Anti-Diabetic Agent Sodium Tungstate Induces the Secretion of Pro- and Anti-Inflammatory Cytokines by Human Kidney Cells.
Bertinat Romina,Westermeier Francisco,Silva Pamela,Shi Jie,Nualart Francisco,Li Xuhang,Yáñez Alejandro J
Journal of cellular physiology
Diabetic kidney disease (DKD) is the major cause of end stage renal disease. Sodium tungstate (NaW) exerts anti-diabetic and immunomodulatory activities in diabetic animal models. Here, we used primary cultures of renal proximal tubule epithelial cells derived from type-2-diabetic (D-RPTEC) and non-diabetic (N-RPTEC) subjects as in vitro models to study the effects of NaW on cytokine secretion, as these factors participate in intercellular regulation of inflammation, cell growth and death, differentiation, angiogenesis, development, and repair, all processes that are dysregulated during DKD. In basal conditions, D-RPTEC cells secreted higher levels of prototypical pro-inflammatory IL-6, IL-8, and MCP-1 than N-RPTEC cells, in agreement with their diabetic phenotype. Unexpectedly, NaW further induced IL-6, IL-8, and MCP-1 secretion in both N- and D-RPTEC, together with lower levels of IL-1 RA, IL-4, IL-10, and GM-CSF, suggesting that it may contribute to the extent of renal damage/repair during DKD. Besides, NaW induced the accumulation of IκBα, the main inhibitor protein of one major pathway involved in cytokine production, suggesting further anti-inflammatory effect in the long-term. A better understanding of the mechanisms involved in the interplay between the anti-diabetic and immunomodulatory properties of NaW will facilitate future studies about its clinical relevance. J. Cell. Physiol. 232: 355-362, 2017. © 2016 Wiley Periodicals, Inc.
Levels of cytokines and GADA in type I and II diabetic patients.
Amin Kawa,Qadr Shnyar Hamid,Hassan Hussein Ridha,Ali Kosar Muhammad,Rahman Heshu Sulaiman
Primary care diabetes
BACKGROUND:Diabetes Mellitus is described as a group of metabolic diseases in which the patient has higher blood glucose levels due to many causes. These include a defect in insulin secretion and failure of the body's cells to respond to the hormone. Cytokines and autoantibodies have a critical role in the pathogenesis of diabetes, especially type I. AIM OF THE STUDY:The aim of this study was to measure the serum levels of interleukin-1 beta (IL-1 β), interleukin-3 (IL-3), interferon-gamma (INF- γ), and glutamic acid decarboxylase autoantibody (GADA) in patients with type I and type II diabetes mellitus. MATERIAL AND METHODS:In this cross-sectional study, serum samples were taken from 250 individuals, including 100 samples from patients with type II diabetes mellitus, 100 samples from healthy controls, and 50 samples from patients with type I diabetes mellitus. Five milliliters of venous blood were taken from each individual and the samples were analyzed for cytokines (IL-1 β, IL-3, and INF- γ) and GABA using ELISA. RESULTS:In the study, we found that the serum levels of IL-1 β were significantly higher in the healthy control group compared to the patients with type I and type II diabetes mellitus. The levels of IL-3 and INF- γ were significantly higher in type II diabetes mellitus, while GABA serum levels were higher in type I diabetes mellitus. CONCLUSION:Our data showed that GADA is an important autoantibody, not only in type I but also in type II diabetes mellitus and can probably be used in the future for diagnosis of this disease. There was also a close association of GADA with systemic immunoregulation in type I and II diabetes mellitus. The relation of cytokines (IL-1 β, IL-3, and INF- γ) and GADA in patients with diabetes will also increase our understanding for the immunology of diabetes mellitus and to propose specific treatment on the basis of our findings. Our data also include correlation between age and the level of cytokines and GADA with different conclusion for each parameter.
Study of 27 Aqueous Humor Cytokines in Type 2 Diabetic Patients with or without Macular Edema.
Dong Ning,Xu Bing,Chu Liqun,Tang Xin
The aim of the present study was to compare the changes in the levels of 27 aqueous humor cytokines between diabetic patients with macular edema (ME) and diabetic patients without ME. Undiluted aqueous humor samples were obtained from 68 consecutive type 2 diabetic patients without ME and 56 consecutive type 2 diabetic patients with ME. The concentrations of 27 cytokines in the aqueous humor samples were measured using a multiplex bead immunoassay. Compared with diabetic patients without ME, diabetic patients with ME had significantly higher concentrations of IL-1β, IL-6, IL-8, IP-10, MCP-1, and VEGF in the aqueous humor. However, the concentrations of IL-10 and IL-12 were significantly lower in the diabetic patients with ME. The aqueous humor levels of IL-1β, IL-6, IL-8, MCP-1, IP-10, and VEGF were closely correlated with retinal macular thickness, retinal macular volume and the severity of ME. In addition, the aqueous humor levels of IL-10 and IL-12 decreased with increasing the severity of ME. A variety of cytokines associated with inflammation and angiogenesis may contribute to the pathogenesis of diabetic macular edema, and both anti-inflammatory and antiangiogenic agents should be included in the treatment of ME simultaneously.
Urinary inflammatory cytokines as indicators of kidney damage in type 2 diabetic patients.
Sangoi Manuela Borges,de Carvalho José Antonio M,Tatsch Etiane,Hausen Bruna S,Bollick Yãnaí S,Londero Sílvia W K,Duarte Thiago,Scolari Rogério,Duarte Marta M M F,Premaor Melissa O,Comim Fabio V,Moretto Maria B,Moresco Rafael N
Clinica chimica acta; international journal of clinical chemistry
BACKGROUND:The aim of this study was to investigate whether urinary levels of interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) are altered in normoalbuminuric patients with type 2 diabetes mellitus (T2DM), and whether these cytokines are able to identify diabetic kidney disease (DKD) among these patients. METHODS:This study included 125 T2DM patients classified into 3 groups according to urinary albumin/creatinine ratio (uACR): uACR <10mg/g creatinine, uACR 10-30mg/g creatinine and uACR >30mg/g creatinine. Urinary inflammatory cytokines were measured. RESULTS:The urinary IL-6 concentrations increased from uACR <10 (97.2±26.4pg/ml) to uACR 10-30 (113.6±28.0pg/ml) and to uACR >30mg/g creatinine (163.5±25.6pg/ml) (P<0.05 and P<0.001, respectively) patients. The urinary IL-10 concentrations decreased in these uACR ranges [100.0 (58.0-141.0) pg/ml vs. 62.0 (54.5-71.5) pg/ml vs. 42.0 (32.0-48.0) pg/ml] (P<0.05 and P<0.001, respectively). All urinary cytokines demonstrated good ability to identify DKD (areas under curves >0.9). CONCLUSIONS:Urinary inflammatory cytokines, especially IL-6 and IL-10, may assist in the identification of DKD in T2DM patients, even in the absence of micro- and macroalbuminuria.
Correlation analysis of urine proteins and inflammatory cytokines with osteoporosis in patients with diabetic nephropathy.
Journal of musculoskeletal & neuronal interactions
OBJECTIVES:To analyze the relationship of urine proteins and inflammatory cytokines with osteoporosis in patients with diabetic nephropathy. METHODS:76 patients with diabetic nephropathy in Xintai Affiliated Hospital of Taishan Medical University were selected and divided into the combination with osteoporosis group (n=28) and the non-combination with osteoporosis group (n=48). The general data of patients was collected, and T scores of lumbar vertebrae and hips of the patients were recorded. RESULTS:Duration of diabetes mellitus (DM) and levels of glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and fasting insulin (FINS) level, levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), level of 24h urine protein (24hndb) of patients in the combination with osteoporosis group was significantly higher, while the value of eGFR was lower than that of patients in the non-combination with osteoporosis group. The bone mineral densities (BMDs) and T scores of lumbar vertebrae and hips of patients in the combination with osteoporosis group were statistically significantly lower than those of patients in the non-combination with osteoporosis group. 24hndb, CRP, TNF-α and IL-6 were all negatively correlated with BMD. Duration of DM, FPG, HbA1c, FINS, 24hndb, BMD and inflammatory cytokines had independent predictive values for patients with diabetic nephropathy combined with osteoporosis. CONCLUSION:24hndb and inflammatory cytokines are closely related to the combination with osteoporosis in patients with diabetic nephropathy.
