Development Of Microvascular Complications In Diabetes Research Articles

Сytokines as promising diagnostic and prognostic biomarkers of microvascular complications of diabetes

Classical knowledge about the pathogenesis of diabetes and its complications in recent years has been supplemented by ideas about the role of chronic inflammation. It has been established that inflammatory reactions play a role in the beta cell dysfunction, the formation of insulin resistance and remodeling of the vascular wall. Cytokines, soluble low molecular weight proteins and peptides that perform informational and regulatory functions, play central role in the development of inflammation. A wide range of biological activity and involvement in many aspects of pathogenesis make it possible to consider cytokines as promising molecules for diagnosing and predicting the complications. In this review, we summarize data from studies that assessed the role of cytokines as diagnostic and prognostic markers for the development of microvascular diabetic complications. Current data indicate that angiogenic and pro-inflammatory cytokines (VEGF, TNF-α, IL-6, IL-8, IL-15, IL-17, MCP-1, IP-10, INF-γ, PEDF, etc.) are promising biomarkers for proliferative diabetic retinopathy, especially when their local production is assessed (in vitreous, aqueous humor and tears). The role of these molecules as biomarkers of non-proliferative diabetic retinopathy and diabetic macular edema needs further research. Serum proinflammatory and fibrogenic cytokines (primarily MCP-1, IL-6, TNF-α, YKL-40, TGF-β and bFGF) and cytokine receptors (sTNFR1, sTNFR2) are considered as promising diagnostic and prognostic markers of diabetic kidney disease. Urinary excretion of IL-6 and MCP-1 turned out to be a predictor of the progression of diabetic nephropathy. Multi-bead assay and mass spectrometry make it possible to study cytokine panels in small samples of biological material. Combined biomarkers, including several cytokines, may increase the reliability of the prognosis of diabetic complications.

Gene Expression Analysis in T2DM and Its Associated Microvascular Diabetic Complications: Focus on Risk Factor and RAAS Pathway.

Prolonged hyperglycemic conditions in type 2 diabetes mellitus (T2DM) cause pathological and functional damage to many organs and tissues, including the kidneys, retina, skin, and neuronal tissues, resulting in the development of microvascular diabetic complications. The altered renin angiotensin aldosterone system (RAAS) pathway has been reported to play an important role in the development of insulin resistance in T2DM and associated complications. The current study was carried out to evaluate the association of risk factors and altered expression of RAAS genes in T2DM patients without complications and T2DM patients with complications (retinopathy, nephropathy, and neuropathy). Four hundred and twenty subjects including 140 healthy controls, 140 T2DM patients with diabetic complications, and 140 T2DM patients without diabetic complications were included in the study. Risk factors associated with the development of T2DM and diabetic complications were evaluated. Further, expression analysis of RAAS genes (AGT, ACE, ACE2, and AGT1R) was carried out using qRTPCR in healthy controls, T2DM patients with complications, and T2DM patients without complications. Various risk factors like urban background, higher BMI, alcoholism, smoking, and family history of diabetes among others were found to be associated with the development of T2DM as well as diabetic complications. The expression level of AGT, ACE, and AGT1R was found to be upregulated whereas ACE2 was found to be downregulated in T2DM patients with complications and T2DM patients without complications as compared to controls. Altered expression of the studied genes of RAAS pathway is associated with the development of microvascular diabetic complications.

Features of the cytokine profile in adolescents with microvascular complications of type 1 diabetes mellitus

Despite advances of modern medical science, the consequences associated with management of complications in type 1 diabetes mellitus (DM1) in children and adolescents represent a serious problem. Common development of microvascular diabetic complications (retinopathy, neuropathy, kidney damage) still remains a sufficient obstacle for achieving high quality of life and social adaptation in the young patients, thus promoting studies of immune mechanisms involved in genesis of microvasculature damage under the conditions of dysmetabolic abnormalities associated with DM1. Our goal was to assess the role of altered cytokine balance in blood serum in development of microangiopathies in adolescents with DM1.140 adolescent patients with type 1 diabetes aged 14-18 years were examined being divided in 2 groups: group I included the patients with glycated hemoglobin (HbA1c) level of > 9.0% (n = 65), and group II which included adolescents with HbA1C level of ≤ 9.0% (n = 75). Each group was divided into subgroups: Ia (n = 50) and IIa (n = 38) included adolescents with diabetic retinopathy, nephropathy or neuropathy, whereas groups Ib (n = 15) and IIb (n = 37) were without microvascular complications. The control group consisted of 36 adolescents with normal body weight, without carbohydrate metabolic disorders, and family history of diabetes mellitus. Determination of TNFα, IL-1β, VCAM-1, fractalkine levels in blood serum was performed by enzyme immunoassay using test systems “RayBiotech” (USA), “BIOSCIENCE” (USA).Development of microangiopathies in adolescents with different glycemic control is associated with increased serum concentration of the factors involved in neoangiogenesis and vascular wall remodeling, i.e., TNFα, IL-1β, VCAM-1, compared with control group (p < 0.05), and a statistically significant decrease in fractalkine level in adolescent patients with either complicated, or uncomplicated DM1. The study allowed us to suggest that occurrence of microvascular complications in adolescents with DM1 is associated with impaired immune response tending for altered cytokine balance towards Th1 type, enhanced intercellular interactions, imbalance of bioregulatory molecules, contributing to development of inflammatory immunoregulatory state. The revealed patterns of laboratory markers, along with assessment of metabolic indices, will enable personalized approaches to early diagnostics of microvascular complications in adolescents with DM1 and prevent their further progression.

