Pathogenesis Of Diabetic Complications Research Articles

Serum Total Bilirubin and Oxidative Stress Status in Diabetic Retinopathy – A Hospital-Based Observational Study

Diabetic retinopathy (DR) is one of the common microvascular complications of Type 2 Diabetes Mellitus (T2DM). As an antioxidant, the serum total bilirubin is associated with vaso-occlusive disorders. Oxidative stress parameters such as Erythrocyte Glutathione (GSH) as an antioxidant and Malondialdehyde (MDA) as an oxidant are critical in the pathogenesis of diabetic complications. This study aimed to explore the possibilities of the endogenous protective role of serum total bilirubin on the retinal vasculature in DR patients by estimating and correlating the levels of serum total bilirubin, GSH, and MDA in DR cases. In this hospital-based case-control study, 288 participants were selected from R.L. Jalappa Hospital and Research Centre, Kolar, divided into three groups with 96 subjects per group. Group I: Controls, Group II: T2DM, and Group III: DR subjects. The fasting blood sugar, glycated hemoglobin, liver function test, and lipid profiles were estimated by standard methods. Oxidative stress parameters viz, GSH and MDA were assayed by chromogen 5,5'- di thiobis 2-nitrobenzoic acid (DTNB) and thiobarbituric acid reactive substances (TBARS) methods, respectively. The prevalence of DR was significantly lower among subjects with the highest bilirubin quartile than those with the lowest. There was a significant mean difference with p<0.001 between the groups for total bilirubin, FBS, HbA1c, GGT, TC, TG, LDL, GSH, and MDA. A Negative correlation of serum total bilirubin with FBS (r = - 0.375), HbA1c (r = -0.351), and MDA(r=-0.323), and a positive correlation with GSH (r = 0.335) was observed in DR group with a significant p-value. T2DM subjects with higher levels of bilirubin within biological reference intervals were less likely to develop retinopathy. The severity of DR was inversely proportional to the total bilirubin levels. Therefore, serum total bilirubin levels could be a biomarker to predict the risk of developing retinopathy in people with T2DM.

Inflammation in diabetes complications: molecular mechanisms and therapeutic interventions.

At present, diabetes mellitus (DM) has been one of the most endangering healthy diseases. Current therapies contain controlling high blood sugar, reducing risk factors like obesity, hypertension, and so on; however, DM patients inevitably and eventually progress into different types of diabetes complications, resulting in poor quality of life. Unfortunately, the clear etiology and pathogenesis of diabetes complications have not been elucidated owing to intricate whole-body systems. The immune system was responsible to regulate homeostasis by triggering or resolving inflammatory response, indicating it may be necessary to diabetes complications. In fact, previous studies have been shown inflammation plays multifunctional roles in the pathogenesis of diabetes complications and is attracting attention to be the meaningful therapeutic strategy. To this end, this review systematically concluded the current studies over the relationships of susceptible diabetes complications (e.g., diabetic cardiomyopathy, diabetic retinopathy, diabetic peripheral neuropathy, and diabetic nephropathy) and inflammation, ranging from immune cell response, cytokines interaction to pathomechanism of organ injury. Besides, we also summarized various therapeutic strategies to improve diabetes complications by target inflammation from special remedies to conventional lifestyle changes. This review will offer a panoramic insight into the mechanisms of diabetes complications from an inflammatory perspective and also discuss contemporary clinical interventions.