Concentrations of Selected Cytokines and Vascular Endothelial Growth Factor in Aqueous Humor and Serum of Diabetic Patients.
Cvitkovic Katarina,Sesar Antonio,Sesar Irena,Pusic-Sesar Anita,Pejic Renato,Kelava Tomislav,Sucur Alan,Cavar Ivan
Seminars in ophthalmology
: To investigate the aqueous humor and serum levels of selected cytokines and vascular endothelial growth factor (VEGF) in diabetic patients, implicating their role in the pathogenesis of diabetic eye complications.: Atotal of 65 patients (27 males and 38 females) who underwent cataract surgery were recruited into the study. The study group consisted of 30 cataract patients with type 2 diabetes mellitus, and this group was divided into two subgroups: 14 patients with diabetic retinopathy (DR group) and 16 patients without DR (NDR group). The control group consisted of 35 non-diabetic cataract subjects.: Patients in the DR group had significantly higher aqueous humor concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, monocyte chemotactic protein (MCP-1) and VEGF. Likewise, serum concentrations of IL-1β, IL-6, IL-8, IL-12, TNF-α and IFN-γ were significantly higher in the DR group as compared to the controls. Aqueous humor concentrations of IL-1β, IL-8, MCP-1 and VEGF were significantly higher in the DR group as compared with the NDR group.: Our findings support the hypothesis that chronic inflammation and a disturbance of the immune system play important roles in the pathogenesis of diabetic cataract and DR.
Swimming Impacts on Pancreatic Inflammatory Cytokines, miR-146a and NF-кB Expression Levels in Type-2 Diabetic Rats.
Alipour Mohammad Reza,Yousefzade Nasibeh,Bavil Fariba Mirzaei,Naderi Roya,Ghiasi Rafighe
Current diabetes reviews
BACKGROUND:Obesity-induced chronic inflammation is a key component in the pathogenesis of insulin resistance and type-2 diabetes Objective: This study aimed to evaluate the effect of swimming exercise on pancreatic expression levels of inflammatory cytokines, miR-146a and NF-кB in type-2 diabetic male rats. METHODS:Twenty- eight male Wistar rats were divided into four groups: control (Con), exercise, diabetes and diabetic exercise (n = 7). Diabetes induction performed by the combination of high-fat diet (HFD, 4 weeks) and streptozotocin (35 mg/kg. ip). After induction of diabetes, the rats swam in the exercise groups for 12 weeks. Then, blood and tissue samples were collected. RESULTS:Our results indicated a significant increase in expression levels of miR-146, NF-κB and inflammatory cytokines (IL-6, TNF-α, and IL-1β) while a significant decrease in pancreatic expression levels of TRAF6 and IRAK1 in diabetic group as compared to the control group. In contrast, swimming exercise resulted in a significant decrease in expression levels of miR-146a, NF-кB and inflammatory cytokines and a significant increase in expression levels of TRAF6 and IRAK1 in the exercise-diabetic group compared to the diabetic group. CONCLUSION:Our results indicated a significant increase in expression levels of miR-146, NF-κB and inflammatory cytokines (IL-6, TNF-α, and IL-1β) while a significant decrease in pancreatic expression levels of TRAF6 and IRAK1 in diabetic group as compared to the control group. In contrast, swimming exercise resulted in a significant decrease in expression levels of miR-146a, NF-кB and inflammatory cytokines and a significant increase in expression levels of TRAF6 and IRAK1 in the exercise-diabetic group compared to the diabetic group.
Deregulation of inflammatory response in the diabetic condition is associated with increased ischemic brain injury.
Kim Eunhee,Tolhurst Aaron T,Cho Sunghee
Journal of neuroinflammation
BACKGROUND:Although elicited inflammation contributes to tissue injury, a certain level of inflammation is necessary for subsequent tissue repair/remodeling. Diabetes, a chronic low-grade inflammatory state, is a predisposing risk factor for stroke. The condition is associated with delayed wound healing, presumably due to disrupted inflammatory responses. With inclusion of the diabetic condition in an experimental animal model of stroke, this study investigates whether the condition alters inflammatory response and influences stroke-induced brain injury. METHODS:C57BL/6 mice were fed a diabetic diet (DD) for 8 weeks to induce an experimental diabetic condition or a normal diet (ND) for the same duration. Gene expression of inflammatory factors including monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), CCR2, and CD36 was assessed in the peripheral immune cells and brains of normal and diabetic mice before and after focal cerebral ischemia. The expression of these factors was also determined in lipopolysaccharide (LPS)-treated cultured normal and diabetic macrophages. Ischemic outcome was assessed in these mice at 3 days post-ischemia. RESULTS:DD intervention in mice resulted in obesity and elevated insulin and glucose level in the blood. The peritoneal immune cells from the diabetic mice showed higher MCP-1 mRNA levels before and after stroke. Compared to normal mice, diabetic mice showed reduced MCP-1, IL-6, and CCR2 gene expression in the brain at 6 h post-ischemia. LPS-stimulated inflammatory responses were also reduced in the diabetic macrophages. The diabetic mice showed larger infarct size and percent swelling. CONCLUSIONS:These results showed that diabetic conditions deregulate acute inflammatory response and that the condition is associated with increased stroke-induced injury. The study suggests that interventions aimed at restoring appropriate inflammatory response in peripheral immune cells/macrophages may be beneficial in reducing stroke-induced brain injury in subjects with chronic inflammatory conditions.
Inflammatory cytokines in type 2 diabetes mellitus as facilitators of hypercoagulation and abnormal clot formation.
Randeria Shehan N,Thomson Greig J A,Nell Theo A,Roberts Timothy,Pretorius Etheresia
BACKGROUND:The global burden of type 2 diabetes mellitus (T2DM), together with the presence of cardiovascular risk in this population, is reaching pandemic levels. A prominent feature of T2DM is chronic and systemic inflammation, with the accompanying presence of circulating and dysregulated inflammatory biomarkers; which in turn is associated with abnormal clot formation. METHODS:Here, we investigate the correlation between abnormal blood clotting, using thromboelastography (TEG), clot ultrastructure using scanning electron microscopy (SEM) and the presence of a dysregulated inflammatory cytokine profile, by examining various circulating biomarkers. RESULTS:Our results show that many biomarkers, across TEG, cytokine and lipid groups, were greatly dysregulated in the T2DM sample. Furthermore, our T2DM sample's coagulation profiles were significantly more hypercoagulable when compared to our heathy sample, and ultrastructural analysis confirmed a matted and denser clot structure in the T2DM sample. CONCLUSIONS:We suggest that dysregulated circulating molecules may in part be responsible for a hypercoagulable state and vascular dysfunction in the T2DM sample. We propose further that a personalized approach could be of great value when planning treatment and tracking the patient health status after embarking on a treatment regimes, and that looking to novel inflammatory and vascular biomarkers might be crucial.
β-Caryophyllene, a natural sesquiterpene lactone attenuates hyperglycemia mediated oxidative and inflammatory stress in experimental diabetic rats.
