|
1
|
Larry M, Rabizadeh S, Mohammadi F, Yadegar A, Jalalpour A, Mirmiranpour H, Farahmand G, Esteghamati A, Nakhjavani M. Relationship between advanced glycation end-products and advanced oxidation protein products in patients with type 2 diabetes with and without albuminuria: A cross-sectional survey. Health Sci Rep 2024; 7:e70057. [PMID: 39355098 PMCID: PMC11439888 DOI: 10.1002/hsr2.70057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 08/02/2024] [Accepted: 08/16/2024] [Indexed: 10/03/2024] Open
Abstract
Background and Aims Literature suggests that oxidative stress plays a crucial role in the progression of diabetes. Since poor glycemic control enhances the formation of advanced glycation end-products (AGEs) and advanced oxidation protein products (AOPP) in individuals with diabetes, exploring the association between glycation and oxidative states in diabetes could also shed light on potential consequences. This study evaluated the effects of albuminuria on AGEs and AOPP levels and measured their relationship in participants with type 2 diabetes (T2D) with or without albuminuria. Methods A cross-sectional, matched case-control study was designed, including 38 T2D subjects with albuminuria and 38 matched T2D subjects with normoalbuminuria. Patients were matched by their body mass index (BMI), age, and duration of diabetes. The unadjusted and adjusted correlation between AGEs and AOPP in the studied groups were analyzed by multiple logistic regression. Using ggplot2, the ties between these two biochemical factors in cases and controls were plotted. Results This study elucidated a significant association between AGEs and AOPP in participants with normoalbuminuria (r = 0.331, p-value < 0.05), which continued to be significant after controlling for BMI, age, systolic blood pressure (SBP), and diastolic blood pressure (DBP) (r = 0.355, p-value < 0.05). However, there was no significant association between AGEs and AOPP in those with albuminuria in the unadjusted model (r = 0.034, p-value = 0.841) or after controlling for BMI, age, SBP, and DBP (r = 0.076, p-value = 0.685). Conclusion Oxidation and glycation molecular biomarkers were correlated in patients without albuminuria; however, this association was not observed in those with albuminuria.
Collapse
Affiliation(s)
- Mehrdad Larry
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Soghra Rabizadeh
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Fatemeh Mohammadi
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Amirhossein Yadegar
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Azadeh Jalalpour
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Hossein Mirmiranpour
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Ghasem Farahmand
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Alireza Esteghamati
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC), Vali‐Asr HospitalTehran University of Medical SciencesTehranIran
| |
Collapse
|
|
2
|
Lapolla A. Thirty years of fruitful collaborations between a physician and mass spectrometrists in diabetes field. MASS SPECTROMETRY REVIEWS 2023; 42:1086-1112. [PMID: 34747543 DOI: 10.1002/mas.21742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 06/26/2021] [Accepted: 06/28/2021] [Indexed: 06/07/2023]
Abstract
The nonenzymatic protein glycation and the subsequent formation of advanced glycation end products is a process involved in the long-term complications of diabetes. In this context the collaboration, in the last 30 years, between my research group, operating in the DPT of Medicine of Padua University, and the mass spectrometric group, operating in CNR of Padua, are described and discussed. The development of new mass spectrometric techniques has allowed investigation more indepth, starting from the applications on small molecules responsible for the browning observed in the interactions between sugars and proteins, and growing up to intact proteins as albumin, immunoglobulin, hemoglobin, and so forth, with the determination of their glycation levels as well as their glycation sites. This study has helped to clarify the role of advanced glycation end products in the pathogenesis of the chronic complications of diabetes. In particular the results obtained in diabetic nephropathy, diabetic cardiovascular disease and in placenta samples of patients affected by gestational diabetes are described in this review.
Collapse
|
|
3
|
Asbaghi O, Nazarian B, Yousefi M, Anjom-Shoae J, Rasekhi H, Sadeghi O. Effect of vitamin E intake on glycemic control and insulin resistance in diabetic patients: an updated systematic review and meta-analysis of randomized controlled trials. Nutr J 2023; 22:10. [PMID: 36800965 PMCID: PMC9936725 DOI: 10.1186/s12937-023-00840-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/30/2023] [Indexed: 02/19/2023] Open
Abstract
Since a 2014 meta-analysis, several randomized controlled trials (RCTs) evaluating the effect of vitamin E intake on glycemic indices and insulin resistance in adults with diabetes have reached inconsistent conclusions. Therefore, we updated the previous meta-analysis to summarize the current evidence in this regard. Online databases including PubMed, Scopus, ISI Web of Science, and Google Scholar were searched to identify relevant studies published up to September 30, 2021, using relevant keywords. Random-effects models were used to obtain overall mean difference (MD) comparing vitamin E intake with a control group. In total, 38 RCTs with a total sample size of 2171 diabetic patients (1110 in vitamin E groups and 1061 in control groups) were included. Combining the results from 28 RCTs on fasting blood glucose, 32 RCTs on HbA1c, 13 RCTs on fasting insulin, and 9 studies on homeostatic model assessment for insulin resistance (HOMA-IR) showed a summary MD of -3.35 mg/dL (95% CI: -8.10 to 1.40, P = 0.16), -0.21% (95% CI: -0.33 to -0.09, P = 0.001), -1.05 µIU/mL (95% CI: -1.53 to -0.58, P < 0.001), and -0.44 (95% CI: -0.82 to -0.05, P = 0.02), respectively. This indicates a significant lowering effect of vitamin E on HbA1c, fasting insulin and HOMA-IR, while no significant effect on fasting blood glucose in diabetic patients. However, in subgroup analyses, we found that vitamin E intake significantly reduced fasting blood glucose in studies with an intervention duration of < 10 weeks. In conclusion, vitamin E intake has a beneficial role in improving HbA1c and insulin resistance in a population with diabetes. Moreover, short-term interventions with vitamin E have resulted in lower fasting blood glucose in these patients. This meta-analysis was registered in PROSPERO with code CRD42022343118.
Collapse
Affiliation(s)
- Omid Asbaghi
- Cancer Research Center, Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Nazarian
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Mojtaba Yousefi
- Department of Nutrition, School of Health and Nutrition, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Javad Anjom-Shoae
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, University of Adelaide, Adelaide, SA, 5005, Australia
| | - Hamid Rasekhi
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute and Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Omid Sadeghi
- Nutrition and Food Security Research Center and Department of Community Nutrition, School of Nutrition & Food Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
- Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran.
| |
Collapse
|
|
4
|
deRamon EA, Sabbasani VR, Streeter MD, Liu Y, Newhouse TR, McDonald DM, Spiegel DA. Pentosinane, a Post-Translational Modification of Human Proteins with Underappreciated Stability. J Am Chem Soc 2022; 144:21843-21847. [PMID: 36410375 PMCID: PMC11000625 DOI: 10.1021/jacs.2c09626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Pentosinane is a structurally complex nonenzymatic post-translational modification of proteins believed to be present in all living things. It falls into the category of advanced glycation end products (AGEs) and is structurally related to the other AGEs pentosidine and glucosepane. Although pentosidine and glucosepane have been widely studied for their role in wide-ranging conditions (e.g., diabetes mellitus, Alzheimer's disease, and human aging), relatively little is known about pentosinane. Interestingly, previous reports have suggested that pentosidine may derive from pentosinane. The (patho)physiological significance of pentosinane in humans is largely unexplored. As a first step to address this knowledge gap, we report herein the first total synthesis of pentosinane. Our synthesis is high yielding (1.7% over seven steps), concise, and enantioselective, and it leverages a strategy for synthesizing 2,5-diaminoimidazoles previously developed by our lab. Access to synthetic pentosinane has allowed us to perform additional studies showing that its oxidation to pentosidine is both pH and oxygen dependent and is substantially slower under physiological conditions than previously believed. Additionally, pentosinane rapidly decomposes under harshly acidic conditions typically employed for pentosidine isolation. Taken together, these results suggest that pentosinane is likely to be more abundant in vivo than previously appreciated. We believe these results represent a critical step toward illuminating the role(s) of pentosinane in human biology.