Beyond blood sugar: exploring the anti-inflammatory frontier of antidiabetic medications to alleviate diabetic complications

Background and objective. Inflammation is closely correlated with diabetes and diabetic complications. Research has shown that individuals with diabetes exhibit an upregulation of circulatory proinflammatory cytokines, resulting in a chronic state of low-grade inflammation. The participation of inflammation in the pathogenesis of diabetic complications, particularly cardiovascular and renal complications, is well-established. Targeting inflammation may produce prominent effects in improving the clinical condition of diabetic patients, reducing the progression of complications, and promoting glucose uptake by insulin-sensitive tissues. This review article aimed to explore the anti-inflammatory effect of antidiabetics beyond their hypoglycemic action and the potential effects of such antidiabetics in reducing diabetic complications. Materials and methods. Based on relevant online publications using the terms anti-diabetics, anti-inflammatory, diabetic complications, and inflammatory mediators up to February 2024 on PubMed and Google Scholar were utilized to construct this review. Results. The majority of antidiabetic drugs pose an indirect effect on inflammation through the hypogly­cemic effect. However, many antidiabetics have an additional anti-inflammatory mechanism independently of their hypoglycemic effects, which augments their anti-inflammatory effects. Conclusion. Suppression of the inflammatory response by anti-diabetics and achieving homeostatic control is an effective approach for preventing diabetic complications.

Association between Plasma LRG1 and Lower Cognitive Function in Asians with Type 2 Diabetes Mellitus.

Leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in the pathogenesis of diabetic complications, but its association with cognitive function remains unclear. Our primary objective is to investigate the longitudinal association between LRG1 and cognitive function in patients with type 2 diabetes mellitus (T2DM). Secondarily, we determine the causal relationship using Mendelian Randomization (MR), and the role of arterial stiffness as a potential mediator. T2DM patients (n = 1039; age = 64.1 ± 6.4 years) were followed-up for 5.3 ± 1.2 years. Plasma LRG1 was measured at baseline using enzyme-linked immunosorbent assay. Baseline and follow-up cognitive function was assessed using Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). One-sample MR was performed with rs4806985 as plasma LRG1-associated single-nucleotide polymorphism (SNP). Mediation analysis was performed to examine if pulse wave velocity (PWV), an arterial stiffness index, mediated the association between plasma LRG1 and follow-up cognitive function. Elevated baseline natural log (Ln)-transformed LRG1 was inversely associated with baseline and follow-up RBANS total score with adjusted coefficients -1.38 (95%CI -2.55 to -0.21; p = 0.021) and -1.38 (95%CI -2.70 to -0.07; p = 0.039), respectively. Genetically-predicted higher levels of plasma LRG1 was associated with lower follow-up RBANS total score with coefficient -7.44 (95%CI -14.14 to -0.74; p = 0.030) per unit increase in LnLRG1. Higher PWV accounted for 27.7% of the association between LnLRG1 and follow-up RBANS total score. Baseline plasma LRG1 was associated with lower cognitive function at follow-up in patients with T2DM, mediated by PWV. MR analysis provided evidence of an association between genetically influenced plasma LRG1 and lower cognitive function at follow-up.

Correlation of Glycated Hemoglobin with Oxidative Stress in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) has a heavy disease burden and is one of the leading causes of death worldwide. It is considered to be evolving from a complex and multifactorial metabolic disorder to an inflammatory condition. The strong link between hyperglycemia and oxidative stress has long been established. Oxidative stress leads to the generation of inflammatory mediators and reactive oxygen species, which results in an inflammatory state, which plays a key role in the pathogenesis of diabetic complications. We aimed to correlate the levels of Glycated Hemoglobin with Oxidative Stress.This cross-sectional study included 200 subjects, 100 were type 2 diabetic patients and 100 were healthy non-diabetic individuals. The data were analyzed using a t test. The results showed that as the Glycated Hb increased, the levels of FBS, MDA increased and Serum SOD, Glutathione and Catalase levels decreased. The results showed a positive correlation between HbA1c and fasting blood glucose (r = 0.417, p= 0.000) and MDA (r= 0.340, p=0.000). Whereas negative correlation was observed between HbA1c and other antioxidant parameters, SOD (r= 0.025, p=0.803) Catalase (r= 0.096, p= 0.342), Glutathione (r= -0.164, p= 0.103). It is hereby concluded for the present study that when glycated Hb increases the natural antioxidants that is SOD, catalase and glutathione decrease to combact the increased formation of ROS. Serum MDA, a marker of lipid peroxidation, increased with increased glycated Hb, and shows a positive correlation, indicating that lipid peroxidation increased, when glycation of Hb increased, thus depicting an increased chance of macrovascular complication in type 2 diabetics.