Basha Rafeek Hidhayath,Sankaranarayanan Chandrasekaran
Oxidative and inflammatory stress has been implicated in the onset and progression of diabetes mellitus and its complications. The present study was designed to evaluate the effect of β-Caryophyllene (BCP) on hyperglycemia mediated oxidative and inflammatory stress in streptozotocin (STZ) induced diabetic rats. Diabetes was induced in experimental rats by a single intraperitoneal injection of STZ (40 mg/kg b.w.) dissolved in 0.1 M citrate buffer (pH 4.5). Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. The activities of antioxidant enzymes and the levels of non-enzymic antioxidants were decreased while increases in the levels of lipidperoxidative markers, protein carbonyls and conjugated dienes were observed in pancreatic tissues of diabetic rats. An elevation of proinflammatory cytokines tumor necrosis factor-α and interleukin-6 were observed in plasma and pancreatic tissues of diabetic rats. Intragastric administration of BCP (200 mg/kg b.w) for 45 days significantly decreased glucose and increased insulin levels in diabetic rats. BCP administration significantly restored antioxidant status and decreased proinflammatory cytokines in diabetic rats. These findings were supported by histological and immunohistochemical studies. Thus, we conclude that oral administration of BCP effectively rescued β-cells by mitigating hyperglycemia through enhancing insulin release and also averted oxidative/inflammatory stress in pancreatic tissue of diabetic rats. The efficacy of BCP was compared with glibenclamide, a standard antidiabetic drug.
Expert Group Consensus Opinion: Role of Anti-inflammatory Agents in the Management of Type-2 Diabetes (T2D).
Das A K,Kalra S,Tiwaskar M,Bajaj S,Seshadri K,Chowdhury S,Sahay R,Indurkar S,Unnikrishnan A G,Phadke U,Pareek A,Purkait I
The Journal of the Association of Physicians of India
Diabetes is a major public health emergency of the 21st century. Results of the Indian Council of Medical Research-INdia DIABetes (ICMR-INDIAB) study have found prevalence of diabetes and prediabetes in India to be as high as 7.3% and 10.3%, respectively with nation-wide projection of 77.2 million people with prediabetes and 69.2 million with diabetes. It is well established that insulin resistance (IR) and islet β-cell failure are the two major features of T2D Multiple mechanisms including glucotoxicity, lipotoxicity, oxidative stress, endoplasmic reticulum stress, formation of amyloid deposits in the islets, etc. have been hypothesized to participate in the pathology of the disease. In the concluding decade of the last century, numerous studies - prospective and cross-sectional, have confirmed the role of chronic low-grade inflammation as a pathogenetic factor of T2D. It has been shown that increased levels of various inflammatory markers and mediators including fundamental markers like white blood cell count, C-reactive protein (CRP) to the more specific circulating cytokines like, interleukin-6 (IL-6), IL-1β, plasminogen activator inhibitor-1 (PAI-1), etc. correlate with incident T2D. Based on the robust evidence implying the role of inflammation in T2D pathogenesis, several studies have proven that the proinflammatory cytokines play a central role in the development of microvascular diabetic complications such as nephropathy, retinopathy, and neuropathy. Inflammation in T2D causes accelerated atherosclerosis which predisposes to CVD, the leading cause of mortality in these patients. Recently there is a considerable increase in the interest among the researchers about anti-inflammatory therapies in the setting of chronic disorders such as T2D and CV diseases. In a multi-country study conducted in Asia, approximately 50% of Indian respondents had poor diabetes control. Most patients initially respond to sulfonylurea and/or metformin, and later these agents lose their effectiveness with time. Therapeutic option in patients uncontrolled on two-drug combination therapy is either to add third oral drug or insulin. However, use of insulin is limited due to its high cost and poor compliance. Majority of new treatment options like GLP1 agonists, insulin analogs and SGLT2 inhibitors are costly considering they are still under patent. The thiazolidinedione class of drugs is associated with adverse effects like fluid retention and weight gain that may result in or exacerbate edema and congestive heart failure. Thus there is a need for a safe and inexpensive treatment option for the management of uncontrolled T2D. Considering the role of inflammation in T2D pathogenesis, the drug should not only have antihyperglycemic effects but also reduce inflammatory burden thus reducing the progression and complications of T2D. The current interest is apparently directed towards drugs targeting inflammation acting at different stages of the inflammatory cascade. In the recently published CANTOS study, canakinumab, a selective, high-affinity, fully human monoclonal antibody which inhibits IL-1β, has no consistent long-term benefits on HbA1c. Other selective inhibitors like anakinra (IL-1 receptor antagonist) and etanercept (TNF inhibitor) too have yielded modest effects on glycemic parameters and insulin sensitivity. However, hydroxychloroquine (HCQ), a broad anti-inflammatory agent has been shown to reduce HbA1c by 0.87%. Hydroxychloroquine (HCQ) is considered as one of the safest disease modifying anti-rheumatic drug, used widely for the treatment of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The effect of HCQ in preventing development of diabetes in patients with chronic inflammatory diseases was highlighted in a prospective observational study of 4905 adults with rheumatoid arthritis and no diabetes with 21.5 years of follow-up. Patients who took HCQ for more than 4 years had a significant 77% lower risk of diabetes compared with non users of HCQ (RR, 0.23; 95% CI, 0.11-0.50). Taking cue from this study highlighting the anti-diabetic effect of HCQ, pioneering research studies evaluating these effects of HCQ were conducted in India. In 2014, hydroxychloroquine 400 mg got DCGI approval as an adjunct to diet and exercise to improve glycemic control of patients on metformin, sulfonylurea combination in Type 2 diabetes.
Pro-inflammatory cytokines are associated with podocyte damage and proximal tubular dysfunction in the early stage of diabetic kidney disease in type 2 diabetes mellitus patients.
Milas Oana,Gadalean Florica,Vlad Adrian,Dumitrascu Victor,Velciov Silvia,Gluhovschi Cristina,Bob Flaviu,Popescu Roxana,Ursoniu Sorin,Jianu Dragos Catalin,Matusz Petru,Pusztai Agneta-Maria,Secara Alina,Simulescu Anca,Stefan Maria,Patruica Mihaela,Petrica Flaviu,Vlad Daliborca,Petrica Ligia
Journal of diabetes and its complications
AIMS:To evaluate if there is a link between inflammation (expressed by inflammatory cytokines) and the early stage of diabetic kidney disease (DKD), as shown by markers of podocyte damage and proximal tubular (PT) dysfunction. METHODS:In this study were enrolled 117 type 2 DM patients (36-normoalbuminuria, 42-microalbuminuria, 39- macroalbuminuria), and 11 healthy subjects. Serum and urinary IL-1 alpha, IL-8, IL-18, urinary albumin:creatinine ratio (UACR), eGFR, biomarkers of podocyte damage (podocalyxin, synaptopodin, nephrin) and of PT dysfunction (KIM-1, NAG) were assessed. RESULTS:In multivariable regression urinary Il-1 alpha correlated positively with podocalyxin and NAG (p < 0.0001, R= 0.57); urinary IL-8 correlated directly with synaptopodin, NAG, nephrin, and KIM-1 (p < 0.0001, R = 0.67); urinary IL-18 correlated directly with synaptopodin, NAG, and nephrin (p < 0.0001, R = 0.59). Serum IL-1 alpha correlated positively with nephrin, synaptopodin, NAG (P < 0.0001, R = 0.68); serum IL-8 correlated directly with synaptopodin and NAG (p < 0.0001, R = 0.66); serum IL-18 correlated directly with NAG, KIM-1, and podocalyxin (p < 0.0001, R=0.647). CONCLUSIONS:Pro-inflammatory interleukins are associated with podocyte injury and PT dysfunction in early DKD. These could exert a key role in the pathogenesis of early DKD, before the development of albuminuria.
