inflammatory markers and soluble adhesion molecules were determined by immunoenzymatic assay. A significant increase in neutrophil surface CD11b expression (P < 0.01) as well as decrease in surface CD62L expression (P < 0.01) were observed in the group with diabetic microangiopathy in comparison with diabetic group without microangiopathic complications and healthy controls. Moreover, significantly higher concentrations of sICAM-1 (P < 0.05), sVCAM-1 (P < 0.05), sE-selectin (P < 0.05), vWF (P < 0.01), hsCRP (P < 0.01), IL-6 (P < 0.01) and fibrinogen (P < 0.001) were also found in patients with microangiopathy in comparison with the control group. IL-6Rs concentrations did not significantly vary between groups. We concluded (1) diabetic microangiopathy is accompanied by increase in CD11b expression and decrease in CD62L expression on peripheral blood neutrophils; (2) in diabetic microangiopathy rise in CD11b expression indicates neutrophil activation and intensified adhesion; (3) the development of diabetic microangiopathy is accompanied by an increase in soluble adhesion molecules and inflammatory markers concentrations in the blood. 10.1007/s00592-008-0040-0
    Inflammasomes, neutrophil extracellular traps, and cholesterol. Tall Alan R,Westerterp Marit Journal of lipid research Activation of macrophage inflammasomes leads to interleukin (IL)-1β and IL-18 secretion and promotes atherosclerosis and its complications in mice and humans. However, the specific role and underlying mechanisms of the inflammasome in atherogenesis are topics of active research. Several studies in hyperlipidemic mouse models found that the NOD-like receptor protein 3 (NLRP3) inflammasome contributes to atherosclerosis, but recent work suggests that a second hit, such as defective cholesterol efflux or accumulation of oxidized mitochondrial DNA, may be required for significant inflammasome activation. Cholesterol crystal uptake or formation in lysosomes may damage membranes and activate NLRP3 inflammasomes. Alternatively, plasma or ER membrane cholesterol accumulation may condition macrophages for inflammasome activation in the presence of danger-associated molecular patterns, such as oxidized LDL. Inflammasome activation in macrophages or neutrophils leads to gasdermin-D cleavage that induces membrane pore formation, releasing IL-1β and IL-18, and eventuating in pyroptosis or neutrophil extracellular trap formation (NETosis). In humans, inflammasome activation and NETosis may contribute to atherosclerotic plaque erosion and thrombosis, especially in patients with type 2 diabetes, chronic kidney disease, or clonal hematopoiesis. Suppression of the inflammasome by activation of cholesterol efflux or by direct inhibition of inflammasome components may benefit patients with CVD and underlying susceptibility to inflammasome activation. 10.1194/jlr.S091280
    Safety and tolerability of canakinumab, an IL-1β inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies. Howard Campbell,Noe Adele,Skerjanec Andrej,Holzhauer Björn,Wernsing Margaret,Ligueros-Saylan Monica,Thuren Tom Cardiovascular diabetology BACKGROUND:We aimed to assess the safety and tolerability of different doses of canakinumab versus placebo in patients with type 2 diabetes mellitus (T2DM). METHODS:Data were pooled from three studies in 1026 T2DM patients with different routes of administration, treatment regimens and follow-up duration. Canakinumab groups were categorised as low (0.03 mg/kg i.v. once; N = 20), intermediate (0.1 and 0.3 mg/kg i.v. once, 5 and 15 mg s.c. monthly; N = 247), medium (1.5 mg/kg i.v. once, 50 mg s.c. monthly and 150 mg s.c. once; N = 268), and high doses (10 mg/kg i.v. once and 150 mg s.c. monthly; N = 137) and compared with placebo (N = 354). Incidences of adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs, deaths, AEs of special interest related to interleukin-1β inhibition and T2DM disease, and laboratory abnormalities related to haematology and biochemistry parameters were reported. Safety was also analysed by age (<65, ≥65) and gender. RESULTS:Average exposure across all groups was ≈ 6 months (maximum ~17 months). No dose response in AEs was observed but a trend towards more patients having at least one AE across canakinumab groups relative to placebo (P = 0.0152) was observed. SAEs were few and the incidence rate for most canakinumab groups was lower than that of placebo group except for the high-dose group (0.94% versus 0.58% per month in placebo). A total of five patients discontinued treatment due to AEs across treatment groups. No death was reported in any of the three studies. A small, non-significant increase in the incidence rate of infection AEs was observed on canakinumab groups relative to placebo. Canakinumab was associated with mostly mild decreases in WBC, neutrophils and platelet counts. Additionally, mild increases in SGPT, SGOT and bilirubin were reported. Overall, despite small differences, no clinically relevant findings were observed with respect to laboratory values and vital signs. CONCLUSIONS:This pooled analysis demonstrated that canakinumab was safe and well tolerated over a treatment period up to 1.4 years at the four pooled doses evaluated, in agreement with safety findings reported in the individual studies. 10.1186/1475-2840-13-94
    Increased expression of activation markers on monocytes and neutrophils in type 2 diabetes. van Oostrom A J,van Wijk J P,Sijmonsma T P,Rabelink T J,Castro Cabezas M The Netherlands journal of medicine BACKGROUND:Activation of leukocytes is obligatory for adherence to the endothelium and atherogenesis. Since leukocyte activation by triglycerides (TG) and glucose has been described in vitro, we hypothesised higher leukocyte activation in patients with type 2 diabetes. METHODS:Using flow cytometry, we studied the expression of the leukocyte activation markers CD11A, CD11B, CD62L and CD66B in 15 patients with type 2 diabetes without clinical evidence of atherosclerosis (55+/-7 years) and in 15 healthy controls (53+/-2 years). All patients were on oral antidiabetic treatment (glyHb 6.3+/-0.9%) and not taking statins or anti-inflammatory drugs. RESULTS:In comparison with controls, the patients had a higher waist circumference (1.08+/-0.09 vs 0.94+/-0.11 m, p<0.005) and higher fasting glucose (8.4+/-2.3 vs 5.3+/-0.7 mM, p<0.005), whereas fasting plasma lipids were not statistically different. The leukocyte count was higher in the patients (6.55+/-1.55 vs 5.07+/-1.10 x 10(9) cells/l, p<0.005) due to higher neutrophils and lymphocytes (+34% and +24%, p<0.05 for each). CD11B on monocytes and CD11B and CD66B on neutrophils were higher in the patients (+30%, +52% and +43%, P<0.05 for each). Fasting glucose, waist circumference, body mass index and systolic blood pressure were positively associated with the leukocyte and neutrophil count. The expressions of CD11B and CD66B on monocytes and neutrophils were strongly positively interrelated, but unrelated to TG and glucose. CONCLUSION:In patients with type 2 diabetes, the expression of activation markers on monocytes and neutrophils is enhanced and not correlated to fasting glucose or TG. These results suggest a proinflammatory situation in type 2 diabetes and most likely represent increased adhesive capacity of neutrophils and monocytes to the endothelium.
    Reduction of circulating neutrophils precedes and accompanies type 1 diabetes. Valle Andrea,Giamporcaro Gian Maria,Scavini Marina,Stabilini Angela,Grogan Pauline,Bianconi Eleonora,Sebastiani Guido,Masini Matilde,Maugeri Norma,Porretti Laura,Bonfanti Riccardo,Meschi Franco,De Pellegrin Maurizio,Lesma Arianna,Rossini Silvano,Piemonti Lorenzo,Marchetti Piero,Dotta Francesco,Bosi Emanuele,Battaglia Manuela Diabetes Human type 1 diabetes (T1D) is an autoimmune disease associated with major histocompatibility complex polymorphisms, β-cell autoantibodies, and autoreactive T cells. However, there is increasing evidence that innate cells may also play critical roles in T1D. We aimed to monitor peripheral immune cells in early stages of T1D (i.e., in healthy autoantibody-positive subjects) and in more advanced phases of the disease (i.e., at disease onset and years after diagnosis). We found a mild but significant and reproducible peripheral neutropenia that both precedes and accompanies the onset of T1D. This reduction was not due to peripheral neutrophil cell death, impaired differentiation, or the presence of anti-neutrophil antibodies. Neutrophils were observed by electron microscopy and immunohistochemical analysis in the exocrine pancreas of multiorgan donors with T1D (both at onset and at later stages of the disease) and not in that of multiorgan donors with type 2 diabetes or nondiabetic donors. These pancreas-infiltrating neutrophils mainly localized at the level of very small blood vessels. Our findings suggest the existence of a hitherto unrecognized clinical phenotype that might reflect unexplored pathogenic pathways underlying T1D. 10.2337/db12-1345
    Relationship between glycemic control and histochemical myeloperoxidase activity in neutrophils in patients with type 2 diabetes. Unubol Mustafa,Yavasoglu Irfan,Kacar Firuzan,Guney Engin,Omurlu Imran Kurt,Ture Mevlut,Kadikoylu Gurhan,Bolaman Zahit Diabetology & metabolic syndrome BACKGROUND:Myeloperoxidase (MPO) is a lysosomal hemoprotein found in the azurophilic granules in neutrophils. Myeloperoxidase plays an important role in oxygen-dependent killing of bacteria, fungi, virus and malignant cells. Diabetes mellitus (DM) is listed among conditions that may lead to secondary MPO deficiency in neutrophils but inconsistent results concerning MPO activity in diabetic patients have been reported in the literature. In this study, we aimed to evaluate the relationship between glycemic control in patients with type 2 DM and MPO activity in neutrophils from a histochemical perspective. METHODS:The study included 40 patients with type 2 DM with poor glycemic control, 30 patients with type 2 DM with good glycemic control and 31 healthy controls. Peripheral blood smears were analyzed for each patient included in the study. Myeloperoxidase dye was used for staining. Myeloperoxidase ratios in neutrophil were evaluated for proportions of staining with MPO in 100 neutrophils in each smear. SPSS 16.0 version was used for statistical analyses. RESULTS:Myeloperoxidase ratios in neutrophils were 70 (58.5-80) in type 2 DM patients with poor glycemic control compared to 80 (73.75-90) in those with good glycemic control and 88 (78-92) in healthy controls. The DM group with poor glycemic control was statistically significantly different from the other groups (p < 0.001). CONCLUSIONS:Poor glycemic control in diabetic patients results in decreased MPO activity in neutrophils histochemically. 10.1186/s13098-015-0115-3