A Systematic Review on Effect of Scoparia Dulcis on Alterations in Antioxidant Status, Oxidative Damage in Diabetes and Other Pharmacological Activities

Oxidative stress is implicated in the pathogenesis of diabetic complications. Diabetes mellitus is presently a burden not only on the individuals affected by the disease but also on society, particularly the national health system of all the countries. The war against diabetes through the development of new drugs is an ongoing continuous process. Despite many advances in the development of oral hypoglycemic agents, an ideal drug for treating diabetes mellitus is still a distant reality. As pointed out by World Health Organisation (WHO), prevention of diabetes and its complications is not only a major challenge for the future, but essential if health for all is to be attainable target. WHO study groups emphasize strongly in this regard the optimal, rational uses of traditional and natural indigenous medicine. The study of such medicinal plants might offer a natural key to unlock diabetologists pharmacy for the future. Indian traditional medicines have a long history to treat diabetic mellitus (DM) by the herbs and herbal extracts. Scoparia dulcis, also known as sweet broom weed, is a perennial herb which is commonly found in tropical and subtropical regions. In these regions, the fresh or dried plant has traditionally been used as one of remedies for diabetes and various diseases. The plant is abundantly found in many countries and can be easily grown and cultivated, should there be a need for mass production. The whole plant is used for ailments like diarrhea, stomach-ache, kidney stones, kidney problems, and fever. S. dulcis is a rich source of flavones, terpenes and steroids S. dulcis is one of the traditional antidiabetic herbs. There were so many research work done on its antidiabetic properties. S. dulcis has been used by human for centuries as a medicinal herb. S. dulcis has also been shown to exhibit analgesic, antimalarial, hepatoprotective, sedative, hypnotic, antiulcer, antisickling, and antimicrobial activities. Given this evidence, it may be concluded that S. dulcis could be promoted among the masses as an alternative and complementary therapy for diabetes, provided further scientific studies on the toxicological and pharmacological aspects are carried out through either in vivo or clinical means.

Pharmacophore derived 3D-QSAR, molecular docking, and simulation studies of quinoxaline derivatives as ALR2 inhibitors

Aldose Reductase 2 (ALR2), a key enzyme of the polyol pathway, plays a crucial role in the pathogenesis of diabetic complications. Quinoxaline scaffold-based compounds have been identified as potential ALR2 inhibitors for the management of diabetic complications. In the present work, molecular dynamic simulation studies in conjugation with pharmacophore mapping and atom-based 3D-QSAR were performed on a dataset of 99 molecules in comparison with Epalrestat (reference) to mark the desirable structural features of quinoxaline analogs to generate a probable template for designing novel and effective ALR2 inhibitors. The most potent compound 81 was subjected to MD simulation studies and found to be stable, with better interactions with the binding pocket as compared to Epalrestat. The MM-GBSA and MM-PBSA calculations showed that compound 81 possessed binding free energies of −35.96 and −4.92 kcal/mol, respectively. Atom-based 3D-QSAR yielded various pharmacophoric features with excellent statistical measures, such as correlation coefficient (R 2 value), F-value (Fischer ratio), Q 2 value (cross-validated correlation coefficient), and Pearson’s R-value for training and test sets. Furthermore, the pharmacophore mapping provided a five-point hypothesis (AADRR) and docking analysis revealed the active ligand-binding orientations on the active site’s amino acid residues TYR 48, HIE 110, TRP 111, and TRP 219. The results of this study will help in designing potent inhibitors of ALR2 for the management of diabetic complications. Communicated by Ramaswamy H. Sarma

Relationship between acute glucose variability and cognitive decline in type 2 diabetes: A systematic review and meta-analysis.