Collapse
Affiliation(s)
- Edward A deRamon
- Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
| | - Venkata R Sabbasani
- Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
| | - Matthew D Streeter
- Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
| | - Yannan Liu
- Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
| | - Timothy R Newhouse
- Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
| | - David M McDonald
- Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
| | - David A Spiegel
- Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520, United States
| |
Collapse
|
|
5
|
Effect of a New Formulation of Nutraceuticals as an Add-On to Metformin Monotherapy for Patients with Type 2 Diabetes and Suboptimal Glycemic Control: A Randomized Controlled Trial. Nutrients 2021; 13:nu13072373. [PMID: 34371883 PMCID: PMC8308828 DOI: 10.3390/nu13072373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/29/2021] [Accepted: 07/09/2021] [Indexed: 11/16/2022] Open
Abstract
The aim of the study was to evaluate the overall biohumoral and metabolic effects of a 12-week add-on therapy consisting of a new nutraceutical formulation (BHC) based on berberine, hesperidin, and chromium picolinate in type 2 diabetes mellitus (T2D) patients with suboptimal glycemic compensation receiving metformin. After 12 weeks, participants in the group receiving metformin plus BHC, compared to the group receiving metformin only, saw a significant improvement in their glucose profile, in terms of both glycated hemoglobin (HbA1c) and fasting blood glucose (FBG). Their FBG dropped from 145 ± 20 mg/dL to 128 ± 23 mg/dL (p < 0.01), a decrease of 11.7% compared with the baseline. This decrease differed significantly from the situation in the control arm (p < 0.05). HbA1c decreased by 7.5% from the baseline, from 53.5 ± 4.3 mmol/mol to 49.5 ± 5.1 mmol/mol (p < 0.01), in the group given BHC, while no difference was seen in the control group. Advanced glycation end products (AGEs) and malondialdehyde (MDA) were found to be significantly reduced (p < 0.01) only in the BHC group, from 9.34 ± 7.61 μg/mL to 6.75 ± 6.13 μg/mL, and from 1.7 ± 0.15 μmol/L to 1.4 ± 0.25 μmol/L, respectively. In patients with T2D taking metformin with suboptimal glycemic compensation, adding BHC for 3 months significantly improved glucose control in terms of FBG and HbA1c, and had a positive effect on the lipid peroxidation profile, as indicated by a decrease in AGEs and MDA.
Collapse
|
|
6
|
Vodošek Hojs N, Bevc S, Ekart R, Hojs R. Oxidative Stress Markers in Chronic Kidney Disease with Emphasis on Diabetic Nephropathy. Antioxidants (Basel) 2020; 9:925. [PMID: 32992565 PMCID: PMC7600946 DOI: 10.3390/antiox9100925] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 09/24/2020] [Indexed: 02/07/2023] Open
Abstract
Diabetes prevalence is increasing worldwide, especially through the increase of type 2 diabetes. Diabetic nephropathy occurs in up to 40% of diabetic patients and is the leading cause of end-stage renal disease. Various factors affect the development and progression of diabetic nephropathy. Hyperglycaemia increases free radical production, resulting in oxidative stress, which plays an important role in the pathogenesis of diabetic nephropathy. Free radicals have a short half-life and are difficult to measure. In contrast, oxidation products, including lipid peroxidation, protein oxidation, and nucleic acid oxidation, have longer lifetimes and are used to evaluate oxidative stress. In recent years, different oxidative stress biomarkers associated with diabetic nephropathy have been found. This review summarises current evidence of oxidative stress biomarkers in patients with diabetic nephropathy. Although some of them are promising, they cannot replace currently used clinical biomarkers (eGFR, proteinuria) in the development and progression of diabetic nephropathy.
Collapse
Affiliation(s)
- Nina Vodošek Hojs
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia; (N.V.H.); (S.B.)
| | - Sebastjan Bevc
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia; (N.V.H.); (S.B.)
- Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia;
| | - Robert Ekart
- Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia;
- Department of Dialysis, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia
| | - Radovan Hojs
- Department of Nephrology, Clinic for Internal Medicine, University Medical Centre Maribor, Ljubljanska 5, 2000 Maribor, Slovenia; (N.V.H.); (S.B.)
- Faculty of Medicine, University of Maribor, Taborska 8, 2000 Maribor, Slovenia;
| |
Collapse
|
|
7
|
Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T, Mohan ML, Li L, Wu Y, Funabashi M, Ramer-Tait AE, Naga Prasad SV, Fiehn O, Rey FE, Tang WHW, Fischbach MA, DiDonato JA, Hazen SL. A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. Cell 2020; 180:862-877.e22. [PMID: 32142679 DOI: 10.1016/j.cell.2020.02.016] [Citation(s) in RCA: 471] [Impact Index Per Article: 94.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 12/16/2019] [Accepted: 02/07/2020] [Indexed: 02/08/2023]
Abstract
Using untargeted metabolomics (n = 1,162 subjects), the plasma metabolite (m/z = 265.1188) phenylacetylglutamine (PAGln) was discovered and then shown in an independent cohort (n = 4,000 subjects) to be associated with cardiovascular disease (CVD) and incident major adverse cardiovascular events (myocardial infarction, stroke, or death). A gut microbiota-derived metabolite, PAGln, was shown to enhance platelet activation-related phenotypes and thrombosis potential in whole blood, isolated platelets, and animal models of arterial injury. Functional and genetic engineering studies with human commensals, coupled with microbial colonization of germ-free mice, showed the microbial porA gene facilitates dietary phenylalanine conversion into phenylacetic acid, with subsequent host generation of PAGln and phenylacetylglycine (PAGly) fostering platelet responsiveness and thrombosis potential. Both gain- and loss-of-function studies employing genetic and pharmacological tools reveal PAGln mediates cellular events through G-protein coupled receptors, including α2A, α2B, and β2-adrenergic receptors. PAGln thus represents a new CVD-promoting gut microbiota-dependent metabolite that signals via adrenergic receptors.
Collapse
Affiliation(s)
- Ina Nemet
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Prasenjit Prasad Saha
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Nilaksh Gupta
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Weifei Zhu
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Kymberleigh A Romano
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Sarah M Skye
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Tomas Cajka
- West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA
| | - Maradumane L Mohan
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Lin Li
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Yuping Wu
- Department of Mathematics, Cleveland State University, Cleveland, OH 44115, USA
| | - Masanori Funabashi
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA
| | - Amanda E Ramer-Tait
- Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | | | - Oliver Fiehn
- West Coast Metabolomics Center, University of California, Davis, Davis, CA 95616, USA
| | - Federico E Rey
- Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - W H Wilson Tang
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA; Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Michael A Fischbach
- Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA
| | - Joseph A DiDonato
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA
| | - Stanley L Hazen
- Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44106, USA; Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44106, USA.