    Inflammation and atherogenic markers in patients with type 2 diabetes mellitus. Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis Type two diabetes mellitus (T2DM) is characterized by a chronic inflammation status. Altered markers such as lipid concentrations are usually found in this disease. Elevated inflammation markers have been described such as cytokines (interleukin 6, tumour necrosis factor-alpha, and IL-8). However, there is a lack of information about the behaviour of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), lipid coefficients, and atherogenic index in T2DM. OBJECTIVE:To describe the atherogenic and inflammation parameters in a group of patients with T2DM. MATERIALS AND METHODS:42 patients with T2DM were included, all patients were surveyed on clinic history (disease history, comorbidity, smoking, and other relevant variables), measurements of haematological, biochemical, and anthropometric parameters were taken and atherogenic coefficients and inflammation ratios were calculated. RESULTS:Inflammation markers such as interleukin 6 and 8, necrosis tumour factor, and NLR were elevated. Of the patients, 88% were classified as high risk according to the atherogenic index. Former smokers had lower levels of IL-8 and higher NLR than non-smokers. CONCLUSION:The atherogenic and inflammation markers such as atherogenic index, IL-8, and NLR make it possible to identify a subgroup of patients that are at risk of severe complications and mortality. 10.1016/j.arteri.2021.03.006
    Transcriptomics of type 2 diabetic and healthy human neutrophils. BMC immunology OBJECTIVES:Chronic inflammatory diseases, including diabetes and cardiovascular disease, are heterogeneous and often co-morbid, with increasing global prevalence. Uncontrolled type 2 diabetes (T2D) can result in severe inflammatory complications. As neutrophils are essential to normal and aberrant inflammation, we conducted RNA-seq transcriptomic analyses to investigate the association between neutrophil gene expression and T2D phenotype. As specialized pro-resolving lipid mediators (SPM) act to resolve inflammation, we further surveyed the impact of neutrophil receptor binding SPM resolvin E1 (RvE1) on isolated diabetic and healthy neutrophils. METHODS:Cell isolation and RNA-seq analysis of neutrophils from N = 11 T2D and N = 7 healthy individuals with available clinical data was conducted. Additionally, cultured neutrophils (N = 3 T2D, N = 3 healthy) were perturbed with increasing RvE1 doses (0 nM, 1 nM, 10 nM, or 100 nM) prior to RNA-seq. Data was evaluated through a bioinformatics pipeline including pathway analysis and post hoc false discovery rate (FDR)-correction. RESULTS:We observed significant differential expression of 50 genes between T2D and healthy neutrophils (p < 0.05), including decreased T2D gene expression in inflammatory- and lipid-related genes SLC9A4, NECTIN2, and PLPP3 (p < 0.003). RvE1 treatment induced dose-dependent differential gene expression (uncorrected p < 0.05) across groups, including 59 healthy and 216 T2D neutrophil genes. Comparing T2D to healthy neutrophils, 1097 genes were differentially expressed across RvE1 doses, including two significant genes, LILRB5 and AKR1C1, involved in inflammation (p < 0.05). CONCLUSIONS:The neutrophil transcriptomic database revealed novel chronic inflammatory- and lipid-related genes that were differentially expressed between T2D cells when compared to controls, and cells responded to RvE1 dose-dependently by gene expression changes. Unraveling the mechanisms regulating abnormalities in diabetic neutrophil responses could lead to better diagnostics and therapeutics targeting inflammation and inflammation resolution. 10.1186/s12865-021-00428-6
    Increased neutrophil elastase and proteinase 3 and augmented NETosis are closely associated with β-cell autoimmunity in patients with type 1 diabetes. Wang Yudong,Xiao Yang,Zhong Ling,Ye Dewei,Zhang Jialiang,Tu Yiting,Bornstein Stefan R,Zhou Zhiguang,Lam Karen S L,Xu Aimin Diabetes Type 1 diabetes (T1D) is an autoimmune disease resulting from the self-destruction of insulin-producing β-cells. Reduced neutrophil counts have been observed in patients with T1D. However, the pathological roles of neutrophils in the development of T1D remain unknown. Here we show that circulating protein levels and enzymatic activities of neutrophil elastase (NE) and proteinase 3 (PR3), both of which are neutrophil serine proteases stored in neutrophil primary granules, were markedly elevated in patients with T1D, especially those with disease duration of less than 1 year. Furthermore, circulating NE and PR3 levels increased progressively with the increase of the positive numbers and titers of the autoantibodies against β-cell antigens. An obvious elevation of NE and PR3 was detected even in those autoantibody-negative patients. Increased NE and PR3 in T1D patients are closely associated with elevated formation of neutrophil extracellular traps. By contrast, the circulating levels of α1-antitrypsin, an endogenous inhibitor of neutrophil serine proteases, are decreased in T1D patients. These findings support an early role of neutrophil activation and augmented neutrophil serine proteases activities in the pathogenesis of β-cell autoimmunity and also suggest that circulating NE and PR3 may serve as sensitive biomarkers for the diagnosis of T1D. 10.2337/db14-0480
    The role of systemic inflammation in the association between serum 25-hydroxyvitamin D and type 2 diabetes mellitus. Wan Zhengce,Song Lulu,Hu Liu,Lei Xiaomei,Huang Yuancheng,Lv Yongman,Yu Shaojing Clinical nutrition (Edinburgh, Scotland) BACKGROUND & AIMS:The association between serum 25-hydroxyvitamin D [25(OH)D] and type 2 diabetes mellitus (T2DM) remains inconclusive. Moreover, whether inflammatory biomarkers are involved in this association has not been explored. This study aims to investigate serum 25(OH)D in relation to T2DM in a Chinese population and provide clues for the inflammatory mechanism whereby serum 25(OH)D deficiency increases T2DM risk. METHODS:A cross-sectional study of 47,803 participants aged 18-96 years was performed in a health management center in 2017. Multivariate linear or logistic regression models and mediation analysis were used to examine the relationships between serum 25(OH)D, inflammatory biomarkers (white blood cell counts and mean platelet volume), and T2DM. RESULTS:Of the 47,803 participants included, 5.2% were diabetic and 51.4% were serum 25(OH)D deficient. The study revealed a significant inverse association between serum 25(OH)D and T2DM risk after adjustment for potential confounders (P for trend = 0.002); the multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) across serum 25(OH)D levels (sufficiency, insufficiency, and deficiency) were 1.00 (reference), 1.17 (1.03-1.33), and 1.25 (1.09-1.43), respectively. This study also showed a significant indirect effect of serum 25(OH)D on T2DM risk through total white blood cell count, neutrophil count, lymphocyte count, and monocyte count (P values < 0.05); the proportions mediated were 9.89%, 7.51%, 2.94%, and 2.82%, respectively. CONCLUSIONS:Serum 25(OH)D deficiency was independently associated with an elevated risk of T2DM in a Chinese adult population and low-grade systemic inflammation might be one of its biological mechanisms. 10.1016/j.clnu.2021.04.029
    [Neutrophil surface expression of adhesion molecule CD11b in patients with type 2 diabetes]. Mastej Krzysztof,Adamiec Rajmund Przeglad lekarski AIMS:1. Assessment of cell surface expression of adhesion molecule CD11b on peripheral blood neutrophils in patients with type 2 diabetes without vascular complications. 2. Analysis of serum levels of soluble adhesion molecules: E-selectin (sE-selectin), soluble Intercellular Adhesion Molecule-1 (sICAM-1), soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) and von Willebrand Factor (vWF). 3. Evaluation of systemic inflammatory markers: Interleukin-6 (IL-6), soluble Interleukin-6 Receptor (IL-6Rs), high sensitivity C-Reactive Protein (hsCRP), fibrinogen and leptin. METHODS:22 patients with type 2 diabetes were enrolled in the study (10-female, 12-male), aged from 40 to 65 yrs, diabetes duration mean 5.32 +/- 1.70 yrs. The control group included 20 healthy volunteers. Flow cytometry was used to analyse neutrophil expression of CD11b. Both inflammatory markers and soluble adhesion molecules were determined by immunoenzymatic assay. RESULTS:Neutrophil surface CD11b expression did not vary between groups. Significantly higher concentrations of sE-selectin, hsCRP, leptin and IL-6 were found in diabetic patients in comparison with the control group, sICAM-1, sVCAM-1, fibrinogen, vWF and IL-6Rs concentrations did not significantly vary between groups. In the diabetic group--a positive correlation was established between neutrophil CD11b expression and hsCRP, HOMA IR, BMI, leptin and fibrinogen. CONCLUSIONS:Type 2 diabetes without vascular complications is not accompanied by increase in CD11b expression on peripheral blood neutrophils. The degree of neutrophil activation is correlated with an increase in leptin serum levels. Obtained results confirm mutual connections between obesity, type 2 diabetes and chronic inflammatory process.