[The role of inflammation in the pathogenesis of late diabetic complications].
Chronic inflammation plays an important role in the development of diabetes and its late complications. Over nutrition, physical inactivity, stress, truncal obesity, dyslipidaemia, hypertension and smoking directly and indirectly activate the family of nuclear factor kappa B, the principal factor of inflammatory response. Hiperglycaemia and especially brittle diabetes affect not only metabolic abnormalities but also modulate cell and humoral immune response. There is good evidence that looking for novel risk factors for development and progression of late diabetic complications among inflammatory markers are needed. Progress in the study on etiopathogenesis of micro- and macro-angiopathy have clinical implications.
Oxidative stress and inflammatory markers in type 2 diabetic patients.
Malik Aastha,Morya Rajesh Kumar,Saha Sarama,Singh Praveen Kumar,Bhadada Sanjay Kumar,Rana Satya Vati
European journal of clinical investigation
BACKGROUND:Type 2 diabetes mellitus (T2DM) is most demanding public health problem of 21st century. Uncontrolled diabetes may cause complications affecting any part of gut from mouth to rectum presenting as vomiting, nausea, bloating, abdominal pain, constipation and diarrhoea. The aim of this study was to compare levels of oxidative stress and inflammatory markers in small intestinal bacterial overgrowth (SIBO)-positive and negative diabetic patients. SUBJECTS AND METHODS:An observational analytical study was conducted on 300 T2DM (>5 years' duration) attending Diabetic Clinic. A total of 200 age- and sex-matched healthy individuals were enrolled as controls. Noninvasive glucose hydrogen breath test was used to diagnose SIBO. A total of 5 mL blood was taken. Plasma was used for measurement of inflammatory cytokines (TNF-α, IL-6 and IL-10) by ELISA. Hemolysate was used for measurement of lipid peroxidation, reduced GSH, superoxide dismutase and catalase. RESULTS:It was observed that constipation was present in 59.6% T2DM patients. SIBO was observed significantly higher (P < .0001) in T2DM patients than controls. Inflammatory and oxidative stress markers were significantly (P < .001) higher in diabetic and SIBO-positive patients than controls and SIBO negative. Reduced GSH was significantly (P < .05) lower whereas superoxide dismutase (SOD) and catalase antioxidant enzymes were significantly (<.05) higher in diabetic and SIBO-positive patients than controls and SIBO-negative patients. CONCLUSION:From this study, it could be concluded that SIBO in T2DM patients can cause oxidative stress and inflammation. Therefore, SIBO should be taken care to prevent further damage to intestine.
The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus.
Har R,Scholey J W,Daneman D,Mahmud F H,Dekker R,Lai V,Elia Y,Fritzler M L,Sochett E B,Reich H N,Cherney D Z I
AIMS/HYPOTHESIS:High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus. METHODS:Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFRINULIN] ≥ 135 ml min⁻¹ 1.73 m⁻², n = 28) or normofiltration (n = 21) and healthy control individuals (n = 18). RESULTS:Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165 ± 9 vs 113 ± 2 and 116 ± 4 ml min⁻¹ 1.73 m⁻², respectively, p < 0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p < 0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophage-derived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colony-stimulating factor (p ≤ 0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p < 0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p < 0.01). CONCLUSIONS/INTERPRETATION:Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.
Oxidative Stress and NLRP3-Inflammasome Activity as Significant Drivers of Diabetic Cardiovascular Complications: Therapeutic Implications.
Sharma Arpeeta,Tate Mitchel,Mathew Geetha,Vince James E,Ritchie Rebecca H,de Haan Judy B
Frontiers in physiology
It is now increasingly appreciated that inflammation is not limited to the control of pathogens by the host, but rather that sterile inflammation which occurs in the absence of viral or bacterial pathogens, accompanies numerous disease states, none more so than the complications that arise as a result of hyperglycaemia. Individuals with type 1 or type 2 diabetes mellitus (T1D, T2D) are at increased risk of developing cardiac and vascular complications. Glucose and blood pressure lowering therapies have not stopped the advance of these morbidities that often lead to fatal heart attacks and/or stroke. A unifying mechanism of hyperglycemia-induced cellular damage was initially proposed to link elevated blood glucose levels with oxidative stress and the dysregulation of metabolic pathways. Pre-clinical evidence has, in most cases, supported this notion. However, therapeutic strategies to lessen oxidative stress in clinical trials has not proved efficacious, most likely due to indiscriminate targeting by antioxidants such as vitamins. Recent evidence now suggests that oxidative stress is a major driver of inflammation and vice versa, with the latest findings suggesting not only a key role for inflammatory pathways underpinning metabolic and haemodynamic dysfunction in diabetes, but furthermore that these perturbations are driven by activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. This review will address these latest findings with an aim of highlighting the interconnectivity between oxidative stress, NLRP3 activation and inflammation as it pertains to cardiac and vascular injury sustained by diabetes. Current therapeutic strategies to lessen both oxidative stress and inflammation will be emphasized. This will be placed in the context of improving the burden of these diabetic complications.
The Inflammasome in Chronic Complications of Diabetes and Related Metabolic Disorders.
Menini Stefano,Iacobini Carla,Vitale Martina,Pugliese Giuseppe
Diabetes mellitus (DM) ranks seventh as a cause of death worldwide. Chronic complications, including cardiovascular, renal, and eye disease, as well as DM-associated non-alcoholic fatty liver disease (NAFLD) account for most of the morbidity and premature mortality in DM. Despite continuous improvements in the management of late complications of DM, significant gaps remain. Therefore, searching for additional strategies to prevent these serious DM-related conditions is of the utmost importance. DM is characterized by a state of low-grade chronic inflammation, which is critical in the progression of complications. Recent clinical trials indicate that targeting the prototypic pro-inflammatory cytokine interleukin-1β (IL-1 β) improves the outcomes of cardiovascular disease, which is the first cause of death in DM patients. Together with IL-18, IL-1β is processed and secreted by the inflammasomes, a class of multiprotein complexes that coordinate inflammatory responses. Several DM-related metabolic factors, including reactive oxygen species, glyco/lipoxidation end products, and cholesterol crystals, have been involved in the pathogenesis of diabetic kidney disease, and diabetic retinopathy, and in the promoting effect of DM on the onset and progression of atherosclerosis and NAFLD. These metabolic factors are also well-established danger signals capable of regulating inflammasome activity. In addition to presenting the current state of knowledge, this review discusses how the mechanistic understanding of inflammasome regulation by metabolic danger signals may hopefully lead to novel therapeutic strategies targeting inflammation for a more effective treatment of diabetic complications.
Oxidative DNA damage is associated with inflammatory response, insulin resistance and microvascular complications in type 2 diabetes.