Cognitive decline is one of the most widespread chronic complications of diabetes, which occurs in more than half of the patients with type 2 diabetes (T2DM). Emerging evidences have suggested that glucose variability (GV) is associated with the pathogenesis of diabetic complications. However, the influence of acute GV on cognitive dysfunction in T2DM is still controversial. The aim of the study was to evaluate the association between acute GV and cognitive defect in T2DM, and provide a most recent and comprehensive summary of the evidences in this research field. PubMed, Cochrane library, EMBASE, Web of science, Sinomed, China National Knowledge Infrastructure (CNKI), and Wanfang were searched for articles that reported on the association between acute GV and cognitive impairment in T2DM. 9 eligible studies were included, with a total of 1263 patients with T2DM involved. Results showed that summary Fisher's z value was -0.23 [95%CI (-0.39, -0.06)], suggesting statistical significance (P = 0.006). Summary r value was -0.22 [95%CI (-0.37, -0.06)]. A lower cognitive performance was found in the subjects with greater glucose variation, which has statistical significance. Mean amplitude of glycemic excursions (MAGE) was associated with a higher risk of poor functional outcomes. Fisher's z value was -0.35 [95%CI (-0.43, -0.25)], indicating statistical significance (P = 0.011). Sensitivity analyses by omitting individual studies showed stability of the results. Overall, higher acute GV is associated with an increased risk of cognitive impairment in patients with T2DM. Further studies should be required to determine whether targeted intervention of reducing acute GV could prevent cognitive decline.

Protective Factors and the Pathogenesis of Complications in Diabetes.

Chronic complications of diabetes are due to myriad disorders of numerous metabolic pathways that are responsible for most of the morbidity and mortality associated with the disease. Traditionally, diabetes complications are divided into those of microvascular and macrovascular origin. We suggest revising this antiquated classification into diabetes complications of vascular, parenchymal, and hybrid (both vascular and parenchymal) tissue origin, since the profile of diabetes complications ranges from those involving only vascular tissues to those involving mostly parenchymal organs. A major paradigm shift has occurred in recent years regarding the pathogenesis of diabetes complications, in which the focus has shifted from studies on risks to those on the interplay between risk and protective factors. While risk factors are clearly important for the development of chronic complications in diabetes, recent studies have established that protective factors are equally significant in modulating the development and severity of diabetes complications. These protective responses may help explain the differential severity of complications, and even the lack of pathologies, in some tissues. Nevertheless, despite the growing number of studies on this field, comprehensive reviews on protective factors and their mechanisms of action are not available. This review thus focused on the clinical, biochemical, and molecular mechanisms that support the idea of endogenous protective factors, and their roles in the initiation and progression of chronic complications in diabetes. In addition, this review also aimed to identify the main needs of this field for future studies.

RAGE signaling regulates the progression of diabetic complications.

Diabetes, the ninth leading cause of death globally, is expected to affect 642 million people by 2040. With the advancement of an aging society, the number of patients with diabetes having multiple underlying diseases, such as hypertension, obesity, and chronic inflammation, is increasing. Thus, the concept of diabetic kidney disease (DKD) has been accepted worldwide, and comprehensive treatment of patients with diabetes is required. Receptor for advanced glycation endproducts (RAGE), a multiligand receptor, belonging to the immunoglobulin superfamily is extensively expressed throughout the body. Various types of ligands, including advanced glycation endproducts (AGEs), high mobility group box 1, S100/calgranulins, and nucleic acids, bind to RAGE, and then induces signal transduction to amplify the inflammatory response and promote migration, invasion, and proliferation of cells. Furthermore, the expression level of RAGE is upregulated in patients with diabetes, hypertension, obesity, and chronic inflammation, suggesting that activation of RAGE is a common denominator in the context of DKD. Considering that ligand-and RAGE-targeting compounds have been developed, RAGE and its ligands can be potent therapeutic targets for inhibiting the progression of DKD and its complications. Here, we aimed to review recent literature on various signaling pathways mediated by RAGE in the pathogenesis of diabetic complications. Our findings highlight the possibility of using RAGE-or ligand-targeted therapy for treating DKD and its complications.