    Neutrophils and their role in the aetiopathogenesis of type 1 and type 2 diabetes. Giovenzana Anna,Carnovale Debora,Phillips Brett,Petrelli Alessandra,Giannoukakis Nick Diabetes/metabolism research and reviews Multiple and complex aetiological processes underlie diabetes mellitus, which invariably result in the development of hyperglycaemia. Although there are two prevalent distinct forms of the disease, that is, type 1 and type 2 diabetes, accumulating evidence indicates that these syndromes share more aetiopathological mechanisms than originally thought. This compels a rethinking of the approaches to prevent and treat the different manifestations of what eventually becomes a hyperglycaemic state. This review aims to address the involvement of neutrophils, the most abundant type of granulocytes involved in the initiation of the acute phase of inflammation, in the aetiopathogenesis of diabetes mellitus, with a focus on type 1 and type 2 diabetes. We review the evidence that neutrophils are the first leucocytes to react to and accumulate inside target tissues of diabetes, such as the pancreas and insulin-sensitive tissues. We then review available data on the role of neutrophils and their functional alteration, with a focus on NETosis, in the progression towards clinical disease. Finally, we review potential approaches as secondary and adjunctive treatments to limit neutrophil-mediated damage in the prevention of the progression of subclinical disease to clinical hyperglycaemia. 10.1002/dmrr.3483
    Abnormal Neutrophil Transcriptional Signature May Predict Newly Diagnosed Latent Autoimmune Diabetes in Adults of South China. Xing Yixuan,Lin Qiuqiu,Tong Yue,Zhou Wenzhi,Huang Juan,Wang Yanfei,Huang Gan,Li Yanhua,Xiang Zhongyuan,Zhou Zhiguang,Li Tian,Xiao Yang Frontiers in endocrinology Objective:Latent autoimmune diabetes in adults (LADA) is an autoimmune diabetes characterized by slowly progressive of β-cell function deterioration. Our previous finding demonstrated that neutrophil numbers and migration abilities display distinct levels in different types of diabetes, including LADA, whereas its pathological alterations in the development of LADA remain unknown. We aimed to investigate the changes in transcriptional levels of peripheral neutrophils in newly diagnosed LADA. Methods:Peripheral blood neutrophils were isolated from newly diagnosed LADA patients (n = 5) and age-and sex-matched healthy controls (n = 5). The Transcriptomic signature was determined by RNA sequencing (RNA-seq). Differentially expressed genes (DEG) were screened, followed by analyzing downstream Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Real-time polymerase chain reaction (qPCR) was applied for validation in LADA patients (n = 9) and age-and sex-matched healthy controls (n = 18), including sequencing samples. Results:Compared with controls, 4105 DEG were screened in LADA patients, including 2661 upregulated and 1444 downregulated DEG. In GO analysis, DEG are mainly involved in leukocyte degranulation, myeloid cell differentiation, and immune response-regulating signaling. The top enriched KEGG pathways included cytokine-cytokine receptor interaction, adhesion molecule signaling, nuclear factor-κB (NF-κB) signaling and Th17 cell differentiation. Consistent with RNA-seq results, , , , , , and are upregulated in neutrophils by qPCR. Conclusion:The present study results provided a profile of DEG in the newly diagnosed LADA of south China. Our study reveals an abnormality in neutrophil disposition at the transcriptional level in LADA. Several essential genes may be involved in of LADA's pathological process, which may be useful to guide prediction for LADA and further investigation into the pathogenesis for this disease. 10.3389/fendo.2020.581902
    Neutrophil:lymphocyte ratio is positively related to type 2 diabetes in a large-scale adult population: a Tianjin Chronic Low-Grade Systemic Inflammation and Health cohort study. Guo Xiaoyan,Zhang Shu,Zhang Qing,Liu Li,Wu Hongmei,Du Huanmin,Shi Hongbin,Wang Chongjin,Xia Yang,Liu Xing,Li Chunlei,Sun Shaomei,Wang Xing,Zhou Ming,Huang Guowei,Jia Qiyu,Zhao Honglin,Song Kun,Niu Kaijun European journal of endocrinology AIM:It is widely known that inflammation is related to type 2 diabetes (T2D), but few studies have shown a direct relationship between the immune system and T2D using a reliable biomarker. Neutrophil:lymphocyte ratio (NLR) is an easy-to-analyze inflammation biomarker, but few studies have assessed the relationship between NLR and T2D. In order to evaluate how NLR is related to T2D, we designed a large-scale cross-sectional and prospective cohort study in an adult population. SUBJECTS AND METHODS:Participants were recruited from the Tianjin Medical University General Hospital-Health Management Centre. Both a baseline cross-sectional (n=87,686) and a prospective (n=38,074) assessment were performed. Participants without a history of T2D were followed up for ∼ 6 years (with a median follow-up of 2.7 years). Adjusted logistic and Cox proportional hazards regression models were used to assess relationships between the quintiles of NLR and T2D (covariates: age, sex, BMI, smoking status, drinking status, hypertension, hyperlipidemia, and family history of cardiovascular disease, hypertension, hyperlipidemia, or diabetes). RESULTS:The prevalence and incidence of T2D were 4.9% and 6.8/1000 person-years respectively. The adjusted odds ratio and hazard ratio (95% CI) of the highest NLR quintile were 1.34 (1.21, 1.49) and 1.39 (1.09, 1.78) (both P for trend <0.01) respectively as compared to the lowest quintile of NLR. Leukocyte, neutrophil, and lymphocyte counts do not significantly predict the eventual development of T2D. CONCLUSION:The present study demonstrates that NLR is related to the prevalence and incidence of T2D, and it suggests that NLR may be an efficient and accurate prognostic biomarker for T2D. 10.1530/EJE-15-0176
    Association of neutrophil-lymphocyte ratio with glucose intolerance: an indicator of systemic inflammation in patients with type 2 diabetes. Shiny Abhijit,Bibin Yesodha S,Shanthirani Coimbatore Subramanian,Regin Bhaskaran S,Anjana Ranjit Mohan,Balasubramanyam Muthuswamy,Jebarani Saravanan,Mohan Viswanathan Diabetes technology & therapeutics BACKGROUND:The neutrophil-lymphocyte ratio (NLR) has been demonstrated to be a better risk factor than total white blood cell count in the prediction of adverse outcomes in various medical conditions. This study analyzed the association of NLR with different grades of glucose tolerance and insulin resistance in Asian Indians. SUBJECTS AND METHODS:Study subjects were recruited from Phase 3 of the Chennai Urban Rural Epidemiology Study (CURES). For this cross-sectional analysis, subjects with normal glucose tolerance (NGT) (n=237), impaired glucose tolerance (IGT) (n=63), and type 2 diabetes mellitus (DM) (n=286) were selected. The hemogram was done in all subjects using a five-part hematology analyzer (model SF-3000; Sysmex, Kobe, Japan). The NLR was calculated as the ratio between counts for neutrophils and total lymphocytes. Fasting insulin was measured by enzyme-linked immunosorbent assay, and insulin resistance was calculated using the homeostasis model assessment (HOMA-IR). RESULTS:Subjects with DM showed a significantly higher NLR (2.2 ± 1.12) compared with IGT subjects (1.82 ± 0.63), who in turn had a higher ratio than NGT subjects (1.5 ± 0.41) (P<0.01). Pearson correlation analysis showed a significant positive correlation of NLR with glycated hemoglobin (r=0.411), fasting plasma glucose (r=0.378), and HOMA-IR (r=0.233) (P<0.001). Regression analysis showed a linear increase in NLR with increasing severity of glucose intolerance even after adjusting for age, waist circumference, blood pressure, triglycerides, and smoking. CONCLUSIONS:This is the first report on the correlation of NLR with different grades of glucose intolerance and insulin resistance. NLR can be used as an adjuvant prognostic marker for macro- and microvascular complications in patients with glucose intolerance. 10.1089/dia.2013.0264
    Baseline neutrophil-to-lymphocyte ratio is associated with long-term T2D remission after metabolic surgery. Bonaventura Aldo,Liberale Luca,Carbone Federico,Vecchié Alessandra,Bonomi Alice,Scopinaro Nicola,Camerini Giovanni Bruno,Papadia Francesco Saverio,Maggi Davide,Cordera Renzo,Dallegri Franco,Adami Giovanni,Montecucco Fabrizio Acta diabetologica AIMS:Metabolic surgery is considered as a therapeutic option for obese patients with type 2 diabetes (T2D). In order to identify novel laboratory variables that could improve the selection of patients who might greatly benefit from a surgical approach, we focused on the neutrophil-to-lymphocyte ratio (NLR) as a predictor of long-term T2D remission following metabolic surgery. METHODS:Thirty-one obese patients with T2D included in this pilot study underwent Roux-en-Y gastric bypass or biliopancreatic diversion (BPD) at the Surgical Department of Genoa University, IRCCS Ospedale Policlinico San Martino in Genoa (Italy). Before surgery, serum samples were collected to evaluate blood count, glycemic profile, and circulating neutrophil degranulation products. RESULTS:The median age was 56 years, median body mass index (BMI) was 32.37 kg/m, and median glycated hemoglobin was 8.4%. White blood cell count was in a range of normality, with a median NLR of 1.97. By a receiver operating characteristic curve analysis, NLR has been found to be significantly associated with T2D remission at 1, 3, and 5 years and the best cutoff of ≤ 1.97 has been identified by Youden index. When comparing study groups according to NLR cutoff, those with NLR ≤ 1.97 were older and underwent more often BPD. By a logistic regression analysis, NLR ≤ 1.97 has been found to predict T2D remission across 5 years, irrespective of baseline BMI. CONCLUSIONS:A baseline low NLR is associated with long-term T2D remission in obese patients undergoing metabolic surgery, suggesting that circulating inflammatory cells (i.e., neutrophils) might negatively impact on T2D remission. 10.1007/s00592-019-01345-2
    Blood Neutrophil-to-Lymphocyte Ratio and Urine IL-8 Levels Predict the Type of Bacterial Urinary Tract Infection in Type 2 Diabetes Mellitus Patients. Infection and drug resistance BACKGROUND:Extended-spectrum ß-lactamase (ESBL)-producing and are the most common uropathogens causing UTI (urinary tract infection) in type 2 diabetes mellitus (T2DM). Circulatory inflammatory markers such as C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) are usually dysregulated during UTI. However, the differential regulation of these inflammatory signatures during and UTI in T2DM has not been determined. METHODS:A case-control study on 466 patients was performed to investigate the inflammatory signatures indicative of ESBL- and UTIs in T2DM. Serum CRP levels and blood NLR for these patients were determined and associated with and ESBL uropathogen using multivariate logistic regression analysis. Urinary interleukin 8 (IL-8) levels were also assessed and associated with these two UTI uropathogens in T2DM. The association of the two ESBL-uropathogens with the survival outcomes of T2DM patients was also analyzed using Cox-proportional hazard model. RESULTS:T2DM patients with ESBL- UTI had lower serum CRP levels (median, CRP mg/dL 33.7 vs 39.8, respectively; P=0.023) and higher blood NLR (median, NLR 3.2 vs 2.6, respectively; P=0.010) compared to those with UTIs (<0.001). Moreover, in T2DM, the urinary IL-8 levels was higher in ESBL- compared to those with UTIs (<0.0001). After adjusting for confounders, including age, gender, serum albumin, hemoglobulin, leukocytes, and platelet counts, T2DM patients with blood NLR ≥ 3.5 were at higher risk for ESBL- UTIs than ESBL- UTIs (odds ratio [OR], 3.61, 95% confidence interval, Cl, 1.49-8.73; P=0.004). Moreover, T2DM patients with ESBL- UTIs had higher all-cause mortality (hazard ratio [HR], 4.09; 95%, 1.14-14.59) than those with UTIs. CONCLUSION:Serum CRP levels, blood NLR, and IL-8 urinary levels differentiate ESBL- from UTIs in T2DM. 10.2147/IDR.S251966