Tatsch Etiane,De Carvalho José A M,Hausen Bruna S,Bollick Yãnaí S,Torbitz Vanessa D,Duarte Thiago,Scolari Rogério,Duarte Marta M M F,Londero Sílvia W K,Vaucher Rodrigo A,Premaor Melissa O,Comim Fabio V,Moresco Rafael N
Urinary markers of nucleic acid oxidation may be useful biomarkers in diabetes. It has been demonstrated that T2DM patients have an increased level of oxidative DNA damage; however, it is unclear whether increased DNA damage may be related to a greater degree of inflammation and insulin resistance. Thus, the aim of this present study was to investigate the relation of the impact of oxidative DNA damage, assessed by urinary 8-OHdG, on the levels of inflammatory cytokines, as well as insulin resistance. In addition, we also investigated the diagnostic ability of urinary 8-OHdG in the identification of microvascular complications in T2DM.A case-control study, enrolling 22 healthy controls and 54 subjects with T2DM, was performed to evaluate the relation between oxidative DNA damage and interleukin-6 (IL-6), IL-1,tumor necrosis factor-alpha (TNF-α), IL-10, and Homeostasis Model Assessment (HOMA-IR) index. T2DM patients presented higher urinary 8-OHdG, IL-6, IL-1, TNF-α levels and HOMA-IR, and lower IL-10 levels than control subjects. Moreover, urinary 8-OHdG levels were significantly higher in the group T2DM with microvascular complications when compared to the without complications. The areas under the curve for urinary 8-OHdG and urinary albumin were, respectively, 0.836 (P<0.001) and 0.786 (P=0.002). Thus, urinary 8-OHdG has a slightly higher ability to discriminate microvascular complications in T2DM compared with urinary albumin. It was also demonstrated that T2DM patients with higher median of urinary 8-OHdG had significantly elevated levels of IL-6, TNF-α and HOMA-IR, and decreased IL-10 levels. Our findings showed that T2DM patients with higher urinary 8-OHdG levels showed a greater inflammatory degree and higher insulin resistance. It is possible to speculate that T2DM patients present a cascade of events as increasing metabolic abnormalities such as insulin resistance and inflammatory activation, as well as increased ROS generation factors that may contribute directly to greater oxidative DNA damage.
Role of Oxidative Stress and Inflammatory Factors in Diabetic Kidney Disease.
Aghadavod Esmat,Khodadadi Samaneh,Baradaran Azar,Nasri Parto,Bahmani Mahmood,Rafieian-Kopaei Mahmoud
Iranian journal of kidney diseases
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus, and its prevalence has been increasing in developed countries. Diabetic nephropathy has become the most common single cause of end-stage renal disease worldwide. Oxidative stress and inflammation factors are hypothesized to play a role in the development of late diabetes complications. Chronic hyperglycemia increases oxidative stress, significantly modifies the structure and function of proteins and lipids, and induces glycoxidation and peroxidation. Therefore, hyperglycemia causes auto-oxidation of glucose, glycation of proteins, and activation of polyol mechanism. Overproduction of intracellular reactive oxygen species contributes to several microvascular and macrovascular complications of DN. On the other hand, reactive oxygen species modulates signaling cascade of immune factors. An increase in reactive oxygen species can increase the production of inflammatory cytokines, and likewise, an increase in inflammatory cytokines can stimulate the production of free radicals. Some studies have shown that kidney inflammation is serious in promoting the development and progression of DN. Inflammatory factors which are activated by the metabolic, biochemical, and hemodynamic derangements are known to exist in the diabetic kidney. This review discusses facts for oxidative stress and inflammatory factors in DN and encompasses the role of immune and inflammatory cells, inflammatory cytokines, and stress oxidative factors.
The association of oxidative stress and pro-inflammatory cytokines in diabetic patients with hyperglycemic crisis.
Li Juan,Huang Minglian,Shen Xingping
Journal of diabetes and its complications
AIMS:To investigate the relationship between oxidative stress and serum levels of pro-inflammatory cytokines in diabetic patients with hyperglycemic crisis. METHODS:Seventy-three patients presenting to hospital with diabetic ketoacidosis or non-ketotic hyperglycemia were studied. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, total antioxidant capacity (TAC), 8-iso-prostaglandin F2α (8-iso-prostaglandinF2α, 8-iso-PGF2α), tumor necrosis factor receptor-I (TNF-RI), interleukin -1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were measured in all patients. The patients were then given an intravenous infusion of insulin 0.1U • kg-1 • h-1, as well as fluids, symptomatic therapy and parenteral and intravenous nutrition. RESULTS CONCLUSION:Patients with hyperglycemic crises have significantly increased oxidative stress and dysregulated serum pro-inflammatory cytokines that can be effectively treated by intensive insulin therapy.
Natural Phyto-Bioactive Compounds for the Treatment of Type 2 Diabetes: Inflammation as a Target.
Gothai Sivapragasam,Ganesan Palanivel,Park Shin-Young,Fakurazi Sharida,Choi Dong-Kug,Arulselvan Palanisamy
Diabetes is a metabolic, endocrine disorder which is characterized by hyperglycemia and glucose intolerance due to insulin resistance. Extensive research has confirmed that inflammation is closely involved in the pathogenesis of diabetes and its complications. Patients with diabetes display typical features of an inflammatory process characterized by the presence of cytokines, immune cell infiltration, impaired function and tissue destruction. Numerous anti-diabetic drugs are often prescribed to diabetic patients, to reduce the risk of diabetes through modulation of inflammation. However, those anti-diabetic drugs are often not successful as a result of side effects; therefore, researchers are searching for efficient natural therapeutic targets with less or no side effects. Natural products' derived bioactive molecules have been proven to improve insulin resistance and associated complications through suppression of inflammatory signaling pathways. In this review article, we described the extraction, isolation and identification of bioactive compounds and its molecular mechanisms in the prevention of diabetes associated complications.
Alteration of oxidative stress and inflammatory cytokines induces apoptosis in diabetic nephropathy.
Sha Jibin,Sui Bo,Su Xiaoqing,Meng Qingfang,Zhang Chenggang
Molecular medicine reports
Diabetic nephropathy (DN) is one of the most significant long‑term complications in terms of morbidity and mortality for diabetic patients; however, the exact cause remains unknown. To address this, the DN model was established, and oxidative stress indexes, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH‑Px), and inflammatory cytokines, includinginterleukin‑6 (IL‑6), tumor necrosis factor‑alpha (TNF‑α) and transforming growth factor‑beta (TGF‑β), were examined by ELISA. Renal pathological alterations and cell apoptosis was examined by hematoxylin and eosin and terminal deoxynucleotidyl transferase mediated dUTP nick‑end labeling staining, respectively. The expression levels of B‑cell lymphoma‑2 (Bcl‑2), Bcl‑2 associated X (Bax) and caspase‑3 wereexamined by immunohistochemistry and western blotting. The DN model was correctly established, with lower body weight and the higher blood glucose in the diabetes model group. The expression levels of SOD and GSH‑Px were significantly decreased in the diabetes model group; however, MDA, IL‑6, TNF‑α and TGF‑β were significantly increased. The kidney was severely damaged in the diabetes model group, with inflammatory cell invasion, increasing amount of interstitial matrix and hypertrophy with vacuolar degeneration of renal tubular cells. Cell apoptosis levels were significantly increased, and Bcl‑2 was significantly decreased in the diabetes model group in contrast with that of the sham group; however, Bax and caspase‑3 were significantly increased. It suggested that increased oxidative stress and inflammatory cytokines may enhance the apoptosis levels in DN, and may provide a significant diagnostic reference for DN in diabetes patients.
Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis.