Transient receptor potential channel 6 knockdown prevents high glucose-induced Müller cell pyroptosis

BackgroundTransient receptor potential channel 6 (TRPC6) is reported to be involved in the pathogenesis of diabetic complications, but its role in diabetic retinopathy (DR) remains unknown. The aim of our study was to determine the role and mechanism of TRPC6 in DR. MethodsHigh glucose was used to construct a DR cell model using rat retinal Müller cells (rMC-1). Intracellular Ca2+, reactive oxygen species (ROS) and cell pyroptosis were evaluated by flow cytometry. Protein levels of NLRP3, pro-caspase-1, active caspase-1, gasdermin D (GSDMD), GSDMD-N, TRPC6 and H3K27ac were detected by Western blot. mRNA levels of EP300 and TRPC6 were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). Levels of IL-1β and IL-18 were estimated by enzyme linked immunosorbent assay (ELISA). The interaction between EP300 and TRPC6 was validated by a chromatin immunoprecipitation assay. ResultsThe knockdown of TRPC6 reduced inflammation and cell pyroptosis in HG induced rMC-1 cells, whereas overexpression of TRPC6 had the opposite effects. The inhibition of ROS and NLRP3 reversed TRPC6-mediated cell pyroptosis in the DR cell model. In addition, EP300 increased the expression of H3K27ac and TRPC6 to promote cell pyroptosis, which was suppressed by the knockdown of TRPC6. ConclusionsOur study revealed a novel EP300/H3K27ac/TRPC6 signaling pathway that may contribute to HG induced Müller cell pyroptosis. TRPC6 played a novel role in Müller cell pyroptosis triggered by HG, and may be a potential target for DR treatment in the future.

Mapping glycation and glycoxidation sites in collagen I of human cortical bone

Accumulation of advanced glycation end products (AGEs), particularly in long-lived extracellular matrix proteins, has been implicated in pathogenesis of diabetic complications and in aging. Knowledge about specific locations of AGEs and their precursors within protein primary structure is critical for understanding their physiological and pathophysiological impact. However, the information on specific AGE sites is lacking. Here, we identified sequence positions of four major AGEs, carboxymethyllysine, carboxyethyllysine, 5-hydro-5-methyl imidazolone, and 5-hydro-imidazolone, and an AGE precursor fructosyllysine within the triple helical region of collagen I from cortical bone of human femurs. The presented map provides a basis for site-specific quantitation of AGEs and other non-enzymatic post-translational modifications and identification of those sites affected by aging, diabetes, and other diseases such as osteoporosis; it can also help in guiding future studies of AGE impact on structure and function of collagen I in bone.

Role of Insulin Action in the Pathogenesis of Diabetic Complications

Role of Insulin Action in the Pathogenesis of Diabetic Complications

Rationale and design of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) in patients with high-risk diabetic cardiomyopathy

Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF). Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers. The ARISE-HF Trial is fully enrolled. This report describes the rationale and study design of ARISE-HF.

