EARLY AND ALTERNATIVE MARKERS OF CHRONIC HEART FAILURE IN PATIENTS WITH DIABETES MELLITUS

2021 ◽  
Vol 5 (1) ◽  
pp. 1122-1127
Author(s):  
V. Vasilkova ◽  
◽  
T. Mokhort ◽  
L. Korotaeva ◽  
Y. Yarets ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Growth Factors ◽  
Growth Factor ◽  
Natriuretic Peptide ◽  
Inflammatory Cytokines ◽  
Tnf Alpha ◽  
Reactive Protein ◽  
Patients With Diabetes ◽  
Fgf 23 ◽  
Pro Inflammatory Cytokines

Aim: to assess the relationship of proinflammatory cytokines and chemokines with the levels of natriuretic peptides in patients with diabetes mellitus (DM). Materials and methods. A total of 155 patients (14 men and 61 women) with type 1 and type 2 diabetes, aged 34 to 84 years, were examined. All patients underwent standard clinical and laboratory examination, with an assessment of the levels of pro-inflammatory cytokines (interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-alpha), chemokines (monokine induced by interferon-gamma (MIG), regulated upon activation, normal T cell expressed and presumably secreted (RANTES), growth factors (fibroblast growth factor-23 (FGF-23), vascular endothelial growth factor (VEGF-A), natriuretic peptides (B‐type natriuretic peptide (BNP), N‐terminal fragment of B‐type natriuretic peptide (proBNP). Renal function was assessed based on the levels of serum creatinine, glomerular filtration rate (GFR), which was calculated according to the CKD-EPI formula, and albuminuria, which was assessed as albumin/creatinine ratio (A/C). An echocardiographic examination was conducted according to the standard protocol with the calculation of dimensional, volume and speed characteristics. Statistical data analysis was performed using smSTATA 14.2 for Mac (2018). Results. 57% DM patients had BNP and proBNP levels exceeding the diagnostic values of BNP >35 pg/ml and/or proBNP >125 pg/ml. The levels of BNP and proBNP positively correlated with the levels of homocysteine, uric acid, IL-6, С-reactive protein (CRP), high-sensitivity C-reactive protein (hsCRP), A/С, creatinine, cystatin C, TNF-alpha, chemokines (MIG, RANTES), growth factors (FGF-23, VEGF-A) (p <0.05). According to multiple regression analysis, predictors for increased proBNP were IL-6, A/K, creatinine (ß=0.70, p<0.001, ß=3.51, p=0.01, ß=0.97, p=0.01, respectively). ROC analysis determined the highest diagnostic significance of creatinine for the prediction of increased proBNP. The significance of IL-6 proved higher than A/С (AUC-0.777). Thus, when the level of IL-6 (AUC-0.789) was 3.1 mg/ml, the sensitivity and specificity for increased proBNP concentration were 71.9% and 71.2%, respectively. Conclusion. IL-6 might be an independent predictor of increased levels of natriuretic peptide in patients with diabetes. Further study of the role of pro-inflammatory cytokines in the development of cardiovascular diseases will make it possible to finally decode the mechanisms of their pathogenesis, which will further allow us to understand their complex effect on the body and obtain information for the development of new effective and safe specific medicines.

scholarly journals The role of pro-inflammatory cytokines in diabetic nephropathy in pregnant women with type 1 diabetes mellitus

2013 ◽  
Vol 94 (1) ◽  
pp. 105-110
Author(s):  
G R Gazizova
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Growth Factors ◽  
Pregnant Women ◽  
Inflammatory Cytokines ◽  
Interstitial Fibrosis ◽  
Inflammatory Reactions ◽  
Patients With Diabetes ◽  
Pro Inflammatory Cytokines

Diabetic nephropathy is one of the most frequent and unfavorable complications of pregnancy in terms of prognosis in patients with diabetes mellitus. The combination of pregnancy and uncompensated diabetes with such complications as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, leads to overproduction of pro-inflammatory cytokines, thromboses and ischemic necroses of the fetoplacental tissues, and low blood level of immunosuppressive cytokines increases the severity of the disease. This mechanism may be one of the reasons of the spontaneous abortion and pregnancy loss in early pregnancy term in women with diabetes. For a long time the leading role in diabetic nephropathy formation was acknowledged for hyperglycemia, dyslipidemia, oxidative stress, and arterial and renal intraglomerular hypertension. Diabetic nephropathy was recognized as non-immune and non-inflammatory process. Currently diabetic nephropathy is considered as a series of inflammatory reactions involving inflammatory cytokines and chemokines, consisting in the migration of monocytes or macrophages to the kidneys and glomerular and interstitial fibrosis development. Recent studies prove the role of immune-inflammatory reactions in diabetic kidney damage development and confirm an imbalance of the collagen exchange regulating factors, even at the stage of reversible renal dysfunction - microalbuminuria. The close relationship found between hyperglycemia, overproduction of growth factors and nephrosclerosis development in diabetes mellitus. The detection of pro-inflammatory cytokines and fibrogenic growth factors in the urine of patients with diabetes, especially in pregnant women with diabetes, can be used to prompt diagnosis and evaluation of processes occurring in the kidneys, to study the degree of sclerosis, and as a consequence, to predict kidney functional disorders development. Keywords: diabetes mellitus, pregnancy, diabetic nephropathy, cytokines, growth factors.