Brennan Eoin P,Mohan Muthukumar,McClelland Aaron,de Gaetano Monica,Tikellis Christos,Marai Mariam,Crean Daniel,Dai Aozhi,Beuscart Ophelie,Derouiche Sinda,Gray Stephen P,Pickering Raelene,Tan Sih Min,Godson-Treacy Molly,Sheehan Stephen,Dowdall Joseph F,Barry Mary,Belton Orina,Ali-Shah Syed Tasadaque,Guiry Patrick J,Jandeleit-Dahm Karin,Cooper Mark E,Godson Catherine,Kantharidis Phillip
Increasing evidence points to the fact that defects in the resolution of inflammatory pathways predisposes individuals to the development of chronic inflammatory diseases, including diabetic complications such as accelerated atherosclerosis. The resolution of inflammation is dynamically regulated by the production of endogenous modulators of inflammation, including lipoxin A4 (LXA). Here, we explored the therapeutic potential of LXA and a synthetic LX analog (Benzo-LXA) to modulate diabetic complications in the streptozotocin-induced diabetic ApoE mouse and in human carotid plaque tissue ex vivo. The development of diabetes-induced aortic plaques and inflammatory responses of aortic tissue, including the expression of , , , and , was significantly attenuated by both LXA and Benzo-LXA in diabetic ApoE mice. Importantly, in mice with established atherosclerosis, treatment with LXs for a 6-week period, initiated 10 weeks after diabetes onset, led to a significant reduction in aortic arch plaque development (19.22 ± 2.01% [diabetic]; 12.67 ± 1.68% [diabetic + LXA]; 13.19 ± 1.97% [diabetic + Benzo-LXA]). Secretome profiling of human carotid plaque explants treated with LXs indicated changes to proinflammatory cytokine release, including tumor necrosis factor-α and interleukin-1β. LXs also inhibited platelet-derived growth factor-stimulated vascular smooth muscle cell proliferation and transmigration and endothelial cell inflammation. These data suggest that LXs may have therapeutic potential in the context of diabetes-associated vascular complications.
Extracellular vesicles participate in the transport of cytokines and angiogenic factors in diabetic patients with ocular complications.
Tokarz Aleksandra,Szuścik Iwona,Kuśnierz-Cabala Beata,Kapusta Maria,Konkolewska Magdalena,Żurakowski Aleksander,Georgescu Adriana,Stępień Ewa
Folia medica Cracoviensia
INTRODUCTION:Extracellular vesicles (EVs), including circulating microvesicles (MVs) or mi- croparticles (MPs) and exosomes, derived from cells or platelets are present in the peripheral blood and are important elements involved in the activation of the coagulation system, transport of macromolecules and intercellular communication. In patients with vascular complications (including diabetes), the number of EVs is significantly increased during the acute phase of the disease. However, less is known about EVs release in the chronic state of diabetes. OBJECTIVES:To analyse the profile of inflammatory cytokines and angiogenic factors in EVs in diabetic patients with ocular and vascular complications. PATIENTS AND METHODS:The study included patients with diabetes and varying degrees of ocular complications including retinopathy (n = 48) and the control group (n = 13). EV-enriched and EV-depleted fractions were obtained from platelet-poor plasma by means of the centrifugation method (16 000 g, for 90 min). In screening, the profile of cytokines with pro-angiogenic effects was preliminary assessed using the protein microarray technology for controlled diabetic patients - CD, uncontrolled diabetic patients - UD and for the control group. In all patients, concentrations of cytokines: RANTES (Regulated on Activation, Normal T-cell Expressed and secreted) and Ang-2 (angiopoietin-2) were assayed using the ELISA method. Common blood and biochemical tests were performed. RESULTS:In patients with diabetes, analysis of supernatant revealed significantly increased concentrations of basic fibroblast growth factor (bFGF) and soluble receptor for vascular endothelial growth factor 2 (V-EGFR2) when compared to the control group: 49 (10.5-122) vs. 24 (2-72.5) SD (p = 0.03) and 260 (195.5-351) vs. 360 (256-461.5) SD (p = 0.01). In UD patients, concentrations of RANTES, angiostatin, tumor necrosis factor-α (TNF), and tissue inhibitors of metalloproteinase 1 and 2 (TIMP1 and TIMP2) were relatively higher in the EV-enriched fraction when compared to the EV-depleted fraction. Post hoc analysis revealed significant differences between UC patients and the control group in RANTES (16.73 (14.41-18.93) vs. 14.62 (12.37-15.28) mg/ml; p = 0.0235) and Ang-2 (2.76 (2.23-4.64) ng/ml vs. 1.74 (1.54-1.93); p = 0.0316) concentrations. These analyses did not reveal any significant differences in RANTES and Ang-2 concentrations between CD patients and the control group. CONCLUSIONS:The profiles of cytokines and angiogenic factors in EVs are significantly increased in patients with diabetes. Also, the formation of specific cytokines related to EVs is strongly influenced by disease duration and successful treatment. EVs seem to be the conveyors of upregulated cytokines and angiogenic agents in diabetic patients.
Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression.
Hameed Iqra,Masoodi Shariq R,Malik Perveez A,Mir Shahnaz A,Ghazanfar Khalid,Ganai Bashir A
BACKGROUND:Diabetic nephropathy is the single strongest predictor of mortality in patients with diabetes. The development of overt nephropathy involves important inter-individual variations, even after adjusting for potential confounding influences of modifiable and non-modifiable risk factors. Genome-wide transcriptome studies have reported the activation of inflammatory signaling pathways and there is mounting indication of the role of genetic factors. METHODS:We screened nine genetic variations in three cytokine genes (TNF-α, IL-6 and IL-β) in 1326 unrelated subjects comprising of healthy controls (n = 464), type 2 diabetics with nephropathy (DN, n = 448) and type 2 diabetes without nephropathy (T2D, n = 414) by sequence-specific amplification. Functional implication of SNPs was elucidated by correlation studies and relative gene expression using Realtime-Quantitative PCR (RT-qPCR). RESULTS:Individual SNP analysis showed highest association of IL-1β rs16944-TT genotype (OR = 3.51, 95%CI = 2.36-5.21, P = 0.001) and TNF-α rs1800629-AA genotype (OR = 2.75, 95% CI = 1.64-4.59, P = 0.001) with T2D and DN respectively. The haplotype frequency showed significant risk of seven combinations among T2D and four combinations among DN subjects. The highest risk of T2D and DN was associated with GGTGAGTTT (OR = 4.25, 95%CI = 3.3-14.20, P = 0.0016) and GACGACCTT (OR = 21.3, 95%CI = 15.1-28.33, P = 0.026) haplotypes respectively. Relative expression by RT-qPCR showed increased cytokine expression in cases as compared to controls. TNF-α expression was increased by more than four-folds (n-fold = 4.43 ± 1.11) in DN. TNF-α, IL-6 and IL-1β transcript levels were significantly modulated by promoter region SNPs. CONCLUSIONS:The present study implicates a strong association between cytokine TNF-α, IL-6 and IL-1β gene promoter polymorphisms and modulation of transcript levels with susceptibility to nephropathy in diabetes subjects.
Mesenchymal Stem Cells Reverse Diabetic Nephropathy Disease via Lipoxin A4 by Targeting Transforming Growth Factor β (TGF-β)/smad Pathway and Pro-Inflammatory Cytokines.
Bai Yihua,Wang Jiaping,He Zhenkun,Yang Min,Li Luohua,Jiang Hongying
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Mesenchymal stem cells (MSCs) treatment has been proved to be effective in DN models by protecting renal function and preventing fibrosis. However, the underlying mechanism is unclear. Previous research indicated diabetes and associated complications may be attributed to failed resolution of inflammation, which is deliberately regulated by pro-resolving lipids, including lipoxins (LXs), resolvins (Rv) D and E series, protectins, and maresins. In this study, we monitored pro-resolving mediators in a DN model to explore the mechanism of MSCs treatment. MATERIAL AND METHODS The DN model was induced by STZ injection in SD rats. UPLC-MS/MS was performed to determine pro-resolving lipids in kidney tissue and serum of DN model before and after MSCs treatment, as well as in supernatants of HBZY-1-MSCs co-culture. RESULTS LXA4 was highly accumulated in renal tissue of DN rats with MSCs treatment; ex vivo, LXA4 was significantly increased in the supernatants of HBZY-1 cells co-cultured with MSCs in a high-glucose (HG) medium. Western blot analysis indicated that ALX/FPR2, the receptor of LXA4, was markedly expressed in renal tissue of the DN-MSC group and HBZY-1 after incubating with MSCs in HG. Intraperitoneal injection of LXA4 inhibited renal fibrosis by targeting TGF-ß/Smad signaling and downregulated serum TNF-alpha, IL-6, IL-8, and IFN-γ in DN rats. Notably, all the protective effects induced by MSCs or LXA4 were abolished by ALX/FRP2 blocking. CONCLUSIONS Our results demonstrate that MSCs intervention prevented DN procession via the LXA4-ALX/FPR2 axis, which inhibited glomerulosclerosis and pro-inflammatory cytokines, eventually contributing to kidney homeostasis.