| |
Collapse
|
|
8
|
Sartore G, Ragazzi E, Burlina S, Paleari R, Chilelli NC, Mosca A, Avemaria F, Lapolla A. Role of fructosamine-3-kinase in protecting against the onset of microvascular and macrovascular complications in patients with T2DM. BMJ Open Diabetes Res Care 2020; 8:8/1/e001256. [PMID: 32467223 PMCID: PMC7259852 DOI: 10.1136/bmjdrc-2020-001256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/02/2020] [Accepted: 04/30/2020] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION Microangiopathic and macroangiopathic complications are the main cause of morbidity and mortality in the diabetic population. Numerous publications have highlighted the role of glycation in the onset of complications of diabetes. In this context, the detection of fructosamine-3-kinase (FN3K)-an enzyme capable of counteracting the effect of hyperglycemia by intervening in protein glycation-has attracted great interest. Several studies have linked FN3K genetic variability to its enzymatic activity and glycated hemoglobin (HbA1c) levels. Here, we investigated the role of FN3K polymorphisms in the development of microvascular and macrovascular complications of diabetes. RESEARCH DESIGN AND METHODS The anthropometric and biochemical parameters, and any medical history of microangiopathic and macroangiopathic complications, were documented in a sample of 80 subjects with type 2 diabetes. All subjects were screened for FN3K gene and analyzed for the combination of three polymorphisms known to be associated with its enzymatic activity (rs3859206 and rs2256339 in the promoter region and rs1056534 in exon 6). RESULTS The combination of allelic variants of FN3K polymorphisms resulted in 13 distinct genotypic variants within the cohort. Comparison between genotypes showed no significant differences in terms of demographic, anthropometric and biochemical parameters, risk markers and long-term complications, except for a higher age and vitamin E levels associated with the genotype presenting GG at position -385, TT at position -232, and CC at c.900 A. Evaluating the microangiopathic and macroangiopathic complications as a whole, we found that they appeared significantly less present in this genotype compared with all other genotypes (p=0.0306). CONCLUSIONS The group of patients carrying the favorable allele for the three polymorphisms of the FN3K gene revealed less severe microangiopathy and macroangiopathy, suggesting a protective role of this genotype against the onset of the complications of diabetes.
Collapse
Affiliation(s)
- Giovanni Sartore
- Department of Medicine (DIMED), University of Padova School of Medicine and Surgery, Padova, Italy
| | - Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova School of Medicine and Surgery, Padova, Italy
| | - Silvia Burlina
- Department of Medicine (DIMED), University of Padova School of Medicine and Surgery, Padova, Italy
| | - Renata Paleari
- Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), Milan, Italy
| | - Nino Cristiano Chilelli
- Department of Medicine (DIMED), University of Padova School of Medicine and Surgery, Padova, Italy
| | - Andrea Mosca
- Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), Milan, Italy
| | - Francesca Avemaria
- Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy
| | - Annunziata Lapolla
- Department of Medicine (DIMED), University of Padova School of Medicine and Surgery, Padova, Italy
| |
Collapse
|
|
9
|
Di Vincenzo A, Tana C, El Hadi H, Pagano C, Vettor R, Rossato M. Antioxidant, Anti-Inflammatory, and Metabolic Properties of Tocopherols and Tocotrienols: Clinical Implications for Vitamin E Supplementation in Diabetic Kidney Disease. Int J Mol Sci 2019; 20:ijms20205101. [PMID: 31618817 PMCID: PMC6834186 DOI: 10.3390/ijms20205101] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 12/23/2022] Open
Abstract
Diabetes mellitus is a metabolic disorder characterized by the development of vascular complications associated with high morbidity and mortality and the consequent relevant costs for the public health systems. Diabetic kidney disease is one of these complications that represent the main cause of end-stage renal disease in Western countries. Hyperglycemia, inflammation, and oxidative stress contribute to its physiopathology, and several investigations have been performed to evaluate the role of antioxidant supplementation as a complementary approach for the prevention and control of diabetes and associated disturbances. Vitamin E compounds, including different types of tocopherols and tocotrienols, have been considered as a treatment to tackle major cardiovascular outcomes in diabetic subjects, but often with conflicting or even negative results. However, their effects on diabetic nephropathy are even less clear, despite several intervention studies that showed the improvement of renal parameters after supplementation in patients with diabetic kidney disease. Then we performed a review of the literature about the role of vitamin E supplementation on diabetic nephropathy, also describing the underlying antioxidant, anti-inflammatory, and metabolic mechanisms to evaluate the possible use of tocopherols and tocotrienols in clinical practice.
Collapse
Affiliation(s)
- Angelo Di Vincenzo
- Department of Medicine-DIMED, Clinica Medica 3, Center for the Study and Integrated Management of Obesity, University-Hospital of Padova, 35100 Padova, Italy.
| | - Claudio Tana
- Internal Medicine and Critical Subacute Care Unit, Medicine Geriatric-Rehabilitation Department, and Department of Medicine and Surgery, University-Hospital of Parma, 43126 Parma, Italy.
| | - Hamza El Hadi
- Department of Medicine-DIMED, Clinica Medica 3, Center for the Study and Integrated Management of Obesity, University-Hospital of Padova, 35100 Padova, Italy.
- Department of Medicine, Klinikum Rheine, 48431 Rheine, Germany.
| | - Claudio Pagano
- Department of Medicine-DIMED, Clinica Medica 3, Center for the Study and Integrated Management of Obesity, University-Hospital of Padova, 35100 Padova, Italy.
| | - Roberto Vettor
- Department of Medicine-DIMED, Clinica Medica 3, Center for the Study and Integrated Management of Obesity, University-Hospital of Padova, 35100 Padova, Italy.
| | - Marco Rossato
- Department of Medicine-DIMED, Clinica Medica 3, Center for the Study and Integrated Management of Obesity, University-Hospital of Padova, 35100 Padova, Italy.
| |
Collapse
|
|
10
|
Puddu A, Sanguineti R, Maggi D, Nicolò M, Traverso CE, Cordera R, Viviani GL. Advanced Glycation End-Products and Hyperglycemia Increase Angiopoietin-2 Production by Impairing Angiopoietin-1-Tie-2 System. J Diabetes Res 2019; 2019:6198495. [PMID: 31828164 PMCID: PMC6881581 DOI: 10.1155/2019/6198495] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 10/11/2019] [Accepted: 10/18/2019] [Indexed: 12/19/2022] Open
Abstract
The angiopoietin-Tie-2 system plays a crucial role in the maintenance of endothelial integrity. Hyperglycemia and advanced glycation end-products (AGEs) are involved in endothelial cell dysfunction responsible of the pathogenesis of microvascular complications of diabetes. Here, we investigated whether glycated serum (GS) or hyperglycemia (HG) affect the angiopoietin-Tie-2 system in the microvascular endothelial cells HMEC-1. We found that culture for 5 days in the presence of AGEs and HG (alone or in combination) decreased cell proliferation, increased reactive oxygen species (ROS) production, and reduced ratio between the oxidized and the reduced form of glutathione. Since angiopoietin-1 (Ang-1) signaling regulates angiopoietin-2 (Ang-2) expression through inactivation of the forkhead transcription factor FoxO1, we investigated intracellular signaling of Ang-1 and expression of Ang-2. HG and AGEs reduced phosphorylation of Akt and abrogated phosphorylation of FoxO1 induced by Ang-1 without affecting neither Tie-2 expression nor its activation. Furthermore, AGEs and/or HG induced nuclear translocation of FoxO1 and increased Ang-2 production. In conclusion, we demonstrated that both hyperglycemia and AGEs affect the angiopoietin-Tie-2 system by impairing Ang-1/Tie-2 signaling and by increasing Ang-2 expression. These results suggest that therapeutic strategies useful in preventing or delaying the onset of diabetic vascular complications should be aimed to preserve Ang-1 signaling.