Abstract 16139: A Targeted Proteomic Approach to Identify Circulating Biomarkers of Heart Failure Risk in Patients With Type 2 Diabetes Mellitus in DECLARE-TIMI 58

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
David Berg ◽  
Stephen D Wiviott ◽  
Itamar RAZ ◽  
Frederick Kamanu ◽  
KyungAh Im ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Growth Factor ◽  
Natriuretic Peptide ◽  
Proteomic Approach ◽  
Increased Risk ◽  
Fgf 23

Background: Patients (pts) with type 2 diabetes mellitus (T2DM) are at increased risk of heart failure (HF); however, the underlying mechanisms by which T2DM contributes to HF are incompletely understood. Hypothesis: We aimed to identify biological pathways associated with risk of hospitalization for HF (HHF) in a well-characterized cohort with T2DM followed for a median of 4.2 yrs. Methods: DECLARE-TIMI 58 was a randomized trial of dapagliflozin in pts with T2DM. We performed a nested case-control study of 184 candidate biomarkers (Olink CV II and CV III) in pts hospitalized for HF (n=432) and controls matched on age, sex, prior HF, prior CV disease, and f/u time (n=432). We evaluated associations between baseline biomarkers and HHF using logistic regression with a stringent threshold for significance (Bonferroni). Biomarkers were ranked according to Wald χ 2 values. ORs for the top 10 biomarkers were further adjusted for the components of the TIMI Risk Score for HF in Diabetes (AF, UACR, eGFR, CAD). ORs are per 1-SD. Results: 45 biomarkers were significantly associated with HHF. The 10 strongest associations were seen with N-terminal pro-B type natriuretic peptide (NT-proBNP), B type natriuretic peptide (BNP), spondin-1 (SPON1), insulin-like growth factor-binding protein 7 (IGFBP7), interleukin-6 (IL-6), fibroblast growth factor-23 (FGF-23), transferrin receptor protein 1 (TR), metalloproteinase inhibitor 4 (TIMP4), matrix metalloproteinase-2 (MMP-2), C-X-C motif chemokine 16 (CXCL16) ( Fig ). All 10 biomarkers were significantly associated with HHF both in pts with and without a history of HF. These proteins represent pathobiological axes implicated in hemodynamic stress, inflammation, myocardial hypertrophy, and cellular senescence, among others. Conclusions: A targeted proteomic approach identified established (NT-proBNP, BNP), investigational (IGFBP7, FGF-23, IL-6, TR, TIMP4, MMP-2, CXCL16), and novel (SPON1) biomarkers of HHF in pts with T2DM.

TNF-alpha stimulates activation of pro-MMP2 in human skin through NF-(kappa)B mediated induction of MT1-MMP

2001 ◽  
Vol 114 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Y.P. Han ◽  
T.L. Tuan ◽  
H. Wu ◽  
M. Hughes ◽  
W.L. Garner
Keyword(s):  
Gene Expression ◽  
Wound Healing ◽  
Human Skin ◽  
Inflammatory Cytokines ◽  
Intracellular Signaling ◽  
Chronic Wounds ◽  
Dermal Fibroblasts ◽  
Tnf Alpha ◽  
Nf Kappa B ◽  
Pro Inflammatory Cytokines