    Investigation of the correlation between some immune system and biochemical indicators in patients with type 2 diabetes. Eftekharian Mohammad Mahdi,Karimi Jamshid,Safe Mojgansadat,Sadeghian Ahmad,Borzooei Shiva,Siahpoushi Ehsan Human antibodies AIMS/INTRODUCTION:Since changes in some immune system indicators such as leukocyte count and neutrophil to lymphocyte ratio in the blood and Inflammation is directly in relation with the pathogenesis of type 2 diabetes, metabolic syndrome and atherosclerosis, measuring these indicators in patients with type 2 diabetes and comparing them with control group can be a suitable indicator of Inflammation and prognosis of the disease. MATERIALS AND METHODS:The current study was done on 75 patients with type 2 diabetes and 72 healthy individuals as patient and healthy group respectively. The selected groups have been matched for age and sex. Fasting blood sugar, lipid profile including triglycerides, total cholesterol, HDL, LDL, as well as the number of white blood cells, neutrophils, lymphocytes, neutrophils to lymphocytes ratio were measured and analyzed in both groups. RESULTS:The results demonstrated that there is a significant relationship between the number of white blood cells and increase in blood sugar and also between the neutrophil to lymphocyte ratio and increase in Fasting blood sugar and triglycerides parameters. Furthermore, the average of fasting blood sugar, triglycerides, total cholesterol, LDL and neutrophil to lymphocyte ratio in patient with type 2 diabetes is significantly higher than control group. CONCLUSION:Considering the findings of current study, we showed the inflammation and the pathogenesis caused by type 2 diabetes can be attributed to neutrophil to lymphocyte ratio. 10.3233/HAB-150290
    A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity. Dowey Rebecca,Iqbal Ahmed,Heller Simon R,Sabroe Ian,Prince Lynne R Frontiers in immunology Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality. 10.3389/fimmu.2021.678771
    Neutrophil-to-lymphocyte ratio is associated with diabetic peripheral neuropathy in type 2 diabetes patients. Liu Siying,Zheng Hangping,Zhu Xiaoming,Mao Fei,Zhang Shuo,Shi Hongli,Li Yiming,Lu Bin Diabetes research and clinical practice OBJECTIVE:Diabetic peripheral neuropathy (DPN) had been demonstrated as a chronic inflammation state and one of the most common complications of type 2 diabetes mellitus (T2DM). Neutrophil-to-lymphocyte ratio (NLR) is a novel marker to reflect many kinds of chronic inflammation disease including diabetes. We aim to evaluate the association between NLR and DPN and to determine whether NLR could be a new indicator of DPN in type 2 diabetes patients. METHODS:We retrospect the consecutive medical files of T2DM patients. Nerve conduction velocity (NCV), vibration perception threshold (VPT) and the data for complete blood count were recorded. Patients were divided into tertiles based on admission NLR values. Clinical parameters were firstly compared among groups. Then, logistic regression and ROC analysis were performed. RESULTS:Percentages of DPN were 42.60%, 54.97% and 65.50%, in the low, middle and high tertile, respectively (n=72, 94 and 112, p<0.05). VPT values were 13.75±7.97, 15.01±9.60 and 16.78±10.92, respectively, (p<0.05). NCV in different nerves decreased with the increase of NLR (p<0.05). After adjusting potential related factors, NLR was still related to status of DPN in the logistic regression (r=1.743, p=0.001). Area under ROC was 0.619 (p<0.001). CONCLUSION:The present study showed that T2DM patients with higher NLR levels might be more likely to develop peripheral neuropathy complication. NLR levels grow with the increase of NCV and VPT results. As a predictor of DPN, NLR could be used in clinical practice to help doctors understand the level of DPN progression. 10.1016/j.diabres.2017.05.008
    High neutrophil-to-lymphocyte ratio is associated with increased carotid artery intima-media thickness in type 2 diabetes. Li Xueqin,Shen Jun,Lu Zhenghong,Chen Min,Fang Xiaozheng,Wang Gongcheng Journal of diabetes investigation AIMS/INTRODUCTION:Emerging evidence suggests that the neutrophil-to-lymphocyte ratio (NLR) is a novel potential marker of inflammatory responses. The objective was to evaluate the association between NLR and carotid artery intima-media thickness (cIMT) in type 2 diabetes. MATERIALS AND METHODS:We carried out a case-control study involving 320 patients with type 2 diabetes, and 250 age-, sex- and body mass index-matched healthy controls who all underwent carotid ultrasonography and took a blood examination. We divided the diabetes patients into two groups according to cIMT: 188 diabetes patients with high cIMT and 132 diabetes patients with low cIMT, and compared baseline characteristics and NLR between the two groups and healthy controls. RESULTS:The mean NLR was significantly higher in the group of diabetes patients with high cIMT than the group of diabetes patients with low cIMT, who in turn showed a significantly higher NLR compared with control participants. Logistic regression analysis showed that the NLR was an independent risk factor for diabetes patients with high cIMT (odds ratio 140.89, 95% CI 1.71-11615.30, P = 0.028). Based on the receiver operating characteristic curve, use of the NLR as an indicator for diabetes patients with high cIMT diagnosis was projected to be 3.16, and yielded a sensitivity and specificity of 36.2% and 93.2%, respectively, with an area under the curve of 0.606 (95% CI 0.544-0.667). CONCLUSIONS:High NLR might be a potential biomarker for the increased cIMT in type 2 diabetes patients. Future studies are required to validate our findings. 10.1111/jdi.12541
    Neutrophil-to-lymphocyte ratio is associated with coronary microvascular dysfunction in type 2 diabetes mellitus patients. Chen Yangwen,Chai Qian,Wang Qian,Zhang Ziying,Shan Yongyan,Lu Dexue,Liu Meili,Wu Weihua Diabetes research and clinical practice AIMS:Our study is aimed to investigate the relationship between neutrophil-to-lymphocyte ratio (NLR) and coronary microvascular dysfunction (CMD) in type 2 diabetes mellitus (T2DM) patients. METHODS:We retrospect the consecutive medical files of 160 T2DM patients and recorded their clinical information and laboratory findings. Patients were divided into CMD group (n = 87) and non-CMD group (n = 73). We compared the NLR values of the two groups. Meanwhile we also observed the prevalence of CMD at different NLR levels. Then, logistic regression and ROC analysis were performed. RESULTS:NLR value of CMD group was significantly lower than non-CMD group (2.01 ± 0.74 vs 2.53 ± 0.69, P<0.001). Prevalence of CMD in low (NLR ≤ 1.53, n = 30), medium (1.53 < NLR ≤ 2.20, n = 53) and high (NLR > 2.20, n = 77) group were 90%, 61.1%, and 39.2% respectively. The prevalence of CMD significantly increased as NLR level decreased. After adjusting potential related factors, NLR was still significantly correlated with CMD (OR = 0.295, 95 %CI:0.162-0.539, P < 0.001). The area under ROC curve (AUC) was 0.707 (95 %CI:0.627-0.786, P < 0.001). CONCLUSIONS:Our results showed that NLR is associated with CMD in T2DM patients, and the prevalence of CMD may increase as NLR level decrease. 10.1016/j.diabres.2021.108983
    Relationship between neutrophil-lymphocyte ratio and insulin resistance in newly diagnosed type 2 diabetes mellitus patients. Lou Meiqin,Luo Peng,Tang Ru,Peng Yixian,Yu Siyuan,Huang Wanjing,He Lei BMC endocrine disorders BACKGROUND:Insulin resistance (IR) plays a vital role in the pathogenesis of Type 2 Diabetes Mellitus (T2DM). The mechanism of IR may be associated with inflammation, whereas the neutrophil-lymphocyte ratio (NLR) is a new indicator of subclinical inflammation. Scholars have rarely investigated the relationship between IR and NLR. This study aims to evaluate the relationship between IR and NLR, and determine whether or not NLR is a reliable marker for IR. METHODS:The sample consists of a total of 413 patients with T2DM, 310 of whom have a HOMA-IR value of > 2.0. The control group consists of 130 age and BMI matched healthy subjects. RESULTS:The NLR values of the diabetic patients were significantly higher than those of the healthy control (P < 0.001), and the NLR values of the patients with a HOMA-IR value of > 2.0 are notably greater than those of the patients with a HOMA-IR value of ≤ 2.0 (P < 0.001). Pearson correlation analysis showed a significant positive correlation of NLR with HOMA-IR (r = 0.285) (P < 0.001). Logistic regression analysis showed that the risk predictors of IR include NLR, TG and HbA1c. NLR (P < 0.001, EXP(B) = 7.231, 95% CI = 4.277-12.223) levels correlated positively with IR. The IR odds ratio increased by a factor of 7.231 (95% CI, 4.277-12.223) for every one unit increase in NLR. CONCLUSIONS:Increased NLR was significantly associated with IR, and high NLR values may be a reliable predictive marker of IR. 10.1186/s12902-015-0002-9
    Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target. Hughes Michael J,McGettrick Helen M,Sapey Elizabeth European respiratory review : an official journal of the European Respiratory Society Multimorbidity is increasingly common and current healthcare strategies are not always aligned to treat this complex burden of disease. COPD, type-2 diabetes mellitus (T2D) and cardiovascular disease, especially atherosclerosis, occur more frequently together than expected, even when risk factors such as smoking, obesity, inactivity and poverty are considered. This supports the possibility of unifying mechanisms that contribute to the pathogenesis or progression of each condition.Neutrophilic inflammation is causally associated with COPD, and increasingly recognised in the pathogenesis of atherosclerosis and T2D, potentially forming an aetiological link between conditions. This link might reflect an overspill of inflammation from one affected organ into the systemic circulation, exposing all organs to an increased milieu of proinflammatory cytokines. Additionally, increasing evidence supports the involvement of other processes in chronic disease pathogenesis, such as cellular senescence or changes in cellular phenotypes.This review explores the current scientific evidence for inflammation, cellular ageing and cellular processes, such as reactive oxygen species production and phenotypic changes in the pathogenesis of COPD, T2D and atherosclerosis; highlighting common mechanisms shared across these diseases. We identify emerging therapeutic approaches that target these areas, but also where more work is still required to improve our understanding of the underlying cellular biology in a multimorbid disease setting. 10.1183/16000617.0102-2019