Collapse
Affiliation(s)
- Alessandra Puddu
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Roberta Sanguineti
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Davide Maggi
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Massimo Nicolò
- Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Genova 16132, Italy
- Fondazione per la Macula Onlus, Genova 16132, Italy
| | - Carlo E. Traverso
- Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Genova 16132, Italy
| | - Renzo Cordera
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| | - Giorgio L. Viviani
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova 16132, Italy
| |
Collapse
|
|
11
|
Abdullah K, Alam MM, Iqbal Z, Naseem I. Therapeutic effect of vitamin B3 on hyperglycemia, oxidative stress and DNA damage in alloxan induced diabetic rat model. Biomed Pharmacother 2018; 105:1223-1231. [DOI: 10.1016/j.biopha.2018.06.085] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/14/2018] [Accepted: 06/14/2018] [Indexed: 02/05/2023] Open
|
|
12
|
Zha ZM, Wang JH, Li SL, Guo Y. Pitavastatin attenuates AGEs-induced mitophagy via inhibition of ROS generation in the mitochondria of cardiomyocytes. J Biomed Res 2018; 32:281-287. [PMID: 29089470 PMCID: PMC6117602 DOI: 10.7555/jbr.31.20160116] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
This study aimed to investigate whether pitavastatin protected against injury induced by advanced glycation end products products (AGEs) in neonatal rat cardiomyocytes, and to examine the underlying mechanisms. Cardiomyocytes of neonatal rats were incubated for 48 hours with AGEs (100μg/mL), receptor for advanced glycation end products (RAGE), antibody (1μg/mL) and pitavastatin (600 ng/mL). The levels of p62 and beclin1 were determined by Western blotting. Mitochondrial membrane potential (ΔΨm) and the generation of reactive oxygen species (ROS) were measured through the JC-1 and DCFH-DA. In the AGEs group, the expression of beclin1 was remarkably increased compared to the control group, while the expression of p62 was significantly decreased. AGEs also markedly decreased ΔΨm and significantly increased ROS compared with the control group. After treatment with RAGE antibody or pitavastatin, the level of beclin1 was markedly decreased compared with the AGEs group, but the level of p62 was remarkably increased. In the AGEs+ RAGE antibody group and AGEs+ pitavastatin group, ΔΨm was significantly increased and ROS was remarkably decreased compared with the AGEs group. In conclusion, AGEs-RAGE may induce autophagy of cardiomyocytes by generation of ROS and pitavastatin could protect against AGEs-induced injury against cardiomyocytes.
Collapse
Affiliation(s)
- Zhi-Min Zha
- Department of Gerontology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Jun-Hong Wang
- Department of Gerontology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.,Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Shi-Ling Li
- Department of Gerontology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yan Guo
- Department of Gerontology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.,Department of Cardioangiology, Shengze Hospital of Jiangsu Province, Suzhou, China
| |
Collapse
|
|
13
|
Papadopoulou-Marketou N, Kanaka-Gantenbein C, Marketos N, Chrousos GP, Papassotiriou I. Biomarkers of diabetic nephropathy: A 2017 update. Crit Rev Clin Lab Sci 2017; 54:326-342. [DOI: 10.1080/10408363.2017.1377682] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Nektaria Papadopoulou-Marketou
- Diabetes Centre of the Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece
- Department of Endocrinology, Department of Medical and Health Sciences, Linkoping University, Linkoping, Sweden
| | - Christina Kanaka-Gantenbein
- Diabetes Centre of the Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece
| | | | - George P. Chrousos
- Diabetes Centre of the Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece
| | - Ioannis Papassotiriou
- Department of Clinical Biochemistry, “Aghia Sophia” Children’s Hospital, Athens, Greece
| |
Collapse
|
|
14
|
Association of paraoxonase 1 and oxidative stress with acute kidney injury in premature asphyxiated neonates. Chem Biol Interact 2017; 272:47-52. [DOI: 10.1016/j.cbi.2017.04.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 04/04/2017] [Accepted: 04/18/2017] [Indexed: 11/30/2022]
|
|
15
|
Campion CG, Sanchez-Ferras O, Batchu SN. Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy. Can J Kidney Health Dis 2017; 4:2054358117705371. [PMID: 28616250 PMCID: PMC5461910 DOI: 10.1177/2054358117705371] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 02/17/2017] [Indexed: 12/11/2022] Open
Abstract
PURPOSE OF REVIEW Diabetic nephropathy (DN) is a progressive kidney disease caused by alterations in kidney architecture and function, and constitutes one of the leading causes of end-stage renal disease (ESRD). The purpose of this review is to summarize the state of the art of the DN-biomarker field with a focus on the new strategies that enhance the sensitivity of biomarkers to predict patients who will develop DN or are at risk of progressing to ESRD. OBJECTIVE In this review, we provide a description of the pathophysiology of DN and propose a panel of novel putative biomarkers associated with DN pathophysiology that have been increasingly investigated for diagnosis, to predict disease progression or to provide efficient personal treatment. METHODS We performed a review of the literature with PubMed and Google Scholar to collect baseline data about the pathophysiology of DN and biomarkers associated. We focused our research on new and emerging biomarkers of DN. KEY FINDINGS In this review, we summarized the critical signaling pathways and biological processes involved in DN and highlighted the pathogenic mediators of this disease. We next proposed a large review of the major advances that have been made in identifying new biomarkers which are more sensitive and reliable compared with currently used biomarkers. This includes information about emergent biomarkers such as functional noncoding RNAs, microRNAs, long noncoding RNAs, exosomes, and microparticles. LIMITATIONS Despite intensive strategies and constant investigation, no current single treatment has been able to reverse or at least mitigate the progression of DN, or reduce the morbidity and mortality associated with this disease. Major difficulties probably come from the renal disease being heterogeneous among the patients. IMPLICATIONS Expanding the proteomics screening, including oxidative stress and inflammatory markers, along with metabolomics approaches may further improve the prognostic value and help in identifying the patients with diabetes who are at high risk of developing kidney diseases.
Collapse
Affiliation(s)
- Carole G. Campion
- Centre de recherche, Centre Hospitalier de l’Université de Montréal (CRCHUM), Québec, Canada
| | - Oraly Sanchez-Ferras
- Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Québec, Canada
| | - Sri N. Batchu
- St. Michael’s Hospital, University of Toronto, Ontario, Canada
| |
Collapse
|
|
16
|
Madonna R, Balistreri CR, Geng YJ, De Caterina R. Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches. Vascul Pharmacol 2017; 90:1-7. [PMID: 28137665 DOI: 10.1016/j.vph.2017.01.004] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 01/26/2017] [Indexed: 12/11/2022]
Abstract
Diabetic microangiopathy, including retinopathy, is characterized by abnormal growth and leakage of small blood vessels, resulting in local edema and functional impairment of the depending tissues. Mechanisms leading to the impairment of microcirculation in diabetes are multiple and still largely unclear. However, a dysregulated vascular regeneration appears to play a key role. In addition, oxidative and hyperosmolar stress, as well as the activation of inflammatory pathways triggered by advanced glycation end-products and toll-like receptors, have been recognized as key underlying events. Here, we review recent knowledge on cellular and molecular pathways of microvascular disease in diabetes. We also highlight how new insights into pathogenic mechanisms of vascular damage in diabetes may indicate new targets for prevention and treatment.