The role of interleukin-19 in diabetic nephropathy

BackgroundProinflammatory cytokines play an important role in the establishment of arteriolosclerosis and kidney injury. Inflammatory cytokines are involved in the development of microvascular diabetic complications, including diabetic nephropathy (DN). Interleukin-19 (IL-19) has vital functions in many inflammatory processes and also can induce the angiogenesis of endothelial cells.ObjectiveTo investigate the role of IL-19 in the development of DN.Patients and methodsA total of 112 participants were included and classified into four main groups: group I was the control group, which included 28 age-matched and sex-matched persons; group II included 28 patients with type 2 diabetes without nephropathy (normoalbuminuria); group III included 28 patients with type 2 diabetes with nephropathy (microalbuminuria); and group IV included 28 patient with type 2 diabetes with nephropathy (macroalbuminuria). All participants were subjected to complete blood count, complete urine analysis, fasting and random blood glucose, glycosylated hemoglobin (HbA1c), serum creatinine and urea, urinary albumin excretion rate (UAE), albumin-creatinine ratio (ACR), lipid profile, and serum IL-19 level assays.ResultsC-reactive protein (CRP) and serum IL-19 levels were significantly higher in diabetic patients compared with controls. IL-19 levels were significantly positively correlated with serum creatinine, ACR, UAE, HbA1c, and CRP. Multivariable logistic regression analysis showed that IL-19 levels were independently associated with patients with DN.ConclusionIL-19 levels were elevated in patients with DN and were positively correlated with ACR, UAE, HbA1c, and CRP. IL-19 may play an important role that contributes to the progression of DN.

The role of IL-20 in chronic kidney disease and diabetic nephropathy: Pathogenic and therapeutic implications.

Chronic kidney disease and its complications are a major public health problem worldwide. Diabetic nephropathy has become the main contributing cause of terminal renal failure. There are now evidences that different inflammatory molecules, including proinflammatory cytokines, play a critical role in the development of microvascular diabetic complications, including nephropathy. IL-20 is emerging as a potent angiogenic, chemotactic, and proinflammatory cytokine related to several chronic inflammatory disorders likes psoriasis, atherosclerosis, and renal failure. This review discusses the role of IL-20 as a pathogenic factor in renal injury, focusing on chronic kidney disease and diabetic nephropathy, and describes potential treatment strategies based on modulation of IL-20's function.

Relations of high sensitive C-reactive protein (hs-CRP) with microalbuminuria as a useful predictor of cardiovascular risk among type 1 diabetes mellitus patients

Background: Inflammation and more specifically inflammatory cytokines are determinant in the development of microvascular diabetic complications, including neuropathy, retinopathy and nephropathy.Objective: The aim of present study is to evaluate the relationships between high sensitive C-reactive protein, microalbuminuria and risk factors for cardiovascular disease.Subjects and methods: the study involved (30) patients with type 1 diabetic mellitus compared to (30) healthy control. A fasting blood sample was drawn from all subjects after an overnight fasting to measure the biochemical parameters which including glycated hemoglobin, lipid profile, atherogenic index of plasma and high sensitive C-reactive protein concentration in blood of all subjects, also evaluating microalbuminuria, creatinine, urea level in urine of type 1 diabetic mellitus patients and healthy control.Results: results revealed a significant increase in the level of glycated hemoglobin, total cholesterol, triglyceride, low density lipoprotein, high sensitive C-reactive protein, microalbuminuria, urea and atherogenic index of plasma. While a significant decrease in high density lipoprotein level in patients group compared with control group. Also, there were a highly significant positive correlation between high sensitive C-reactive protein and glycated hemoglobin, atherogenic index of plasma and microalbuminuria.Conclusions: the results of this study suggests that high sensitive C-reactive protein can be use with microalbuminuria as a biochemical marker to predict the early stage of cardiovascular disease in children and adolescents with type 1 diabetic mellitus.