Correlation of oxidative stress with vitamin D and glycated hemoglobin in patients with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) has a heavy disease burden and is one of the leading causes of death worldwide. It is considered to be evolving from a complex and multifactorial metabolic disorder to an inflammatory condition. The strong link between hyperglycemia and oxidative stress has long been established. Oxidative stress leads to the generation of inflammatory mediators and reactive oxygen species, which results in an inflammatory state, which plays a key role in the pathogenesis of diabetic complications. Vitamin D is also known to affect insulin sensitivity. We aimed to correlate the levels of glycated hemoglobin (HbA1c) and vitamin D with oxidative stress. This cross-sectional study included 100 patients with T2DM. Oxidative stress was estimated by lipid peroxidation assay for activity of malondialdehyde (MDA), as well as superoxide dismutase (SOD) levels. HbA1c was estimated using ion-exchange chromatography. Vitamin D was estimated using enzyme-linked immunosorbent assay. The data were analyzed using a t test. The results showed that as the duration of T2DM increased, the levels of SOD and MDA also increased. No significant correlation was found between SOD and MDA with HbA1c (P = 0.995 and 0.195) and vitamin D (P = 0.874 and 0.051), respectively.

Endogenous advanced glycation end products in the pathogenesis of chronic diabetic complications.

Diabetes is a common metabolic illness characterized by hyperglycemia and is linked to long-term vascular problems that can impair the kidney, eyes, nerves, and blood vessels. By increasing protein glycation and gradually accumulating advanced glycation end products in the tissues, hyperglycemia plays a significant role in the pathogenesis of diabetic complications. Advanced glycation end products are heterogeneous molecules generated from non-enzymatic interactions of sugars with proteins, lipids, or nucleic acids via the glycation process. Protein glycation and the buildup of advanced glycation end products are important in the etiology of diabetes sequelae such as retinopathy, nephropathy, neuropathy, and atherosclerosis. Their contribution to diabetes complications occurs via a receptor-mediated signaling cascade or direct extracellular matrix destruction. According to recent research, the interaction of advanced glycation end products with their transmembrane receptor results in intracellular signaling, gene expression, the release of pro-inflammatory molecules, and the production of free radicals, all of which contribute to the pathology of diabetes complications. The primary aim of this paper was to discuss the chemical reactions and formation of advanced glycation end products, the interaction of advanced glycation end products with their receptor and downstream signaling cascade, and molecular mechanisms triggered by advanced glycation end products in the pathogenesis of both micro and macrovascular complications of diabetes mellitus.

Association of MMP-2 and MMP-9 Polymorphisms with Diabetes and Pathogenesis of Diabetic Complications.

Type 2 diabetes mellitus (T2D) affects millions of people around the world, and its complications have serious health consequences. In addition to external factors, the causes of morbidity and increased risk were also sought in the variability of the human genome. A phenomenon that can answer these questions is the occurrence of single-nucleotide polymorphisms (SNP). They constitute a field for research into genetic determinants responsible for the increase in the risk of the discussed metabolic disease. This article presents the outline of two enzymes: metalloproteinases 2 and 9 (MMP-2, MMP-9), their biological activity and the effect caused by differences in individual alleles in the population, as well as the reports on the importance of these DNA sequence variations in the occurrence of diabetes mellitus type 2 and associated conditions. The results of the conducted research indicate a relationship between two MMP-2 polymorphisms (rs243865, rs243866) and two MMP-9 polymorphisms (rs3918242, rs17576) and the presence of T2D. This could offer a promising possibility to use them as predictive and diagnostic markers. However, due to the low number of reports, more research is needed to clearly confirm the link between these SNPs and diabetes.

Role of insulin action in the pathogenesis of diabetic complications.

Among the various pathological conditions associated with type 2 diabetes, insulin resistance has long been reported to be a potent risk factor for diabetic complications. The liver, skeletal muscle, and adipose tissue are the major organs of action of insulin in systemic glucose metabolism, but insulin receptors and their downstream insulin signaling molecules are also constitutively expressed in vascular endothelial cells, vascular smooth muscle, and monocytes/macrophages. Forkhead box class O family member proteins (FoxOs) of transcription factors are essential regulators of cellular homeostasis, including glucose and lipid metabolism, oxidative stress response and redox signaling, cell cycle progression and apoptosis. In vascular endothelial cells, FoxOs strongly promote atherosclerosis via suppressing nitric oxide production and enhancing inflammatory responses. In liver sinusoidal endothelial cells, FoxOs induces hepatic insulin resistance by inducing nitration of insulin receptor in hepatocytes. Insulin resistance in adipose tissue limits capacity of lipid accumulation in adipose tissue, which promotes ectopic lipid accumulation and organ dysfunction in liver, vascular, and kidney. Modulation of insulin sensitivity in adipose tissue to induce healthy adipose expansion is expected to be a promising strategy for diabetic complications.