Collapse
Affiliation(s)
- Rosalinda Madonna
- Center of Excellence on Aging (CesiMet), Institute of Cardiology, Department of Neurosciences, Imaging and Clinical Sciences, "G. d'Annunzio" University, Chieti, Italy; The Texas Heart Institute, Center for Cardiovascular Biology and Atherosclerosis Research, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Carmela Rita Balistreri
- Department of Pathobiology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | - Yong-Jian Geng
- The Texas Heart Institute, Center for Cardiovascular Biology and Atherosclerosis Research, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Raffaele De Caterina
- Center of Excellence on Aging (CesiMet), Institute of Cardiology, Department of Neurosciences, Imaging and Clinical Sciences, "G. d'Annunzio" University, Chieti, Italy.
| |
Collapse
|
|
17
|
Lin CH, Chang YC, Chuang LM. Early detection of diabetic kidney disease: Present limitations and future perspectives. World J Diabetes 2016; 7:290-301. [PMID: 27525056 PMCID: PMC4958689 DOI: 10.4239/wjd.v7.i14.290] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/29/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common diabetic complications, as well as the leading cause of chronic kidney disease and end-stage renal disease around the world. To prevent the dreadful consequence, development of new assays for diagnostic of DKD has always been the priority in the research field of diabetic complications. At present, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate (eGFR) are the standard methods for assessing glomerular damage and renal function changes in clinical practice. However, due to diverse tissue involvement in different individuals, the so-called “non-albuminuric renal impairment” is not uncommon, especially in patients with type 2 diabetes. On the other hand, the precision of creatinine-based GFR estimates is limited in hyperfiltration status. These facts make albuminuria and eGFR less reliable indicators for early-stage DKD. In recent years, considerable progress has been made in the understanding of the pathogenesis of DKD, along with the elucidation of its genetic profiles and phenotypic expression of different molecules. With the help of ever-evolving technologies, it has gradually become plausible to apply the thriving information in clinical practice. The strength and weakness of several novel biomarkers, genomic, proteomic and metabolomic signatures in assisting the early diagnosis of DKD will be discussed in this article.
Collapse
|
|
18
|
Development of albuminuria and enhancement of oxidative stress during chronic renin-angiotensin system suppression. J Hypertens 2016; 32:2082-91; discussion 2091. [PMID: 25033166 DOI: 10.1097/hjh.0000000000000292] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Albuminuria has been recently described in hypertensive patients under chronic renin-angiotensin system (RAS) suppression. We investigated whether this fact could be related to an increase in oxidative stress. METHODS We examined normoalbuminuric and albuminuric patients in stage 2 chronic kidney disease, both with more than 2 years of RAS blockade. The relationship between albuminuria and circulating biomarkers for both oxidative damage, that is carbonyl and malondialdehyde, as well as antioxidant defense, that is reduced glutathione, thiol groups, uric acid, bilirubin, or catalase, and superoxide scavenging activity, was assessed. RESULTS We found that only patients with albuminuria showed an important increase in carbonyls (P < 0.001) and malondialdehyde (P < 0.05) compared to normoalbuminuric patients. This increase in oxidative damage was also accompanied by a rise in catalase activity (P < 0.05) and low-molecular-weight antioxidants only when they were measured as total antioxidant capacity (P < 0.01). In order to establish the specific oxidative status of each group, new indexes of oxidative damage and antioxidant defense were calculated with all these markers following a mathematical and statistical approach. Although both pro-oxidant and antioxidant indexes were significantly increased in patients with albuminuria, only the oxidative damage index positively correlated with the increase of albumin/creatinine ratio (P = 0.0024). CONCLUSIONS We conclude that albuminuria is accompanied by an amplified oxidative damage in patients in early stages of chronic kidney disease. These results indicate that chronic RAS protection must be directed to avoid development of albuminuria and oxidative damage.
Collapse
|
|
19
|
Pulsatile Hyperglycaemia Induces Vascular Oxidative Stress and GLUT 1 Expression More Potently than Sustained Hyperglycaemia in Rats on High Fat Diet. PLoS One 2016; 11:e0147412. [PMID: 26790104 PMCID: PMC4720376 DOI: 10.1371/journal.pone.0147412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 01/04/2016] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Pulsatile hyperglycaemia resulting in oxidative stress may play an important role in the development of macrovascular complications. We investigated the effects of sustained vs. pulsatile hyperglycaemia in insulin resistant rats on markers of oxidative stress, enzyme expression and glucose metabolism in liver and aorta. We hypothesized that liver's ability to regulate the glucose homeostasis under varying states of hyperglycaemia may indirectly affect oxidative stress status in aorta despite the amount of glucose challenged with. METHODS Animals were infused with sustained high (SHG), low (SLG), pulsatile (PLG) glucose or saline (VEH) for 96 h. Oxidative stress status and key regulators of glucose metabolism in liver and aorta were investigated. RESULTS Similar response in plasma lipid oxidation was observed in PLG as in SHG. Likewise, in aorta, PLG and SHG displayed increased expression of glucose transporter 1 (GLUT1), gp-91PHOX and super oxide dismutase (SOD), while only the PLG group showed increased accumulation of oxidative stress and oxidised low density lipoprotein (oxLDL) in aorta. CONCLUSION Pulsatile hyperglycaemia induced relatively higher levels of oxidative stress systemically and in aorta in particular than overt sustained hyperglycaemia thus supporting the clinical observations that pulsatile hyperglycaemia is an independent risk factor for diabetes related macrovascular complications.
Collapse
|
|
20
|
Nita M, Grzybowski A. The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:3164734. [PMID: 26881021 PMCID: PMC4736974 DOI: 10.1155/2016/3164734] [Citation(s) in RCA: 902] [Impact Index Per Article: 100.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 11/16/2015] [Accepted: 11/17/2015] [Indexed: 12/18/2022]
Abstract
The reactive oxygen species (ROS) form under normal physiological conditions and may have both beneficial and harmful role. We search the literature and current knowledge in the aspect of ROS participation in the pathogenesis of anterior and posterior eye segment diseases in adults. ROS take part in the pathogenesis of keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, stimulating apoptosis of corneal cells. ROS play a role in the pathogenesis of glaucoma stimulating apoptotic and inflammatory pathways on the level of the trabecular meshwork and promoting retinal ganglion cells apoptosis and glial dysfunction in the posterior eye segment. ROS play a role in the pathogenesis of Leber's hereditary optic neuropathy and traumatic optic neuropathy. ROS induce apoptosis of human lens epithelial cells. ROS promote apoptosis of vascular and neuronal cells and stimulate inflammation and pathological angiogenesis in the course of diabetic retinopathy. ROS are associated with the pathophysiological parainflammation and autophagy process in the course of the age-related macular degeneration.
Collapse
Affiliation(s)
- Małgorzata Nita
- Domestic and Specialized Medicine Centre “Dilmed”, Ulica Bohaterów Monte Cassino 3, 40-231 Katowice, Poland
| | - Andrzej Grzybowski
- Department of Ophthalmology, Poznan City Hospital, Ulica Szwajcarska 3, 61-285 Poznań, Poland
- Chair of Ophthalmology, Medical Faculty, University of Warmia and Mazury, Ulica Żołnierska 14 C, 10-719 Olsztyn, Poland
| |
Collapse
|
|
21
|
Gluhovschi C, Gluhovschi G, Petrica L, Timar R, Velciov S, Ionita I, Kaycsa A, Timar B. Urinary Biomarkers in the Assessment of Early Diabetic Nephropathy. J Diabetes Res 2016; 2016:4626125. [PMID: 27413755 PMCID: PMC4927990 DOI: 10.1155/2016/4626125] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 05/12/2016] [Indexed: 12/12/2022] Open
Abstract
Diabetic nephropathy (DN) is a frequent and severe complication of diabetes mellitus (DM). Its diagnosis in incipient stages may allow prompt interventions and an improved prognosis. Towards this aim, biomarkers for detecting early DN can be used. Microalbuminuria has been proven a remarkably useful biomarker, being used for diagnosis of DN, for assessing its associated condition-mainly cardiovascular ones-and for monitoring its progression. New researches are pointing that some of these biomarkers (i.e., glomerular, tubular, inflammation markers, and biomarkers of oxidative stress) precede albuminuria in some patients. However, their usefulness is widely debated in the literature and has not yet led to the validation of a new "gold standard" biomarker for the early diagnosis of DN. Currently, microalbuminuria is an important biomarker for both glomerular and tubular injury. Other glomerular biomarkers (transferrin and ceruloplasmin) are under evaluation. Tubular biomarkers in DN seem to be of a paramount importance in the early diagnosis of DN since tubular lesions occur early. Additionally, biomarkers of inflammation, oxidative stress, podocyte biomarkers, and vascular biomarkers have been employed for assessing early DN. The purpose of this review is to provide an overview of the current biomarkers used for the diagnosis of early DN.