    Neutrophil-to-lymphocyte ratio and red blood cell distribution width as predictors of microalbuminuria in type 2 diabetes. Assulyn Tikva,Khamisy-Farah Rola,Nseir William,Bashkin Amir,Farah Raymond Journal of clinical laboratory analysis BACKGROUND AND AIM:Chronic inflammation has an important role in the development and progression of type 2 diabetes through immunologic inflammatory mechanisms. Simple new inexpensive inflammatory markers may contribute to the detection of microalbuminuria. Aim of our study is to evaluate the predictive value of neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), and red blood cell distribution width (RDW) for microalbuminuria in type 2 diabetic patients for possible application as prognostic factors for the prediction of microalbuminuria and the progression of disease in patients with diabetes. METHODS:A total of 168 patients with type 2 diabetes mellitus were classified into gender- and BMI-matched three groups according to hemoglobin A1c and microalbuminuria: Group A: 53 patients with controlled diabetes, Group B: 57 patients with uncontrolled diabetes, both without microalbuminuria, and Group C: 58 patients with uncontrolled diabetes with microalbuminuria. Levels of NLR, MPV, and RDW between the study groups were examined and compared. RESULTS:A significant difference in NLR was found between Group C and groups A and B (P < .001, P = .005, respectively). A statistically significant difference in RDW was found between groups B and C (P = .014). Receiver operating characteristic curve analysis of inflammatory markers and microalbuminuria prediction showed an area under curve (AUC) of 0.675 for NLR (CI 0.58-0.76, P < .001) and 0.614 for RDW (CI 0.52-0.70, P = .013). NLR value of 2.54 has 39.7% sensitivity, 78.8% specificity, and 45% positive predictive value (PPV). RDW value of 14.44 has 37.9% sensitivity, 76% specificity, and 41.5% PPV. CONCLUSIONS:Neutrophil-to-lymphocyte ratio and RDW have PPV for microalbuminuria in diabetic patients. 10.1002/jcla.23259
    Predictors of neutrophil extracellular traps markers in type 2 diabetes mellitus: associations with a prothrombotic state and hypofibrinolysis. Bryk Agata H,Prior Shannon M,Plens Krzysztof,Konieczynska Malgorzata,Hohendorff Jerzy,Malecki Maciej T,Butenas Saulius,Undas Anetta Cardiovascular diabetology BACKGROUND:Type 2 diabetes mellitus (T2DM) is associated with a hypercoagulable state and increased neutrophil extracellular traps formation (NETosis). We investigated predictors of NETosis and cell death markers in circulating blood and their association with a prothrombotic state in T2DM. METHODS:In a cross-sectional study involving 113 T2DM patients aged 63.7 ± 8.2 years, we investigated citrullinated histone H3 (H3Cit), cell-free deoxyribonucleic acid (cfDNA), myeloperoxidase, neutrophil elastase, and inflammation markers, along with thrombin generation (TG), plasma clot lysis time (CLT), clot permeability (K) and fibrinolysis inhibitors. RESULTS:On multivariate logistic regression analysis adjusted for age and gender, predictors of high H3Cit (≥ 7.36 ng/mL, upper quartile) were: glycated hemoglobin (HbA1c) ≥ 7.0% and interleukin-6. Interleukin-6 was also found to be a predictor of high cfDNA (≥ 2.84 µg/mL, upper quartile) along with glucose. Citrullinated histone H3 and cfDNA correlated positively with CLT and inversely with K, while TG associated solely with cfDNA. These associations were not seen with myeloperoxidase and neutrophil elastase. Patients with previous myocardial infarction (n = 21, 18.6%) had higher H3Cit (+108%, p < 0.001) and cfDNA (+45%, p = 0.022). On multivariable analysis adjusted for potential confounders, H3Cit and cfDNA, along with plasminogen activator inhibitor-1 and concomitant cardiovascular disease, were predictors of CLT. Citrullinated histone H3 alone was a predictor of K and only cfDNA was a predictor of peak thrombin generated. CONCLUSIONS:In T2DM, NETosis detectable in circulating blood is associated with inflammatory state and a prothrombotic state, especially hypofibrinolysis. 10.1186/s12933-019-0850-0
    Enhanced syndecan-1 expression on neutrophils in patients with type 2 diabetes mellitus. Wang Jing-Bo,Zhang Yan-Jun,Guan Juan,Zhou Li,Sheng Yu,Zhang Yan,Si Yan-Fang Acta diabetologica The peripheral neutrophils are one of the main inflammatory cells and significantly influence the damage of endothelium. Type 2 diabetes is a manifestation of an ongoing low-grade inflammation. In diabetes, impairment of neutrophil adhesion to the endothelium and migration to the site of inflammation were detected, which associated closely with adhesion molecules expressed on neutrophils and endothelial cells. To detect the expression of syndecan-1 on neutrophils in patients with type 2 diabetes mellitus, we recruited 29 patients with type 2 diabetes mellitus without any diabetic complication and 24 healthy subjects (controls). Expression of syndecan-1 was determined by flow cytometry, and potential correlations between syndecan-1 and clinical characteristics were analyzed. On neutrophils, percentage of positive syndecan-1 cells was significantly higher in subjects with diabetes (10.363 ± 1.689%) than that of the controls (3.775 ± 0.634%, P = 0.001). An association between body mass index (BMI) and percentage of positive syndecan-1 neutrophils was detected (r = 0.415, P = 0.025). When BMI was categorized into subgroups of ≤25 kg/m(2) (n = 10) and >25 kg/m(2) (n = 19), the average percentages of positive syndecan-1 neutrophils in patients with diabetes were 5.733 ± 1.842% and 12.642 ± 2.251%, respectively (t = -2.137, P = 0.042). A multiple regression analysis showed that BMI (β = 0.783, P < 0.000) was a significant predictor of positive syndecan-1 neutrophils in subjects with type 2 diabetes. 10.1007/s00592-011-0265-1
    Neutrophil Resolvin E1 Receptor Expression and Function in Type 2 Diabetes. Freire Marcelo O,Dalli Jesmond,Serhan Charles N,Van Dyke Thomas E Journal of immunology (Baltimore, Md. : 1950) Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1, and inversed coexpression when compared to neutrophils from type 2 diabetes subjects. Stimulation with TNF-α or LPS increased the expression of ERV-1 by healthy and diabetic neutrophils. RvE1 counteracted LPS and TNF-α induction of ERV-1 overexpression and endogenous diabetic overexpression, activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein ribosomal S6. Receptor-antagonism experiments revealed that the increase in phosphorylation of ribosomal S6 was mediated by BLT-1 in healthy subject neutrophils and by ERV-1 in diabetes. Metabololipidomics reveal a proinflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than in healthy controls. RvE1 rescues the dysregulation seen on neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution signals in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes. 10.4049/jimmunol.1601543
    Distinct neutrophil counts and functions in newly diagnosed type 1 diabetes, latent autoimmune diabetes in adults, and type 2 diabetes. Huang Juan,Xiao Yang,Zheng Peilin,Zhou Wenzhi,Wang Yanfei,Huang Gan,Xu Aimin,Zhou Zhiguang Diabetes/metabolism research and reviews BACKGROUND:Recent discoveries from animal models demonstrated that neutrophils can induce type 1 diabetes (T1D) through infiltrating into the islets. However, the evidence of their actions in T1D patients is relatively rare, and the change trend of neutrophil numbers and functions in different subtypes of diabetes has not been investigated. METHODS:Patients with newly diagnosed T1D (n = 189), latent autoimmune diabetes in adults (LADA) (n = 86), T2D (n = 235), and healthy controls (n = 709) were enrolled. Circulating neutrophil counts were measured, and their correlations with clinical parameters were analysed. Neutrophils were isolated by density gradient centrifugation and magnetic bead cell sorting method. Neutrophil migration rate and chemokine levels in the blood were explored by trans-well and ELISA, respectively. Neutrophil phagocytosis rate, adhesion molecules and chemokine receptors expression were investigated by flow cytometry. RESULTS:Compared with controls, neutrophil counts decreased in T1D patients but increased in T2D patients, with no change in LADA patients. The numbers showed a gradual increase trend from T1D, LADA to T2D. In autoimmune diabetes, neutrophil counts were associated with the number and titre of positive autoantibodies against β-cell antigens. No difference was found in neutrophil phagocytosis rate, but neutrophil migration in T1D patients was impaired and associated with CD62L expression, which was related closely to the titre of autoantibody. CONCLUSIONS:Neutrophil numbers and migration abilities displayed distinct levels in different types of diabetes. In T1D, CD62L seems to play an important role in the migration of neutrophils and β-cell autoimmunity. 10.1002/dmrr.3064
    A New Chemiluminescent Method for Evaluation of the Functional Activity of Neutrophils in Patients with Type 2 Diabetes Mellitus. Proskurnina E V,Sozarukova M M,Polimova A M,Prudnikova M A,Ametov A S,Vladimirov Yu A Bulletin of experimental biology and medicine Functional activity of neutrophils was evaluated by the chemiluminescent method with successive double stimulation by soluble stimuli with different mechanisms of action: phorbol-12-myristate-13-acetate (PMA) and phormyl-methionyl-leucyl-phenilalanine (fMLP). The study was carried out in 26 patients receiving oral sugar-reducing therapy. In addition to the functional activity of neutrophils, the levels of TBA reactive products, inflammation markers, blood clotting values, and biochemical parameters were measured. The results showed mainly reduction of the granulocytic component of the immune system in the patients. 10.1007/s10517-016-3405-3
    Glucose induces metabolic reprogramming in neutrophils during type 2 diabetes to form constitutive extracellular traps and decreased responsiveness to lipopolysaccharides. Joshi Manjunath B,Ahamed Rayees,Hegde Mangala,Nair Aswathy S,Ramachandra Lingadakai,Satyamoorthy Kapaettu Biochimica et biophysica acta. Molecular basis of disease Recurrent infections are one of the common morbidities in Type 2 Diabetes (T2D) subjects. Bidirectional activation of innate immune cells such as neutrophils and glucose metabolism in T2D conditions leads to a pro-inflammatory milieu and reduced neutrophil function, which can be a potential cause for recurrent infections. In pathological conditions of sterile inflammation associated T2D, neutrophils form constitutive extracellular traps (NETs) due to hyperglycemia and respond poorly to infections. The present study was aimed at understanding the cellular and metabolic consequences, and NETs formation in T2D. We show that glucose induces NADPH oxidase derived reactive oxygen species and further citrullinates the histones to form weaker NETs leading to reduced response to lipopolysaccharide (LPS). Untargeted metabolomics analysis in neutrophils cultured under high glucose and from T2D subjects revealed enrichment of polyol pathway intermediates (1-anhydrosorbitol) and reduced glutathione metabolism products (cysteinylglycine). NADPH is an absolute requirement for three independent pathways of formation of 1-anhydrosorbitol via aldose reductase under excess glucose, induction of glutathione synthesis and glucose induced NETs formation. During T2D and in presence of high glucose, there is a competition for NADPH between these processive reactions, which leads to its insufficiency to produce NETs in response to LPS. Interestingly, supplementation of NADPH and pharmacological inhibitor of aldose reductase, ranirestat, restored NETs formation in presence of LPS. Our study provides novel insights on the metabolic reprogramming of neutrophils, which may lead to susceptibility of T2D subjects to infections. 10.1016/j.bbadis.2020.165940
    Usefulness of the neutrophil-to-lymphocyte ratio to prediction of type 2 diabetes mellitus in morbid obesity. Yilmaz H,Ucan B,Sayki M,Unsal I,Sahin M,Ozbek M,Delibasi T Diabetes & metabolic syndrome BACKGROUND:There is growing consensus in the literature that inflammation plays a central role in the pathophysiology of obesity and type 2 diabetes mellitus (T2DM) and cardiovascular complications. Neutrophil-to-lymphocyte ratio (NLR) provides a simple method for assessment of inflammatory status and it is a new, inexpensive marker. The aim of the present study was to investigate the predictive value of preprocedural (before the OGTT) NLR on development of type 2 diabetes (T2DM) in morbid obesity patients (MOP). METHODS:306 MOP (body mass index ≥ 40 kg/m(2)) and 95 normal weight patients with normal OGTT [fasting plasma glucose (FPG)<100mg/dL. Two-hour glucose during OGTT<140 mg/dL] were evaluated in this study. RESULTS:The mean ± SD NLR of MOP was significantly higher than that of patients with normal weight healthy patients (3.67 ± 0.95 vs. 1.82 ± 1.02, P<0.001, respectively). In receiver operating characteristics curve analysis, NLR>3.12 had 79.2% sensitivity and 64.9% specificity in predicting T2DM. Logistic regression analysis showed that elevated NLR (OR: 2.577, 95% CI: 1.363-4.872, P=0.004) was an independent variable for predicting T2DM in MOP. CONCLUSIONS:MOP have higher NLR than healthy controls. High NLR is a powerful and independent predictor of T2DM in MOP. Elevated NLR levels are usually considered as an inflammatory marker. The results of this study suggested that inflammation plays a role in the pathogenesis of T2DM with MOP. 10.1016/j.dsx.2014.04.009