Regulation of CD163 expression in human macrophages in diabetic conditions

Scavenging function of monocytes and macrophages is essential for the control of inflammatory reactions. The monocyte- and macrophage-specific scavenger receptor CD163 internalizes and degrades haemoglobin-haptoglobin complexes built due to intravascular haemolysis. This circumstance particularly occurs in inflammation, supporting the development of microvascular diabetic complications. The shedding of CD163 from the cell surface in inflammation leads to an impaired scavenging function and consequently increases the risk of vascular oxidative damage. The project aims to examine how high glucose conditions affect the CD163-mediated scavenging of human primary differentially activated macrophages. CD14+-monocytes were isolated from the peripheral blood of healthy donors by density gradient centrifugation and magnetic separation. M0 (non-stimulated), M1 (IFNgamma-stimulated) and M2 (IL-4-stimulated) macrophages were differentiated within 6 days in low (5mM) and high (25mM) glucose conditions. CD163-mRNA expression was quantified by qRT-PCR. CD163 surface expression was analysed by flow cytometry. Increased glucose had a suppressing effect on CD163 mRNA expression in 8 out of 10 donors in M1; and in 7 out of 10 donors in M2. The suppressive effect of glucose was more pronounced in M2 compared to M1. Regarding surface expression, the effect of high glucose was donor-dependent in M0 and M2, whereas the expression of CD163 uniformly decreased in M1. Our data suggest that elevated glucose levels affect both transcriptional and posttranscriptional mechanisms of CD163 production in a donor-specific manner. We concluded that the suppression of CD163 expression in macrophages by high glucose can contribute to the development of inflammation-mediated complications in diabetic patients.

Role of Mindin in Diabetic Nephropathy

A number of studies have shown that proinflammatory cytokines have important roles in determining the development of microvascular diabetic complications, including nephropathy. Inflammatory biomarkers should be useful for diagnosis or monitoring of diabetic nephropathy. Mindin (spondin 2) is a member of the mindin-/F-spondin family of secreted extracellular matrix (ECM) proteins. Recent studies showed that mindin is essential for initiation of innate immune response and represents a unique pattern-recognition molecule in the ECM. Previously, we demonstrated that the levels of urinary mindin in patients with type 2 diabetes were higher than those in healthy individuals. We propose that urinary mindin is a potent biomarker for the development of diabetic nephropathy.

Pathogenic perspectives for the role of inflammation in diabetic nephropathy

Diabetes and its complications have become a public health problem. One of the most important complications is diabetic nephropathy, which is nowadays the main cause of chronic renal failure. In spite of our greater understanding of this complication, the intimate mechanisms leading to the development and progression of renal injury are not well understood. New perspectives in activated innate immunity and inflammation appear to be relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including adipokines, Toll-like receptors, chemokines, adhesion molecules and pro-inflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic considerations, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatments for diabetic nephropathy.

The role of TNF-α in diabetic nephropathy: Pathogenic and therapeutic implications

Diabetes mellitus and its complications are a public health problem. Diabetic nephropathy has become the main cause of renal failure, and furthermore is associated with a dramatic increase in cardiovascular risk. Unfortunately, the mechanisms leading to the development and progression of renal injury in diabetes are not yet fully known. There is now evidence that activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Furthermore, different inflammatory molecules, including pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), play a critical role in the development of microvascular diabetic complications, including nephropathy. This review discusses the role of TNF-α as a pathogenic factor in renal injury, focusing on diabetic nephropathy, and describes potential treatment strategies based on modulation of TNF-α activity.

Inflammation and diabetic nephropathy

Diabetic nephropathy has become the main cause of renal failure, but unfortunately the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, different inflammatory molecules, including chemokines, adhesion molecules, and proinflammatory cytokines, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective leads to important therapeutic considerations, with new pathogenic pathways becoming important therapeutic targets that can be translated into clinical treatments for diabetic nephropathy.

Diabetes, Inflammation, Proinflammatory Cytokines, and Diabetic Nephropathy

Diabetes and its complications have become a public health problem. Diabetic nephropathy is the main cause of renal failure. In spite of our higher knowledge on this complication, the intimate mechanisms leading to the development and progression of renal injury are not yet fully known. Activated innate immunity and inflammation are relevant factors in the pathogenesis of diabetes. Moreover, inflammation, and more specifically proinflammatory cytokines and other molecules with a relevant role within the inflammatory process, may be critical factors in the development of microvascular diabetic complications, including nephropathy. This new pathogenic perspective may lead to important new therapeutic considerations and new therapeutic goals for the treatment of diabetic nephropathy.