Collapse
Affiliation(s)
- Cristina Gluhovschi
- Division of Nephrology, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
- *Cristina Gluhovschi:
| | | | - Ligia Petrica
- Division of Nephrology, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Romulus Timar
- Department of Diabetes and Metabolic Diseases, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Silvia Velciov
- Division of Nephrology, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Ioana Ionita
- Division of Hematology, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Adriana Kaycsa
- Department of Biochemistry, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| | - Bogdan Timar
- Department of Diabetes and Metabolic Diseases, University of Medicine and Pharmacy “V. Babes”, 300041 Timisoara, Romania
| |
Collapse
|
|
22
|
Lodovici M, Bigagli E, Luceri C, Mannucci E, Rotella CM, Raimondi L. Gender-related drug effect on several markers of oxidation stress in diabetes patients with and without complications. Eur J Pharmacol 2015; 766:86-90. [PMID: 26424110 DOI: 10.1016/j.ejphar.2015.09.041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 09/23/2015] [Accepted: 09/24/2015] [Indexed: 01/10/2023]
Abstract
We previously reported that circulating lipid (malondialdehyde, MDA) and protein oxidation (carbonyl residues, CO) products can be used as markers of risk for complications in poorly controlled type 2 diabetics. Now, we aimed to evaluate the existence of a gender effect on classical disease markers and oxidative stress parameters and on the effectiveness of metformin and/or statins in reducing CV risk in poorly controlled type 2 diabetics with and without complications. Our results show that diabetics with complications had higher plasma levels of FRAP, SOD and hs-CRP than those without complications, with FRAP and SOD found increased in both genders. Interestingly, male and female patients with complications had higher plasma levels of hs-CRP and MDA respectively, over patients without complications. Multivariate analysis indicated metformin and statin treatments effective in reducing plasma hs-CRP only in female and not in male diabetics with complications. In these latter females, a positive correlation between hs-CRP and triglycerides (TG) levels was found suggesting a causal relationship between them. Statin treatment was effective in reducing MDA in diabetics with complications irrespective of the gender. These data support the addition of statins to diabetic standard therapy to control oxidation injury and inflammation and, for the first time, indicate female patients with complications more responsive than males to the CV protection offered by metformin.
Collapse
Affiliation(s)
- Maura Lodovici
- Department of NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
| | - Elisabetta Bigagli
- Department of NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - Cristina Luceri
- Department of NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | | | - Carlo Maria Rotella
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Laura Raimondi
- Department of NEUROFARBA, Section of Pharmacology and Toxicology, University of Florence, Florence, Italy
| |
Collapse
|
|
23
|
Sartore G, Seraglia R, Burlina S, Bolis A, Marin R, Manzato E, Ragazzi E, Traldi P, Lapolla A. High-density lipoprotein oxidation in type 2 diabetic patients and young patients with premature myocardial infarction. Nutr Metab Cardiovasc Dis 2015; 25:418-425. [PMID: 25636381 DOI: 10.1016/j.numecd.2014.12.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 12/10/2014] [Accepted: 12/12/2014] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND AIMS ApoA-I can undergo oxidative changes that reduce anti-atherogenic role of HDL. The aim of this study was to seek any significant differences in methionine sulfoxide (MetO) content in the ApoA-I of HDL isolated from young patients with coronary heart disease (CHD), type 2 diabetics and healthy subjects. METHODS AND RESULTS We evaluated the lipid profile of 21 type 2 diabetic patients, 23 young patients with premature MI and 21 healthy volunteers; we determined in all patients the MetO content of ApoA-I in by MALDI/TOF/TOF technique. The typical MALDI spectra of the tryptic digest obtained from HDL plasma fractions all patients showed a relative abundance of peptides containing Met(112)O in ApoA-I in type 2 diabetic and CHD patients. This relative abundance is given as percentages of oxidized ApoA-I (OxApoA-I). OxApoA-I showed no significant correlations with lipoproteins in all patients studied, while a strong correlation emerged between the duration of diabetic disease and OxApoA-I levels in type 2 diabetic patients. CONCLUSIONS The most remarkable finding of our study lies in the evidence it produced of an increased HDL oxidation in patients highly susceptible to CHD. Levels of MetO residues in plasma ApoA-I, measured using an accurate, specific method, should be investigated and considered in prospective future studies to assess their role in CHD.
Collapse
Affiliation(s)
- G Sartore
- Department of Medicine - DIMED, University of Padova, Italy
| | | | - S Burlina
- Department of Medicine - DIMED, University of Padova, Italy.
| | - A Bolis
- Department of Medicine - DIMED, University of Padova, Italy
| | - R Marin
- Department of Medicine - DIMED, University of Padova, Italy
| | - E Manzato
- Department of Medicine - DIMED, University of Padova, Italy
| | - E Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Italy
| | | | - A Lapolla
- Department of Medicine - DIMED, University of Padova, Italy
| |
Collapse
|
|
24
|
Tabur S, Korkmaz H, Eren MA, Oğuz E, Sabuncu T, Aksoy N. Urotensin-II level and its association with oxidative stress in early diabetic nephropathy. J Diabetes Complications 2015; 29:115-9. [PMID: 25179234 DOI: 10.1016/j.jdiacomp.2014.07.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 07/24/2014] [Accepted: 07/24/2014] [Indexed: 10/24/2022]
Abstract
OBJECTIVE Diabetic nephropathy is the most common cause of end stage renal failure. Early treatment of diabetic nephropathy depends on understanding the underlying mechanisms of the disease. In this study we investigated the role of U-II in early nephropathy and ıts association with oxidative stress, paraoxonase (PON)-1 and arylesterase. RESEARCH DESIGN AND METHODS Twenty-three diabetic patients with microalbuminuria, 23 diabetic patients with normoalbuminuria and 25 healthy individuals were enrolled in the study. Serum total antioxidant status (TAS), total oxidant status (TOS), PON-1, arylesterase, and urotensin-II (U-II) levels were measured. Oxidative stress index (OSI) percent ratio of TOS to TAS level was accepted as OSI. RESULTS Serum U-II levels were higher in the microalbuminuric diabetes group compared to the normoalbuminuric diabetic group and the healthy control group (p=0.009 and p=0.0001, respectively). Normoalbuminuric diabetic group's U-II levels were significantly higher compared to those of the healthy control group (p=0.0001). Correlation analysis yielded that plasma U-II levels are negatively correlated to TAS, arylesterase, and PON-1 levels (r=-0.395, p=0.001; r=-0.291, p=0.014; and r=-0.279, p=0.018, respectively) and that they had a positive correlation with OSI levels (r=0.312, p=0.008). These associations were confirmed in the multiple regression analysis. The results of multiple logistic regression analysis showed that oxidative stress is important in the development of microalbuminuria. CONCLUSION The data of this study reveal that increased serum U-II has a role in the development of diabetic nephropathy. This effect of U-II may be related to high levels oxidative stress parameters.