    Expression of neutrophil elastase and myeloperoxidase mRNA in patients with newly diagnosed type 2 diabetes mellitus. Ferdous Mokerroma,R Sonam C,Mudi Sonchita R,Ali Mohammad,Jasmin Shahana,Fariduddin Mohammad,Alam Sheikh M K,Arslan M I,Biswas Subrata K Diabetes & metabolic syndrome BACKGROUND AND AIMS:Neutrophil elastase and myeloperoxidase enzymes protect us from infection by killing pathogens. However, exaggerated activities of these enzymes can induce tissue damage, inflammation and oxidative stress. The present study was aimed to explore the expressions of neutrophil elastase and myeloperoxidase mRNA in the peripheral blood leukocytes (PBL) in patients with newly diagnosed type 2 diabetes mellitus. METHODS:In this cross-sectional study, 104 participants including 65 normoglycemic control subjects and 39 newly diagnosed type 2 diabetes patients were recruited. Glycemic and metabolic markers were evaluated from fasting blood samples. The mRNA levels of neutrophil elastase and myeloperoxidase genes in the PBL were quantified by real-time quantitative PCR. RESULTS:Compared to control subjects, diabetes patients showed a significant down regulation of both neutrophil elastase (p = 0.039) and myeloperoxidase (p = 0.023) mRNA expressions in the PBL. The neutrophil elastase and myeloperoxidase mRNA levels showed a negative trend with fasting glucose levels but did not show any significant correlations with HbA1c, insulin level, insulin resistance or sensitivity status. CONCLUSIONS:It was concluded that type 2 diabetes mellitus is associated with a decrease in neutrophil elastase and myeloperoxidase gene expression in the PBL. 10.1016/j.dsx.2020.01.001
    The relationship between neutrophil-to-lymphocyte ratio and diabetic peripheral neuropathy in Type 2 diabetes mellitus. Xu Tingting,Weng Zihua,Pei Chu,Yu Siyuan,Chen Yating,Guo Wenjie,Wang Xingzuo,Luo Peng,Sun Jia Medicine To explore the relationship between neutrophil-to-lymphocyte ratio (NLR) and diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus.A total of 557 newly diagnosed Type 2 Diabetes Mellitus (T2DM) patients were recruited, including 397 T2DM patients without complication (DM group) as well as 160 T2DM patients complicated with DPN (DPN group). Student t test, Mann-Whitney U test, or χ test was applied to the data of the 2 groups, including the levels of neutrophils and lymphocytes as well as the NLR values of peripheral blood and other biochemistry indexes; Pearson correlation analysis was used to calculate the correlation of NLR and detected factors; risk factors of DPN were estimated via logistic regression analysis and multivariate analysis.The values of triglyceride (TG), neutrophils, fasting insulin, urinary albumin, and 2 hour postglucose in DPN group were significantly higher than those of the DM group, whereas the number of lymphocytes of DPN group was considerably lower than that of the DM group (P < .05 respectively); NLR values were remarkably higher in DPN group compared with those of DM group (2.58 ± 0.50 vs 2.18 ± 0.61, P < .001); logistic regression analysis showed that NLR (P = .002, OR = 4.960, 95% CI = 1.843-13.349) was a risk factor of DPN. Multivariate logistic regression analysis showed that DPN was independently related to NLR (P = .002, OR = 4.960, 95% CI = 1.843-13.349). The ROC curve analysis confirmed that the optimal cut-off point, specificity, and sensitivity in diagnosing DPN by NLR were 2.13%, 48.1%, and 81.3% respectively.Our results showed that NLR is significantly correlated with DPN, which suggested that NLR may be an independent risk factor of DPN. 10.1097/MD.0000000000008289
    Obesity and Type 2 Diabetes mellitus induce lipopolysaccharide tolerance in rat neutrophils. Kuwabara Wilson Mitsuo Tatagiba,Yokota Caroline Naomi Fukusawa,Curi Rui,Alba-Loureiro Tatiana Carolina Scientific reports Obesity and diabetes implicate in various health complications and increased mortality caused by infection. Innate immune system is broadly affected by these diseases, leading the patients to an immunosuppressive state. A mechanism that leads innate immune cells to a less capacity of killing microorganism is the impaired TLR4 activation. TLR4 recognizes a component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS), and when activated increases the production of inflammatory substances. Neutrophils are components of the innate immune system and are the first responders to an invading agent. The correct activation of TLR4 in these cells is required for the initiation of the inflammatory process and elimination of the microorganisms. The aim of this study was to evaluate the influence of type 2 diabetes and obesity in the TLR4 pathway in rat neutrophils. Two experimental models were used: Goto-Kakizaki rats and high-fat-diet induced obese Wistar rats. To evaluate neutrophil response to LPS, intratracheal LPS instillation was used. Neutrophils from obese and diabetic animals exhibited tolerance to LPS, mainly by the impaired production of cytokines and chemokines and the low content of phospho-NFκB and phospho-IKBα. Neutrophils from both experimental models had increased cell death, impaired in vivo migration and myeloperoxidase activity. 10.1038/s41598-018-35809-2
    sFasL-mediated induction of neutrophil activation in patients with type 2 diabetes mellitus. Margaryan Sona,Witkowicz Agata,Arakelyan Arsen,Partyka Anna,Karabon Lidia,Manukyan Gayane PloS one Fas/Fas ligand system was shown to be related to insulin resistance and type 2 diabetes mellitus (T2DM). However, the role of soluble Fas ligand (sFasL) in functioning of immune cells in type 2 diabetes mellitus (T2DM) has not been studied yet. The aim of the present study was to determine in vitro effects of sFasL on neutrophil activation and apoptosis. We demonstrate here that sFasL exhibited proinflammatory effect and induced mRNA levels of caspase-1, NF-κB, IL-1β and CD18 expression. At the same time, sFasL induced reactive oxygen species (ROS) production. Activation of caspase-1 activity abolished sFasL-dependent apoptosis, and suppressed Fas expression and mRNA levels of caspase-3 in neutrophils from T2DM patients. Collectively, our findings identify a novel proinflammatory role of sFasL in T2DM neutrophils that is dependent of caspase activity. Thus, sFasL enhances inflammatory response of neutrophils from T2DM patients without increasing apoptosis suggesting its triggering role in T2DM inflammation. 10.1371/journal.pone.0201087
    Clarithromycin Enhances the Antibacterial Activity and Wound Healing Capacity in Type 2 Diabetes Mellitus by Increasing LL-37 Load on Neutrophil Extracellular Traps. Arampatzioglou Athanasios,Papazoglou Dimitrios,Konstantinidis Theocharis,Chrysanthopoulou Akrivi,Mitsios Alexandros,Angelidou Iliana,Maroulakou Ioanna,Ritis Konstantinos,Skendros Panagiotis Frontiers in immunology Type 2 diabetes mellitus (T2D) is characterized by susceptibility to bacterial infections and impaired wound healing. Neutrophil extracellular traps (NETs) and the cathelicidin antimicrobial peptide LL-37 have been implicated both in defense against bacterial infections and in wound healing process. Recently, it was shown that macrolide antibiotic clarithromycin induces the release of LL-37-bearing NETs. In T2D there has not been identified any link between NETs and LL-37 and the effect of clarithromycin in neutrophils/NETs is unknown yet. Peripheral blood neutrophils were obtained from treatment-naive hyperglycemic T2D patients (naive), normoglycemic T2D patients under antidiabetic treatment (well-controlled) and healthy donors (controls). NET release and NET proteins were studied. Co-culture systems of NET structures with NCTC 9001 and primary skin fibroblasts were deployed to examine the antibacterial and fibrotic NET properties, respectively. The effect of clarithromycin was also investigated. Analysis was performed using immunofluorescence confocal microscopy, myeloperoxidase-DNA complex and LL-37 ELISA, immunoblotting and qRT-PCR. NETs were characterized by the presence of LL-37, however they lacked antibacterial activity, in both groups of T2D patients. Clarithromycin significantly increased the externalization of LL-37 on NETs generated from well-controlled T2D neutrophils, thus restoring NET antibacterial capacity and promoting the wound healing process via fibroblast activation and differentiation. This study suggests that clarithromycin may add further advantage to well-controlled T2D patients, by enhancing their antibacterial defense and improving wound healing capacity of fibroblasts, through upregulation of LL-37 on NET structures. 10.3389/fimmu.2018.02064
    Abnormal Peripheral Neutrophil Transcriptome in Newly Diagnosed Type 2 Diabetes Patients. Journal of diabetes research AIM:There are increasing evidence demonstrating that neutrophil-mediated inflammation plays a role in the etiology of type 2 diabetes. However, the molecular mechanisms by which neutrophils contribute to type 2 diabetes remain largely unknown. The aim of the present work was to identify possible changes in circulating neutrophils to better elucidate neutrophil involvement in human type 2 diabetes. METHODS:Patients newly diagnosed with type 2 diabetes ( = 5) and age- and sex-matched healthy controls ( = 5) were recruited. Neutrophils were purified from type 2 diabetes patients and controls, and RNA sequencing (RNA-seq) was used for comprehensive transcriptome analysis. Differentially expressed genes (DEGs) were screened, and Gene Ontology (GO) and KEGG pathway enrichment analyses were performed. Real-time polymerase chain reaction (qPCR) was used for validation in external samples of type 2 diabetes patients ( = 8) and healthy controls ( = 8). RESULTS:Gene expression analysis showed that, compared with neutrophils from healthy controls, there were 1990 upregulated DEGs and 1314 downregulated DEGs in neutrophils from type 2 diabetes patients. GO analysis demonstrated that the DEGs were mainly involved in myeloid leukocyte activation, T cell activation, adaptive immunity, and cytokine production. The top 20 enriched KEGG pathways included the cytokine-cytokine receptor interaction pathway, NF-B signaling pathway, cell adhesion molecules, and chemokine signaling pathway. Furthermore, qPCR of genes related to neutrophil activation revealed that the expression of SELL, SELP, CXCR1, and S100A8 was significantly increased in neutrophils from type 2 diabetes patients compared with that in neutrophils from controls. CONCLUSIONS:Our study reveals an abnormal activation of circulating neutrophils at the transcriptome level in type 2 diabetes patients. These findings suggest a potential involvement of neutrophil dysfunction in the pathologic process of type 2 diabetes and provide insight into potential therapeutic targets for type 2 diabetes. 10.1155/2020/9519072