Alterations in monocyte CD16 in association with diabetes complications.
Min Danqing,Brooks Belinda,Wong Jencia,Salomon Robert,Bao Wensheng,Harrisberg Brian,Twigg Stephen M,Yue Dennis K,McLennan Susan V
Mediators of inflammation
Monocytes express many cell surface markers indicative of their inflammatory and activation status. Whether these markers are affected by diabetes and its complications is not known and was investigated in this study. Blood was obtained from 22 nondiabetic and 43 diabetic subjects with a duration of diabetes >10 years, including 25 without and 18 with clinically significant complications. The number of CD45(+)CD14(+) monocytes and the percentage expressing the proinflammatory marker CD16 were determined by flow cytometry. Other markers of monocyte activation and expression of chemokine receptors were also examined. The relationship between monocyte CD16 and clinical data, selected cytokines, and chemokines was also investigated. Diabetes had no effect on total white cell number but increased monocyte number. Diabetes also significantly decreased the number of CD16(+) monocytes but only in those with diabetic complications. Other markers of monocyte activation status and chemokine receptors were not affected by diabetes or complications status. Diabetes induced plasma proinflammatory cytokines and they were lower in diabetic subjects with complications compared to those without complications. These results suggest that the circulating monocyte phenotype is altered by diabetic complications status. These changes may be causally related to and could potentially be used to predict susceptibility to diabetic complications.
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
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.
The effects of adiponectin and inflammatory cytokines on diabetic vascular complications in obese and non-obese patients with type 2 diabetes mellitus.
Hong Seong Bin,Lee Jung Jin,Kim So Hun,Suh Young Ju,Han Ju Young,Kim Yong Seong,Nam Moonsuk
Diabetes research and clinical practice
AIMS:To evaluate the associations between inflammatory cytokines and adiponectin and various vascular complications in type 2 diabetes mellitus (T2DM). METHODS:A total of 761 patients with T2DM were divided into a non-obese group and an obese group to enable the effects of obesity and T2DM on vascular complications to be differentiated. The serum levels of circulating inflammatory cytokines, that is, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, total adiponectin, and high molecular weight (HMW) adiponectin were measured, and carotid intima media thickness (IMT), the presence of carotid plaque, and the severities of retinopathy and nephropathy, were assessed. RESULTS:The obese group had significantly lower serum total and HMW adiponectin levels than the non-obese group. In the obese group, serum levels of total and HMW adiponectin, and TNF-α were significantly higher in patients with proliferative retinopathy than in those without retinopathy after adjusting for covariates. In the non-obese group, only IL-6 levels were significantly higher in patients with proliferative retinopathy than in those without. Serum levels of total and HMW adiponectin were significantly higher in patients with macroalbuminuria than in those with normoalbuminuria. No significant difference of three cytokines levels were observed depending on the carotid IMT or the presence of plaque. Logistic regression analysis revealed that serum total adiponectin (OR=1.209, P=0.038), diabetes duration (OR=1.230, P=0.014), and HbA1c (OR=2.359, P=0.006) were significantly associated with proliferative retinopathy in the obese group. CONCLUSION:The study shows total adiponectin may influence proliferative retinopathy in obese patient with T2DM.
Inflammasome as a New Therapeutic Target for Diabetic Complications.
Volpe Caroline M O,Anjos Paula M F,Nogueira-Machado José A
Recent patents on endocrine, metabolic & immune drug discovery
BACKGROUND:Inflammation is an innate immune response which is considered a common basis for several diseases such as ageing, diabetes, obesity, gout, neurodegenerative diseases and others. Among other platforms, inflammasomes are part of a superfamily of Pattern Recognition Receptors (PRR) and act as cytoplasmatic sensors for stimulation with Pathogen Associated Molecular Pattern (PAMPs) and/or Danger/Damage-Associated Molecular Patterns (DAMPs) leading to an infectious/ pathogenic or sterile inflammation. Inflammasomes constitute a complex platform with high molecular weight and functionality, divided into two families: NOD-like or NLR and PYHIN (pyrin and HIN200 - hematopoietic interferoninducible nuclear antigens). After activation by PAMPs or DAMPs, NLRP3 inflammasome promotes conversion of procaspase 1 in caspase-1 to form the active complex which is able to cleave pro-IL-1β and pro-IL-18 in respective active inflammatory cytokines IL-1β and IL-18 inducing cellular death by pyroptosis. Diabetes has a very intricate pathology with metabolic adaptation and inflammatory components apparently responsible for diabetic complications. OBJECTIVE:The present review evaluates the role of inflammasome, emphasizing NRLP3 on diabetes. An overview on several inflammatory diseases in which inflammasomes appear to play a role is included. Patents on inflammasomes associated with diabetes are evaluated and discussed. CONCLUSION:There are a significant number of patents on inflammation but few of them are specifically on inflammasome and diabetes. The patents WO2015003246; US20130273588; WO2012016145; and CN104258398 are shown and their mechanisms are discussed. In conclusion, deeply studies on inflammasomes mechanisms will help the proposition of new therapeutic targets for controlling inflammatory process in diabetic complications.
Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment.
Li Yuanmin,Liu Jingping,Liao Guangneng,Zhang Jie,Chen Younan,Li Lan,Li Li,Liu Fang,Chen Bo,Guo Gang,Wang Chengshi,Yang Lichuan,Cheng Jingqiu,Lu Yangrong
International journal of molecular medicine
Diabetic nephropathy (DN) is a major complication of diabetes and represents the leading cause of end-stage renal disease. Mesenchymal stem cell (MSC) treatment has been demonstrated to be effective in DN models by reducing albuminuria and attenuating glomerular injury; however, limited in-depth understanding of the underlying mechanism and a lack of clinical trials hinders its clinical use. Additionally, most of these experimental studies were conducted on the advanced stage of nephropathy, which is difficult to reverse and consequently showed limited therapeutic efficacy. We sought to evaluate whether early intervention by MSCs has the potential to prevent DN onset and progression as well as protect kidney function when intravenously administered to rats with diabetes. Diabetes was induced in adult male SD rats by streptozotocin (STZ) injection (55 mg/kg, i.p.). The diabetic rats were injected with or without bone marrow-derived MSCs (5x106 per rat), via tail vein at 2, 4, 5 and 7 weeks after diabetes onset. Fasting blood glucose (FBG), blood urea nitrogen (BUN) and serum creatinine (Scr) levels in serum samples and glycosuria (GLU), microalbumin (MAU), and albumin to creatinine ratio (ACR) in urine samples were determined. Renal pathology and immunohistochemistry (IHC) for CD68, MCP-1, fibronectin (FN), transforming growth factor-β (TGF-β) and pro-inflammatory cytokines were also performed. Expression levels of the above factors as well as interleukin-10 (IL-10), and epidermal growth factor (EGF) were assessed by qPCR and multiplex bead-based suspension array system, respectively. Additionally, MSC tracing in vivo was performed. Ex vivo, peritoneal macrophages were co-cultured with MSCs, and expression of inflammatory cytokines was detected as well. MSC treatment profoundly suppressed renal macrophage infiltration and inflammatory cytokine secretion in diabetic rats, resulting in prominently improved kidney histology, systemic homeostasis, and animal survival, although no significant effect on hyperglycemia was observed. Engrafted MSCs were primarily localized in deteriorated areas of the kidney and immune organs 48 h after infusion. MSC treatment upregulated serum anti-inflammatory cytokines IL-10 and EGF. Ex vivo, MSCs inhibited lipopolysaccharide (LPS)-stimulated rat peritoneal macrophage activation via the downregulation of inflammatory-related cytokines such as IL-6, MCP-1, tumor necrosis factor-α (TNF-α) and IL-1β. Our results demonstrated that early intervention with MSCs prevented renal injury via immune regulation in diabetic rats, which restored the homeostasis of the immune microenvironment, contributing to the prevention of kidney dysfunction and glomerulosclerosis.