Collapse
Affiliation(s)
- Suzan Tabur
- Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Gaziantep University, Sahinbey, Gaziantep 27100, Turkey
| | - Hakan Korkmaz
- Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Gaziantep University, Sahinbey, Gaziantep 27100, Turkey.
| | - Mehmet Ali Eren
- Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Harran University, 63300 Sanliurfa, Turkey
| | - Elif Oğuz
- Department of Medical Pharmacology, Faculty of Medicine, Harran University, 63300 Sanliurfa, Turkey
| | - Tevfik Sabuncu
- Division of Endocrinology, Department of Internal Medicine, Faculty of Medicine, Harran University, 63300 Sanliurfa, Turkey
| | - Nurten Aksoy
- Department of Clinical Biochemistry, Faculty of Medicine, Harran University, 63300 Sanliurfa, Turkey
| |
Collapse
|
|
25
|
Currie G, McKay G, Delles C. Biomarkers in diabetic nephropathy: Present and future. World J Diabetes 2014; 5:763-776. [PMID: 25512779 PMCID: PMC4265863 DOI: 10.4239/wjd.v5.i6.763] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 10/03/2014] [Accepted: 10/27/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy (DN) is the leading cause of end stage renal disease in the Western world. Microalbuminuria (MA) is the earliest and most commonly used clinical index of DN and is independently associated with cardiovascular risk in diabetic patients. Although MA remains an essential tool for risk stratification and monitoring disease progression in DN, a number of factors have called into question its predictive power. Originally thought to be predictive of future overt DN in 80% of patients, we now know that only around 30% of microalbuminuric patients progress to overt nephropathy after 10 years of follow up. In addition, advanced structural alterations in the glomerular basement membrane may already have occurred by the time MA is clinically detectable.Evidence in recent years suggests that a significant proportion of patients with MA can revert to normoalbuminuria and the concept of nonalbuminuric DN is well-documented, reflecting the fact that patients with diabetes can demonstrate a reduction in glomerular filtration rate without progressing from normo-to MA. There is an unmet clinical need to identify biomarkers with potential for earlier diagnosis and risk stratification in DN and recent developments in this field will be the focus of this review article.
Collapse
|
|
26
|
Kerkeni M, Weiss IS, Jaisson S, Dandana A, Addad F, Gillery P, Hammami M. Increased serum concentrations of pentosidine are related to presence and severity of coronary artery disease. Thromb Res 2014; 134:633-8. [PMID: 25065554 DOI: 10.1016/j.thromres.2014.07.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Revised: 05/26/2014] [Accepted: 07/03/2014] [Indexed: 11/18/2022]
Abstract
BACKGROUND There are limited data regarding the contribution of advanced glycation end products (AGEs) in the presence of coronary artery disease (CAD). We investigated whether serum pentosidine and Nε-carboxymethyllysine (CML) were related to the presence and the severity of CAD. METHODS 69 Tunisian patients with CAD (≥ 50% obstruction in ≥ 1 coronary artery), 32 Tunisian patients without CAD but with potential cardiovascular risk factors and 60 Tunisian control subjects were included in a cross-sectional study. Patients were classified as CAD and non CAD patients according to angiographic results. The severity of CAD was assessed using the Gensini score. Serum pentosidine and CML were measured by LC-MS/MS. RESULTS Serum pentosidine and CML concentrations were significantly higher in non-CAD patients vs control subjects (P<0.001). Serum pentosidine concentrations were significantly higher in CAD patients vs non-CAD patients (P<0.001). A multiple logistic regression analysis demonstrated that pentosidine was independently associated with the presence of CAD (OR=1.52, 95% CI: 1.12-2.07, P=0.007). The area under curve (AUC) determined by ROC analysis was 0.74 (95% CI: 0.64-0.84, P<0.001) and the optimal cut-off value of pentosidine to predict the presence of CAD was 3.2 μmol/mol Lys, with 64% sensitivity and 78% specificity. Furthermore, in a multivariate stepwise regression analysis, pentosidine was independently correlated with Gensini score (standardized β= 0.46, 95% CI: 0.70-1.99, P<0.001). CONCLUSIONS High concentrations of pentosidine show the presence and the severity of CAD with high sensitivity.
Collapse
Affiliation(s)
- Mohsen Kerkeni
- Laboratory of Biochemistry, LR12ES05, Faculty of Medicine, University of Monastir, Tunisia.
| | - Izabella Santos Weiss
- Laboratory of Paediatric Biology and Research, American Memorial Hospital, University Hospital of Reims, Faculty of Medicine, Reims, France; Laboratory of Biochemistry and Molecular Biology, UMR CNRS/URCA n°7369, Faculty of Medicine, Reims, France
| | - Stephane Jaisson
- Laboratory of Paediatric Biology and Research, American Memorial Hospital, University Hospital of Reims, Faculty of Medicine, Reims, France; Laboratory of Biochemistry and Molecular Biology, UMR CNRS/URCA n°7369, Faculty of Medicine, Reims, France
| | - Azza Dandana
- Laboratory of Biochemistry, CHU-Farhat Hached, Sousse, Tunisia
| | - Faouzi Addad
- Department of Cardiology-University Hopital A. Mami, Ariana, Tunisia
| | - Philippe Gillery
- Laboratory of Paediatric Biology and Research, American Memorial Hospital, University Hospital of Reims, Faculty of Medicine, Reims, France; Laboratory of Biochemistry and Molecular Biology, UMR CNRS/URCA n°7369, Faculty of Medicine, Reims, France
| | - Mohamed Hammami
- Laboratory of Biochemistry, LR12ES05, Faculty of Medicine, University of Monastir, Tunisia
| |
Collapse
|
|
27
|
Abdelhady MIS, Kamal AM, Othman SM, Mubarak MS, Hadda TB. Total polyphenolic content, antioxidant, cytotoxic, antidiabetic activities, and polyphenolic compounds of Sophora japonica grown in Egypt. Med Chem Res 2014. [DOI: 10.1007/s00044-014-1101-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
28
|
Hopps E, Canino B, Montana M, Lo Presti R, Averna MR, Caimi G. Behavior of the total antioxidant status in a group of subjects with metabolic syndrome. Diabetes Metab Syndr 2014; 8:166-169. [PMID: 25220920 DOI: 10.1016/j.dsx.2014.04.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
AIMS Our purpose was to examine the total antioxidant status (TAS) in subjects with metabolic syndrome (MS) subdivided according to the presence or not of diabetes mellitus. METHODS We enrolled 106 subjects (45 women, 61 men) with MS subsequently subdivided in diabetics (14 women, 29 men) and nondiabetics (31 women, 29 men). TAS was obtained using an Assay kit which relies on the ability of plasma antioxidant substances to inhibit the oxidation of 2,2'-azino-bis(3-ethylbenzthiazoline sulfonic acid) to the radical ABTS·+. RESULTS In the group of MS subjects a significant decrease in TAS (p<0.05) in comparison with normal controls was evident. This difference was present between normal subjects and nondiabetic subjects with MS (p<0.001) but not between normal and diabetic subjects with MS. Examining the linear regression among TAS, age, anthropometric profile, blood pressure values and glycometabolic pattern, conflicting data were found. CONCLUSIONS Although we know that TAS includes several enzymatic and non enzymatic antioxidants, we retain that the difference observed in the two subgroups of subjects with MS must be looked in particular into two pathophysiological aspects regarding bilirubin and uric acid.