    Vitamin D affects the neutrophil-to-lymphocyte ratio in patients with type 2 diabetes mellitus. Wang Si-Yang,Shen Ting-Ting,Xi Bei-Li,Shen Zhan,Zhang Xian Journal of diabetes investigation AIMS/INTRODUCTION:Chronic inflammation is an underlying feature of type 2 diabetes mellitus. Hypovitaminosis D is associated with type 2 diabetes mellitus, but whether it contributes to chronic inflammation is unclear. We examined the effects of vitamin D on various immune markers to evaluate its contribution to systemic inflammation in type 2 diabetes mellitus. MATERIALS AND METHODS:We retrospectively analyzed data from type 2 diabetes mellitus patients, people with prediabetes and control patients without diabetes (n = 9,746). Demographic and clinical variables were evaluated using descriptive statistics and generalized linear regression. A stratified analysis based on total serum vitamin D was also carried out. RESULTS:Neutrophil count was a significant predictor of 1,5-anhydroglucitol and glycated hemoglobin (HbA1c) in patients with prediabetes (1,5-anhydroglucitol: β = -0.719, P < 0.001 and HbA1c: β = -0.006, P = 0.002) and patients with diabetes (1,5-anhydroglucitol: β = 0.207, P = 0.004 and HbA1c: β = -0.067, P = 0.010). Lymphocyte count was a significant predictor of HbA1c in patients without diabetes (β = 0.056, P < 0.001) and patients with prediabetes (β = 0.038, P < 0.001). The neutrophil-to-lymphocyte ratio (NLR) was a significant predictor of HbA1c in patients without diabetes (β = -0.001, P = 0.032). No immune markers differed significantly based on vitamin D level among patients without diabetes (P> 0.05 for all). Among patients with prediabetes, those who were vitamin D-deficient had the highest NLR (P = 0.040). Among patients with diabetes, those who were vitamin D-deficient had the highest neutrophil count (P = 0.001), lowest lymphocyte count (P = 0.016) and highest NLR (P < 0.001). CONCLUSIONS:The NLR is strongly influenced by serum vitamin D level. Given the high prevalence of hypovitaminosis D and elevated NLR among chronic disease patients and the elderly, our results suggest that clinical interpretation of NLR as a predictive marker of type 2 diabetes mellitus-related inflammation should consider vitamin D level, age and pre-existing morbidity. 10.1111/jdi.13338
    MPO activity and generation of active O2 species in leukocytes from poorly controlled diabetic patients. Sato N,Shimizu H,Suwa K,Shimomura Y,Kobayashi I,Mori M Diabetes care OBJECTIVE:This study was undertaken to determine which part of ROI generation is reduced in the neutrophils from patients with NIDDM. RESEARCH DESIGN AND METHODS:Superoxide anion (O2-) production, LDCL activity in response to opsonized zymosan, and MPO activity were measured in leukocytes of poorly controlled NIDDM patients (FBG greater than 8.89 mM, HbA1 greater than 10%). RESULTS:In diabetic subjects, both O2- production and LDCL activity assessed with initial slope gradient and peak value were significantly reduced. MPO activity was also decreased in diabetic subjects, and there was a significant correlation between HbA1 levels and MPO activity of diabetic subjects. CONCLUSIONS:This study demonstrated that every step in leukocyte ROI generation should be reduced in the leukocytes from poorly controlled diabetic patients. 10.2337/diacare.15.8.1050
    Decreased polymorphonuclear leukocyte deformability in NIDDM. Pécsvarády Z,Fisher T C,Darwin C H,Fabók A,Maqueda T S,Saad M F,Meiselman H J Diabetes care OBJECTIVE:To determine the rheological properties of polymorphonuclear leukocytes (PMN) from non-insulin-dependent diabetes mellitus (NIDDM) patients. RESEARCH DESIGN AND METHODS:The deformability of PMN from 33 NIDDM subjects, 13 with impaired glucose tolerance (IGT), and 22 with normal glucose tolerance (NGT) was studied. A Cell Transit Analyzer that measures the transit time of PMN through 8-microns pores was used. Studies were performed under three different conditions: 1) basal state; 2) after incubation with cytochalasin B (20 microM) to dissociate f-actin from the cytoskeleton; and 3) following activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP, 1 nM). RESULTS:PMN from diabetic patients were more rigid (i.e., had longer transit time) than those from subjects with NGT or IGT under basal conditions and after cytochalasin B, but not after stimulation with fMLP. The deformability of PMN from subjects with IGT was similar to those of the NGT group. In the pooled data, basal transit time correlated with age; systolic and diastolic blood pressure; HbA1c; and serum creatinine, cholesterol, and triglyceride concentrations (r = 0.29, 0.34, 0.37, 0.48, 0.25, 0.36, 0.29, respectively, P < 0.05 for each). Hypertensive diabetic patients had less deformable PMN than normotensive ones. No relation was found between PMN deformability and the duration of diabetes, type of treatment, or the presence of retinopathy. CONCLUSIONS:These data indicate increased rigidity of PMN in NIDDM that may contribute to development of microcirculatory disturbances and microangiopathy. 10.2337/diacare.17.1.57
    Impairment of polymorphonuclear leukocyte function and metabolic control of diabetes. Marhoffer W,Stein M,Maeser E,Federlin K Diabetes care OBJECTIVE:In this study, ingestion of Staphylococcus aureus and "bacteria killing" (BK) were measured to evaluate polymorphonuclear leukocyte (PMN) phagocytic functions and chemiluminescence response (CL) to phorbol-myristic acetate (PMA) as respiratory burst activity with regard to metabolic control parameters in diabetic patients. RESEARCH DESIGN AND METHODS:PMN phagocytic functions were assessed in 40 diabetic patients, all receiving insulin and in poor metabolic control, with 3H-thymidine-labeled Staphylococcus aureus in a modified radiometric assay. Bacteria killing was determined by pure-plate counting of surviving bacteria (colony-forming units [cfu]) and luminol-enhanced CL in response to PMA as a measure of respiratory burst. PMN function data were correlated to HbA1 as parameter of recent metabolic control. RESULTS:PMN of diabetic patients showed a significant reduction in Staphylococcus aureus (50.7 +/- 4.1%) and BK (29.4 +/- 4.2%) compared with healthy nondiabetic control subjects (76.6 +/- 4.6% and 16.3 +/- 3.1%, respectively, P less than 0.001), and PMN CL response was markedly reduced in diabetic patients also. Linear regression analysis showed a highly significant negative correlation of HbA1 versus Staphylococcus aureus (r = -0.67, P = 0.001) and a positive correlation for BK (r = 0.73, P less than 0.001). This was also true for CL, although this did not reach statistical significance (P = 0.06). CONCLUSIONS:The data obtained demonstrate impaired PMN phagocytic functions and CL response in diabetic patients. These findings suggest inhibitory effects of elevated glucose concentrations on PMNs, a possible role of protein glycosylation for impairing PMN function, thus contributing in part to altered host defense. 10.2337/diacare.15.2.256
    Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: abnormalities in metabolism and function. Alexiewicz J M,Kumar D,Smogorzewski M,Klin M,Massry S G Annals of internal medicine OBJECTIVE:To determine basal levels of cytosolic calcium ([Ca2+]i) and phagocytic activity in polymorphonuclear leukocytes (PMNLs) from patients with non-insulin-dependent diabetes (NIDDM). DESIGN:Prospective cohort study. SETTING:A university-county hospital. MEASUREMENTS:Cytosolic calcium levels, adenosine triphosphate (ATP) content, and phagocytosis of PMNLs from patients with NIDDM and from controls. INTERVENTION:In patients with NIDDM, we evaluated the effect of treatment with an oral hypoglycemic agent (glyburide) on [Ca2+]i levels, ATP content, and the phagocytosis of PMNLs. PATIENTS:22 controls and 34 patients with NIDDM were examined. Fifteen patients were studied before and after 3 months of treatment with glyburide. RESULTS:Polymorphonuclear leukocytes from patients with NIDDM showed significantly elevated basal levels of [Ca2+]i (68 +/- 9.6 compared with 43 +/- 4.9 nmol/L; P < 0.01); reduced ATP content (1.30 +/- 0.58 compared with 2.35 +/- 0.45 nmol/10(6) PMNLs; P < 0.01); and impaired phagocytosis (117 +/- 21.0 compared with 145 +/- 17.4 micrograms oil/10(7) PMNLs per minute; P < 0.01) compared with controls. There was a direct and significant correlation (P < 0.01, r = 0.80) between [Ca2+]i levels in PMNLs and serum glucose levels and an inverse correlation between phagocytic ability and [Ca2+]i levels (P < 0.01; r = 0.62) as well as between phagocytic activity and fasting serum glucose levels (P < 0.01, r = 0.54) in patients with NIDDM. Glyburide therapy resulted in significant reduction in fasting serum glucose levels; in PMNLs, this treatment resulted in a significant reduction in [Ca2+]i levels, a significant increase in ATP content, and a significant improvement of phagocytosis. CONCLUSIONS:Patients with NIDDM have elevated [Ca2+]i levels in PMNLs. This abnormality is probably induced by hyperglycemia and is primarily responsible for the imparied phagocytosis seen in these patients. 10.7326/0003-4819-123-12-199512150-00004
    Peripheral total and differential leukocyte count in diabetic nephropathy: the relationship of plasma leptin to leukocytosis. Chung Fu-Mei,Tsai Jack C-R,Chang Dao-Ming,Shin Shyi-Jang,Lee Yau-Jiunn Diabetes care OBJECTIVE:Because of increasing evidence that white blood cells (WBCs) play a role in the development and progression of diabetes complications, this study aimed to investigate the relation of circulating total and differential leukocyte counts to nephropathy in patients with type 2 diabetes. Plasma leptin levels were also measured to investigate their role in peripheral leukocytosis. RESEARCH DESIGN AND METHODS:For this study, 1,480 subjects with type 2 diabetes who were enrolled in a disease management program were stratified according to urinary microalbumin and serum creatinine measurements. The total and differential leukocyte profiles of peripheral blood were measured and plasma leptin was examined by enzyme-linked immunosorbent assay. Demographic and potential metabolic confounding factors were analyzed with linear and logistic regression to calculate the effects of leukocyte count on diabetic nephropathy. RESULTS:The peripheral total WBC, monocyte, and neutrophil counts increased in parallel with the advancement of diabetic nephropathy. In contrast, the lymphocyte count decreased. When WBC counts were analyzed per quartile and as continuous variables after adjusting for age, sex, and other known risk factors with multiple regression analysis, peripheral total WBC, monocyte, neutrophil, and lymphocyte counts were independently and significantly associated with diabetic nephropathy. Plasma leptin levels increased in patients with nephropathy and correlated significantly with total WBC count (r = 0.194, P = 0.014). CONCLUSIONS:Because leukocytes are activated and secrete cytokines in the diabetic state and leptin stimulates leukocyte proliferation and differentiation, our results suggest that circulating leukocytes contribute to the development and progression of nephropathy, partially through the effects of leptin, in patients with type 2 diabetes. 10.2337/diacare.28.7.1710