Tumor necrosis factor-alpha (TNF-(alpha)) is an important mediator during the inflammatory phase of wound healing. Excessive amounts of pro-inflammatory cytokines such as TNF-(alpha) are associated with inflammatory diseases including chronic wounds. Matrix metalloproteinases (MMPs) are involved in matrix re-modeling during wound healing, angiogenesis and tumor metastasis. As with pro-inflammatory cytokines, high levels of MMPs have been found in inflammatory states such as chronic wounds. In this report we relate these two phenomena. TNF-(alpha) stimulates secretion of active MMP-2, a type IV collagenase, in organ-cultured full-thickness human skin. This suggests a mechanism whereby excess inflammation affects normal wound healing. To investigate this observation at the cellular and molecular levels, we examined TNF-(alpha) mediated activation of pro-MMP-2, induction of MT1-MMP, and the intracellular signaling pathways that regulate the proteinase in isolated human dermal fibroblasts. We found that TNF-(alpha) substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-(alpha) individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-(alpha) significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-(alpha) and collagen activate the NF-(kappa)B pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-(kappa)B is essential to induce MT1-MMP expression in fibroblasts after TNF-(alpha) exposure. First, SN50, a peptide inhibitor for NF-(kappa)B nuclear translocation, simultaneously blocked the TNF-(alpha) and collagen mediated MT1-MMP induction and pro-MMP-2 activation. Secondly, TNF-(alpha) induced I(kappa)B to breakdown in fibroblasts within the collagen lattice, a critical step leading to NF-(kappa)B activation. Lastly, a consensus binding site for p65 NF-(kappa)B (TGGAGCTTCC) was found in the 5′-flanking region of human mt1-mmp gene. Based on these results and previous reports, we propose a model to explain TNF-(alpha) activation of MMP-2 in human skin. Activation of NF(kappa)B signaling in fibroblasts embedded in collagen induces mt1-mmp gene expression, which subsequently activates the pro-MMP-2. The findings provide a specific mechanism whereby TNF-(alpha) may affect matrix remodeling during wound healing and other physiological and pathological processes.

P1139EXPRESSION OF TOLL LIKE RECEPTORS, CELL ADHESION MOLECULES AND PRO-INFLAMMATORY CYTOKINES IN ESRD PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Mantabya Singh ◽  
Narayan Prasad ◽  
Nida Fatima ◽  
Amit Gupta ◽  
Chinmoy Sahu
Keyword(s):  
Cell Adhesion ◽  
Mrna Expression ◽  
Inflammatory Cytokines ◽  
Fungal Pathogens ◽  
Tnf Alpha ◽  
Rt Pcr ◽  
Cell Counts ◽  
Co Morbidity ◽  
Esrd Patients ◽  
Pro Inflammatory Cytokines

Abstract Background and Aims CAPD is well established modality of treatment for patients with end stage renal disease (ESRD). Peritonitis is a leading cause of technique failure and death in patients on CAPD. Studies on expressions of host factors like TLRs, CAMs and their relationship with inflammatory cytokines (IL-6, IL-12, TNF-alpha and IL-1 beta) involved in peritonitis and other co-morbidity and functional status are lacking throughout the world. Hence the present study has to be done to determine the expressions of TLR2 and TLR4, and CAMs in ESRD patients. To compare the expression of TLR2, TLR4, ICAM 1 and Pro-inflammatory cytokines (IL-6, IL-12, TNF-alpha and IL-1-beta) in Peritonitis, CAPD and CRF group patients. Method A total of 85 ESRD patients recruited and sub-divided into 3 groups. Group1- CAPD patient (n=25), Group 2- Peritonitis patient (n=30), and Group 3- CRF (n=30 patients). mRNA expression of TLR-2, TLR-4 were examined at gene levels by RT PCR and cell adhesion molecule (ICAM-1) were examined at gene and protein levels by RT PCR and ELISA respectively in Serum and Pro-inflammatory cytokines level were also examined by ELISA in serum. We performed microbiological culture for bacterial and fungal pathogens using automated BACTEC culture system. Cell counts were routinely done on every dialysate. Results Out of 30 samples of peritonitis group 15 were culture positive and 15 were culture negative. We found that in peritonitis group the mRNA expression of TLR-2 and TLR-4 was higher as compared to CRF (4.183±2.857vs 3.633±2.41) (p=0.049), (4.314±2.91vs 4.14±1.99) (p=0.015) and CAPD (4.183±2.857vs3.683±2.85) (p=0.041), (4.314±2.91vs 3.88±1.91) (p=0.009) respectively. At gene and protein level ICAM-1 was higher in peritonitis patient compared to CAPD (mRNA expression 4.76±2.64vs 4.36±3.48) (level in sera 660±201.2vs 514±157) (p=0.003). The IL-6 and IL-12 expression was higher in Peritonitis group as compared to CAPD (66.87±64.51vs214.35±220.05) (p=0.04) and (230.17±153.45vs417.04±302.96) (p=0.028) respectively. The TNF-alpha and IL-1-beta expression was not significant among the groups. Conclusion TLRs activation by bacterial molecules leads to the induction of cytokines (IL-6 and IL-12) and chemokine through the activation of NF-ķB pathway and may be responsible for atherosclerosis, morbidity and mortality in ESRD patients. Elevated level of ICAM-1, IL-6 and IL-12 may be responsible for chronic inflammation in Peritonitis group patients.

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