Neutrophil Activation by Mineral Microparticles Coated with Methylglyoxal-Glycated Albumin.

Hyperglycemia-induced protein glycation and formation of advanced glycation end-products (AGEs) plays an important role in the pathogenesis of diabetic complications and pathological biomineralization. Receptors for AGEs (RAGEs) mediate the generation of reactive oxygen species (ROS) via activation of NADPH-oxidase. It is conceivable that binding of glycated proteins with biomineral particles composed mainly of calcium carbonate and/or phosphate enhances their neutrophil-activating capacity and hence their proinflammatory properties. Our research managed to confirm this hypothesis. Human serum albumin (HSA) was glycated with methylglyoxal (MG), and HSA-MG was adsorbed onto mineral microparticles composed of calcium carbonate nanocrystals (vaterite polymorph, CC) or hydroxyapatite nanowires (CP). As scopoletin fluorescence has shown, H2O2 generation by neutrophils stimulated with HSA-MG was inhibited with diphenyleneiodonium chloride, wortmannin, genistein and EDTA, indicating a key role for NADPH-oxidase, protein tyrosine kinase, phosphatidylinositol 3-kinase and divalent ions (presumably Ca2+) in HSA-MG-induced neutrophil respiratory burst. Superoxide anion generation assessed by lucigenin-enhanced chemiluminescence (Luc-CL) was significantly enhanced by free HSA-MG and by both CC-HSA-MG and CP-HSA-MG microparticles. Comparing the concentrations of CC-bound and free HSA-MG, one could see that adsorption enhanced the neutrophil-activating capacity of HSA-MG.

A correlative study of copper, ceruloplasmin, iron, total iron binding capacity and total antioxidant capacity in diabetic nephropathy

Introduction and Aim: Diabetic nephropathy is the common cause of final stage of kidney disease. Studies on trace elements and oxidant-antioxidant status in diabetes mellitus are required for establishing the mechanisms involved in pathogenesis of diabetic complications, and also to establish biomarkers of diabetic nephropathy in addition to the conventional markers. The present study aimed to assess and correlate the blood levels of copper, iron, ceruloplasmin, total iron binding capacity (TIBC) and total antioxidant capacity (TAC) in diabetic nephropathy patients in comparison to diabetic individuals without complications and normal healthy controls. Materials and Methods: The study subjects were, diabetic patients with nephropathy (group 1), diabetic patients without complications (group 2), and healthy controls (group 3). In the serum samples of all study subjects levels of copper, iron, ceruloplasmin, TIBC and TAC were estimated by standard spectrophotometric methods. Results: Levels of copper, ceruloplasmin, iron and TIBC in serum were significantly higher and TAC was lower in diabetic patients when compared to controls, and more pronounced changes were seen in diabetic nephropathy patients when compared to diabetic patients with no complications. There was significant positive correlation among glycated hemoglobin, copper, iron and microalbumin in diabetic patients with or without nephropathy. Serum Total antioxidant capacity showed significant negative correlation with HbA1c, microalbuminuria, copper, and iron in diabetic patients with and without nephropathy. Conclusion: Serum levels of trace elements could serve as diagnostic and prognostic biomarkers of diabetic nephropathy complimentary to microalbuminuria and glycated haemoglobin. Monitoring the trace elements and oxidative stress biomarkers in diabetic patients could be beneficial to prevent oxidative stress and pathogenesis of diabetic complications.