    Involvement of peripheral polymorphonuclear leukocytes in oxidative stress and inflammation in type 2 diabetic patients. Shurtz-Swirski R,Sela S,Herskovits A T,Shasha S M,Shapiro G,Nasser L,Kristal B Diabetes care OBJECTIVE:To determine the extent to which peripheral polymorphonuclear leukocytes (PMNs) contributed to oxidative stress (OS) and inflammation in type 2 diabetic patients. RESEARCH DESIGN AND METHODS:PMNs and plasma were separated from blood withdrawn from 18 type 2 diabetic patients and 16 age- and sex-matched normal control subjects. The rate of superoxide release from phorbol 12-myristate 13-acetate (PMA)-stimulated PMNs and the plasma glutathione (GSH) levels served as measures of OS. Inflammation was assessed by PMN recruitment, expressed by peripheral blood PMN counts, and the in vitro survival of PMNs, which reflects cell necrosis. RESULTS:PMA-stimulated PMNs from diabetes released superoxide significantly faster, and plasma-reduced GSH was lower in diabetic patients than in normal control subjects. The rate of superoxide release from diabetic PMNs showed no correlation with the plasma glucose concentrations, whereas a positive linear correlation with HbA1c was found. The in vitro survival of diabetic PMNs was lower than normal control PMNs when each was incubated in its own serum. The in vitro survival of normal control PMNs was reduced when incubated with diabetic serum, whereas normal control sera promoted the survival of diabetic PMNs. Peripheral PMN counts were higher in diabetic patients than in normal control patients. CONCLUSIONS:Type 2 diabetes is accompanied by a priming of PMNs, resulting in OS and increased self-necrosis. Necrosis starts a chain of inflammatory reactions that result in cell recruitment and in the long run, with OS, may result in endothelial dysfunction. Understanding the contribution of PMNs to OS and inflammation in diabetes may illuminate new mechanisms through which endothelial dysfunction evolves and causes angiopathy and atherosclerosis. 10.2337/diacare.24.1.104
    Epalrestat, an aldose reductase inhibitor, improves an impaired generation of oxygen-derived free radicals by neutrophils from poorly controlled NIDDM patients. Sato N,Kashima K,Uehara Y,Ohtani K,Shimizu H,Mori M Diabetes care OBJECTIVE:To study the in vivo effect of epalrestat (Epa), an aldose reductase inhibitor, on the generation of oxygen-derived free radicals by neutrophils from poorly controlled NIDDM patients (HbA1c > 10%). RESEARCH DESIGN AND METHODS:A total of 31 diabetic patients were randomly divided into two groups: an Epa(+) group of 16 patients treated with 150 mg/day epalrestat and an Epa(-) group of 15 patients treated without epalrestat. A control group of 20 age- and sex-matched normal healthy subjects also participated. HbA1c, postprandial plasma glucose (PPG), and neutrophil bactericidal function were measured before and at the end of the drug treatment period (4 weeks). Neutrophil bactericidal function was measured as chemilu-minescence amplified by a Cypridina luciferin analog (CLA), which is dependent on O2- generation, and by luminol (L), which is highly dependent on OCl- generation, in response to formyl-methonyl-leucyl-phenylalanine (fMLP). RESULTS:At the start of the experiment, both CLA-dependent chemiluminescence (CLA-DCL) and L-dependent chemiluminescence (L-DCL) were clearly decreased in diabetic subjects (64 and 54%, respectively; P < 0.05) compared with control subjects (2,182 +/- 144 and 3,221 +/- 173 kc.min-1.10(-6) cells, respectively). At the end of the experiment, CLA-DCL and L-DCL in the Epa(+) group were significantly improved by 44 and 46%, respectively; however, these values were still lower than the corresponding results in the control group. HbA1c and PPG in both the Epa(+) and Epa (-) groups were significantly higher than in the control group, and treatment had no effect on either HbA1c or PPG. CONCLUSIONS:These data suggest that epalrestat may be a useful drug to prevent infection by improving the impaired O2- and OCl- generation by neutrophils from poorly controlled NIDDM patients. 10.2337/diacare.20.6.995
    Increased spontaneous adherence of neutrophils from type 2 diabetic patients with overt proteinuria: possible role of the progression of diabetic nephropathy. Takahashi T,Hato F,Yamane T,Inaba M,Okuno Y,Nishizawa Y,Kitagawa S Diabetes care 10.2337/diacare.23.3.417
    T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Guarda Greta,Dostert Catherine,Staehli Francesco,Cabalzar Katrin,Castillo Rosa,Tardivel Aubry,Schneider Pascal,Tschopp Jürg Nature Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process. The inflammatory response must be actively terminated, however, because failure to do so can result in 'bystander' damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4(+) T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1beta release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with selected ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4(+) T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact. 10.1038/nature08100
    Reconstituted high-density lipoprotein increases plasma high-density lipoprotein anti-inflammatory properties and cholesterol efflux capacity in patients with type 2 diabetes. Patel Sanjay,Drew Brian G,Nakhla Shirley,Duffy Stephen J,Murphy Andrew J,Barter Phillip J,Rye Kerry-Anne,Chin-Dusting Jaye,Hoang Anh,Sviridov Dmitri,Celermajer David S,Kingwell Bronwyn A Journal of the American College of Cardiology OBJECTIVES:Our aim was to investigate the effects of reconstituted high-density lipoprotein (rHDL) infusions on plasma high-density lipoprotein (HDL) anti-inflammatory properties and ex vivo cholesterol efflux in patients with type 2 diabetes. BACKGROUND:The anti-inflammatory effects of HDL contribute to protection from cardiovascular events. Individuals with type 2 diabetes are at elevated risk for cardiovascular disease, and typically have low HDL with reduced anti-inflammatory properties. METHODS:Thirteen fasting male patients (mean age 52 years) with type 2 diabetes mellitus received both rHDL (80 mg/kg of apolipoprotein A-I) and a saline placebo on separate occasions in a randomized cross-over design study. Changes in the ability of isolated HDL to influence the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in human coronary artery endothelial cells was the main outcome measure. Other outcome measures included expression of the key integrin, CD11b on patient monocytes, adhesiveness of patient neutrophils to fibrinogen, and the ability of plasma to promote cholesterol efflux to THP-1 macrophages. RESULTS:Four and 72 h post-rHDL infusion, the anti-inflammatory properties of isolated HDL increased in parallel to their concentration in plasma (by up to 25%, p < 0.01). Participants' peripheral blood monocyte CD11b expression and neutrophil adhesion to a fibrinogen matrix was also reduced 72 h post-rHDL, compared with that seen in placebo (p = 0.02). rHDL increased the capacity of plasma to receive cholesterol from THP-1 macrophages by 1 h up to 72 h post-infusion (by 40% to 60%, p < 0.05). CONCLUSIONS:rHDL infusions have significant, potentially atheroprotective effects in individuals with diabetes, including suppression of inflammation and enhancement of cholesterol efflux. 10.1016/j.jacc.2008.12.008
    Type 2 diabetes mellitus is associated with impaired cytokine response and adhesion molecule expression in human endotoxemia. Andreasen Anne Sofie,Pedersen-Skovsgaard Theis,Berg Ronan M G,Svendsen Kira Dynnes,Feldt-Rasmussen Bo,Pedersen Bente K,Møller Kirsten Intensive care medicine PURPOSE:Type 2 diabetes is associated with an increased risk of acquiring infectious diseases and developing sepsis. This may partly be due to immune dysfunction. We investigated the in vivo innate immune response of type 2 diabetic persons to an intravenous injection of E. coli lipopolysaccharide (LPS). METHODS:After ethics approval, informed consent and a thorough physical examination, 19 type 2 diabetic patients and 23 healthy controls were included. LPS was given as an intravenous bolus injection of 0.3 ng/kg. Physiological variables, white blood cell count, and plasma concentrations of tumour necrosis factor (TNF), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and the adhesion molecules E-selectin, vascular adhesion molecule (VCAM)-1, and intracellular adhesion molecule (ICAM)-1 were measured hourly for 8 h. RESULTS:LPS injection induced a systemic inflammatory response with increases in neutrophils, temperature, heart rate and plasma concentrations of cytokines and adhesion molecules in healthy and type 2 diabetic volunteers. Type 2 diabetes was associated with less pronounced LPS-induced increases in TNF, IL-1ra, VCAM-1 and ICAM-1. There was a trend towards an attenuated upregulation of E-selectin in diabetics, even though the plasma concentration tended to be generally higher compared to healthy controls. CONCLUSIONS:Patients with type 2 diabetes exhibit an attenuated increase in plasma levels of TNF and IL-1ra, as well as an attenuated upregulation of VCAM-1 and ICAM-1 to LPS in vivo. This finding may provide a mechanistic explanation for the adverse outcome seen during infectious diseases in diabetic patients. 10.1007/s00134-010-1845-1
    Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. Kraakman Michael J,Lee Man Ks,Al-Sharea Annas,Dragoljevic Dragana,Barrett Tessa J,Montenont Emilie,Basu Debapriya,Heywood Sarah,Kammoun Helene L,Flynn Michelle,Whillas Alexandra,Hanssen Nordin Mj,Febbraio Mark A,Westein Erik,Fisher Edward A,Chin-Dusting Jaye,Cooper Mark E,Berger Jeffrey S,Goldberg Ira J,Nagareddy Prabhakara R,Murphy Andrew J The Journal of clinical investigation Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes. 10.1172/JCI92450
    Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Talukdar Saswata,Oh Da Young,Bandyopadhyay Gautam,Li Dongmei,Xu Jianfeng,McNelis Joanne,Lu Min,Li Pingping,Yan Qingyun,Zhu Yimin,Ofrecio Jachelle,Lin Michael,Brenner Martin B,Olefsky Jerrold M Nature medicine Chronic low-grade adipose tissue and liver inflammation is a major cause of systemic insulin resistance and is a key component of the low degree of insulin sensitivity that exists in obesity and type 2 diabetes. Immune cells, such as macrophages, T cells, B cells, mast cells and eosinophils, have all been implicated as having a role in this process. Neutrophils are typically the first immune cells to respond to inflammation and can exacerbate the chronic inflammatory state by helping to recruit macrophages and by interacting with antigen-presenting cells. Neutrophils secrete several proteases, one of which is neutrophil elastase, which can promote inflammatory responses in several disease models. Here we show that treatment of hepatocytes with neutrophil elastase causes cellular insulin resistance and that deletion of neutrophil elastase in high-fat-diet–induced obese (DIO) mice leads to less tissue inflammation that is associated with lower adipose tissue neutrophil and macrophage content. These changes are accompanied by improved glucose tolerance and increased insulin sensitivity. Taken together, we show that neutrophils can be added to the extensive repertoire of immune cells that participate in inflammation-induced metabolic disease. 10.1038/nm.2885
    Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor. Wortmann Saskia B,Van Hove Johan L K,Derks Terry G J,Chevalier Nathalie,Knight Vijaya,Koller Andreas,Oussoren Esmee,Mayr Johannes A,van Spronsen Francjan J,Lagler Florian B,Gaughan Sommer,Van Schaftingen Emile,Veiga-da-Cunha Maria Blood Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease type Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose cotransporter sodium glucose cotransporter 2 (SGLT2). Off-label use of empagliflozin in 4 GSD-Ib patients with incomplete response to granulocyte colony-stimulating factor (GCSF) treatment decreased serum 1,5AG and neutrophil 1,5AG6P levels within 1 month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in 2 patients and tapered by 57% and 81%, respectively, in the other 2. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further demonstrated improved neutrophil function: normal oxidative burst (in 3 of 3 patients tested), corrected protein glycosylation (2 of 2), and normal neutrophil chemotaxis (1 of 1), and bactericidal activity (1 of 1) under treatment. In summary, the glucose-lowering SGLT2 inhibitor empagliflozin, used for type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement in neutrophil function resulting from the reduction of the intracellular concentration of 1,5AG6P. 10.1182/blood.2019004465