Inflammatory cytokines in diabetic nephropathy.
Donate-Correa Javier,Martín-Núñez Ernesto,Muros-de-Fuentes Mercedes,Mora-Fernández Carmen,Navarro-González Juan F
Journal of diabetes research
Probably, the most paradigmatic example of diabetic complication is diabetic nephropathy, which is the largest single cause of end-stage renal disease and a medical catastrophe of worldwide dimensions. Metabolic and hemodynamic alterations have been considered as the classical factors involved in the development of renal injury in patients with diabetes mellitus. However, the exact pathogenic mechanisms and the molecular events of diabetic nephropathy remain incompletely understood. Nowadays, there are convincing data that relate the diabetes inflammatory component with the development of renal disease. This review is focused on the inflammatory processes that develop diabetic nephropathy and on the new therapeutic approaches with anti-inflammatory effects for the treatment of chronic kidney disease in the setting of diabetic nephropathy.
Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism.
Liang Guang,Song Lintao,Chen Zilu,Qian Yuanyuan,Xie Junjun,Zhao Longwei,Lin Qian,Zhu Guanghui,Tan Yi,Li Xiaokun,Mohammadi Moosa,Huang Zhifeng
Inflammation plays a central role in the etiology of diabetic nephropathy, a global health issue. We observed a significant reduction in the renal expression of fibroblast growth factor 1, a known mitogen and insulin sensitizer, in patients with diabetic nephropathy and in mouse models implying that fibroblast growth factor 1 possesses beneficial anti-inflammatory and renoprotective activities in vivo. To test this possibility, we investigated the effects of chronic intraperitoneal administration of fibroblast growth factor 1 into both the streptozotocin-induced type 1 diabetes and db/db type 2 diabetes models. Indeed, recombinant fibroblast growth factor 1 significantly suppressed renal inflammation (i.e., cytokines, macrophage infiltration), glomerular and tubular damage, and renal dysfunction in both type 1 and type 2 diabetes mice. Fibroblast growth factor 1 was able to correct the elevated blood glucose levels in type 2 but not in type 1 diabetic mice, suggesting that the anti-inflammatory effect of fibroblast growth factor 1 was independent of its glucose-lowering activity. The mechanistic study demonstrated that fibroblast growth factor 1-mediated inhibition of the renal inflammation in vivo was accompanied by attenuation of the nuclear factor κB and c-Jun N-terminal kinase signaling pathways, further validated in vitro using cultured glomerular mesangial cells and podocytes. Thus, fibroblast growth factor 1 holds great promise for developing new treatments for diabetic nephropathy through countering inflammatory signaling cascades in injured renal tissue.
The role of inflammatory cytokines in diabetes and its complications.
King George L
Journal of periodontology
The prevalence of diabetes worldwide is increasing rapidly in association with the increase in obesity. Complications are a major fear of patients with diabetes. Complications of diabetes affect many tissues and organs, causing retinopathy, nephropathy, neuropathy, cardiovascular diseases, peripheral vascular diseases, stroke, and periodontal pathologies. Immunologic abnormalities are associated with type 1 and type 2 diabetes and diabetic complications. T cell abnormalities are believed to be the major cause of autoimmune disease in type 1 diabetes, leading to the destruction of pancreatic islets. In type 2 diabetes, inflammation and activation of monocytes are postulated to be important for enhancing insulin resistance and may contribute to the loss of insulin secretory function by islet cells. Many factors can enhance insulin resistance, including genetics, a sedentary lifestyle, obesity, and other conditions, such as chronic inflammation or infection. Increases in inflammation, such as activation of monocytes and increased levels of inflammatory markers, e.g., C-reactive protein, plasminogen activator inhibitor-1, and other cytokines, were reported in insulin-resistant states without diabetes. One possible mechanism is that abnormal levels of metabolites, such as lipids, fatty acids, and various cytokines from the adipose tissue, activate monocytes and increase the secretion of inflammatory cytokines, enhancing insulin resistance. According to this model, obesity activates monocytes and enhances insulin resistance, increasing the risk for type 2 diabetes. Abnormalities in innate immunity might also participate in the development of diabetic complications. In general, hyperglycemia is the main initiator of diabetic retinopathy, nephropathy, and neuropathy, and it participates in the development of diabetic cardiovascular diseases. Although the precise role of inflammation in the development of diabetic microvascular diseases is still unclear, it is likely that inflammation induced by diabetes and insulin resistance can accelerate atherosclerosis in patients with diabetes. Also, it was shown that conditions with an inflammatory basis, such as obesity and type 2 diabetes, can contribute to periodontal disease, suggesting that periodontal abnormalities may be partly influenced by inflammatory changes. Further research is required to confirm the role of inflammation and the onset of diabetes, microvascular diseases, and periodontal pathologies.
The prognostic value of inflammatory and vascular endothelial dysfunction biomarkers in microvascular and macrovascular complications in type 1 diabetes.
Wołoszyn-Durkiewicz Anna,Myśliwiec Małgorzata
Pediatric endocrinology, diabetes, and metabolism
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterised by a destruction of pancreatic cells, which leads to absolute insulin deficiency. Persistently high glycaemia causes vascular damage throughout the body. Microvascular complications com-prise the following: nephropathy, retinopathy, and neuropathy. Macrovascular complications include coronary heart disease (CHD), which may result in myocardial infarction, cerebrovascular disease (leading to strokes), and peripheral vascular disease. The pathogene-sis of vascular complications is multifactorial and is probably the combination of direct glucose-mediated endothelial damage, oxidative stress, production of sorbitol, and advanced glycation end-products. Precise understanding of these mechanisms could help clinicians to identify diabetic complications earlier and subsequently implement indispensable therapy on time. It is vital to determine biomarkers of microvascular and macrovascular complications in children affected with T1DM. Advanced glycation end-products and their receptors, adhesive molecules, pro- and anti-inflammatory cytokines, enzymes such as N-acetyl-β-D-glucosaminidase, and growth factors are the subject of ongoing studies. Numerous biomarkers of diabetic microangiopathy are already known and may constitute therapeutic targets in the future. Unfortunately, despite substantial progress in the understanding of the processes by which microvascular and macrovascu-lar complications develop, much effort still needs to be devoted to the matter, and further investigations are required.
The cut-off value for interleukin 34 as an additional potential inflammatory biomarker for the prediction of the risk of diabetic complications.
Zorena Katarzyna,Jachimowicz-Duda Olga,Wąż Piotr
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals
In the present study, we have decided to evaluate whether serum interleukin 34 (IL-34) levels may have diagnostic value in predicting the risk of vascular diabetic complications. The study included 49 patients with type 2 diabetes mellitus (T2DM) and 23 high-risk group. The receiver operating characteristic (ROC) curve analysis has shown that IL-34 has more discriminatory power than C-reactive protein (CRP) for the risk of diabetic complications. The cut-off value for IL-34 was established as 91.2 pg/mL. The gist of our research was identification of IL-34 as an additional potential inflammatory biomarker for the prediction of the risk of vascular diabetic complications.