Collapse
Affiliation(s)
- Eugenia Hopps
- Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Via del vespro 129, 90100 Palermo, Italy.
| | - Baldassare Canino
- Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Via del vespro 129, 90100 Palermo, Italy
| | - Maria Montana
- Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Via del vespro 129, 90100 Palermo, Italy
| | - Rosalia Lo Presti
- Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Via del vespro 129, 90100 Palermo, Italy
| | - Maurizio R Averna
- Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Via del vespro 129, 90100 Palermo, Italy
| | - Gregorio Caimi
- Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Via del vespro 129, 90100 Palermo, Italy
| |
Collapse
|
|
29
|
Modak MA, Parab PB, Ghaskadbi SS. Tissue specific oxidative stress profile in relation to glycaemic regulation in mice. Diabetes Metab Res Rev 2014; 30:31-41. [PMID: 24038904 DOI: 10.1002/dmrr.2460] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 08/22/2013] [Accepted: 08/22/2013] [Indexed: 12/27/2022]
Abstract
BACKGROUND Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia resulting from uncontrolled glucose regulation. Reactive oxygen species are recognized as one link between hyperglycaemia and diabetic complications. Studies have shown that diabetes mellitus is associated with decreases in antioxidant potential and increased formation of free radicals leading to oxidative stress. The present study was undertaken because an unequivocal demonstration that control of hyperglycaemia can reduce oxidative stress is still lacking. METHODS In the present study, we investigated oxidative stress profile of normal, streptozotocin-induced diabetic, insulin-treated and untreated diabetic animals. On the one hand, oxidative damage caused to lipids, proteins and DNA was measured. On other hand, antioxidant defense was measured in terms of specific activities of antioxidant enzymes (AOEs) and antioxidant molecules. RESULTS It was observed that the damage to lipids, proteins and DNA caused by free radicals increased in diabetic animals compared with that in controls. In diabetic animals not treated with insulin, damage to all biological molecules increased further significantly (p ≤ 0.005). Changes in AOEs from different tissues were complex depicting a varied AOE level in different tissues. Insulin treatment significantly improved the oxidative stress profile in all tissues studies. CONCLUSIONS The control of hyperglycaemia improves oxidative stress profile, that is, the ability of cells to cope up with oxidative stress.
Collapse
Affiliation(s)
- Manisha A Modak
- Department of Zoology, University of Pune, Ganeshkhind, Pune, 411 007, India
| | | | | |
Collapse
|
|
30
|
Markers of Oxidative Stress during Diabetes Mellitus. J Biomark 2013; 2013:378790. [PMID: 26317014 PMCID: PMC4437365 DOI: 10.1155/2013/378790] [Citation(s) in RCA: 434] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Accepted: 11/07/2013] [Indexed: 11/17/2022] Open
Abstract
The prevalence of diabetes mellitus is rising all over the world. Uncontrolled state of hyperglycemia due to defects in insulin secretion/action leads to a variety of complications including peripheral vascular diseases, nephropathy, neuropathy, retinopathy, morbidity, and/or mortality. Large body of evidence suggests major role of reactive oxygen species/oxidative stress in development and progression of diabetic complications. In the present paper, we have discussed the recent researches on the biomarkers of oxidative stress during type 2 diabetes mellitus.
Collapse
|
|
31
|
Chilelli NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: a "glycoxidation-centric" point of view. Nutr Metab Cardiovasc Dis 2013; 23:913-919. [PMID: 23786818 DOI: 10.1016/j.numecd.2013.04.004] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 03/18/2013] [Accepted: 04/12/2013] [Indexed: 12/30/2022]
Abstract
AIMS Advanced glycation end products (AGE) excess is one of the most important mechanisms involved in the pathophysiology of chronic diabetic complications. This review first summarizes the role of these compounds in microvascular pathogenesis, particularly in the light of recently proposed biochemical mechanisms for diabetic retinopathy, nephropathy and neuropathy. Then we focus on the relationship between AGE and metabolic memory, trying to clarify the former's role in the missing link between micro- and macrovascular complications. DATA SYNTHESIS An excessive AGE formation has been demonstrated in the newly disclosed biochemical pathways involved in the microvascular pathobiology of type 2 diabetes, confirming the central role of AGE in the progression of diabetic neuropathy, retinopathy and nephropathy. As shown by recent studies, AGE seem to be not "actors", but "directors" of processes conducting to these complications, for at least two main reasons: first, AGE have several intra- and extracellular targets, so they can be seen as a "bridge" between intracellular and extracellular damage; secondly, whatever the level of hyperglycemia, AGE-related intracellular glycation of the mitochondrial respiratory chain proteins has been found to produce more reactive oxygen species, triggering a vicious cycle that amplifies AGE formation. This may help to explain the clinical link between micro- and macrovascular disease in diabetes, contributing to clarify the mechanisms behind metabolic memory. CONCLUSIONS The pathophysiological cascades triggered by AGE have a dominant, hyperglycemia-independent role in the onset of the microvascular complications of diabetes. An effective approach to prevention and treatment must therefore focus not only on early glycemic control, but also on reducing factors related to oxidative stress, and the dietary intake of exogenous AGE in particular.
Collapse
Affiliation(s)
- N C Chilelli
- Department of Medicine, Division of Metabolic Diseases, University of Padova, Via Giustiniani n 2, 35128 Padova, Italy
| | | | | |
Collapse
|
|
32
|
Piarulli F, Sartore G, Lapolla A. Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update. Acta Diabetol 2013; 50:101-10. [PMID: 22763581 PMCID: PMC3634985 DOI: 10.1007/s00592-012-0412-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 06/05/2012] [Indexed: 12/18/2022]
Abstract
Diabetes is associated with a greatly increased risk of cardiovascular disease (CVD), which cannot be explained only by known risk factors, such as smoking, hypertension, and atherogenic dyslipidemia, so other factors, such as advanced glycation end-products (AGEs) and oxidative stress, may be involved. In this frame, hyperglycemia and an increased oxidative stress (AGE formation, increased polyol and hexosamine pathway flux, and protein kinase C activation) lead to tissue damage, thus contributing to the onset of cardiovascular complications. Several studies have identified in various cell systems, such as monocytes/macrophages and endothelial cells, specific cellular receptors (RAGE) that bind AGE proteins. The binding of AGEs on RAGE induces the production of cytokines and intracellular oxidative stress, thus leading to vascular damage. Soluble RAGE levels have been identified as hypothetical markers of CVD, but, in this regard, there are sparse and conflicting data in the literature. The purpose of this review was to examine all the available information on this issue with a view to clarifying or at least highlighting the points that are still weak, especially from the point of clinical view.
Collapse
Affiliation(s)
- Francesco Piarulli
- Department of Medicine - DIMED, University of Padova, Via dei Colli 4, 35143 Padua, Italy
| | - Giovanni Sartore
- Department of Medicine - DIMED, University of Padova, Via dei Colli 4, 35143 Padua, Italy
| | - Annunziata Lapolla
- Department of Medicine - DIMED, University of Padova, Via dei Colli 4, 35143 Padua, Italy
| |
Collapse
|
|
33
|
Moresco RN, Sangoi MB, De Carvalho JAM, Tatsch E, Bochi GV. Diabetic nephropathy: traditional to proteomic markers. Clin Chim Acta 2013; 421:17-30. [PMID: 23485645 DOI: 10.1016/j.cca.2013.02.019] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Revised: 02/06/2013] [Accepted: 02/09/2013] [Indexed: 01/11/2023]
Abstract
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes and it is defined as a rise in the urinary albumin excretion (UAE) rate and abnormal renal function. Currently, changes in albuminuria are considered a hallmark of onset or progression of DN. However, some patients with diabetes have advanced renal pathological changes and progressive kidney function decline even if urinary albumin levels are in the normal range, indicating that albuminuria is not the perfect marker for the early detection of DN. The present article provides an overview of the literature reporting some relevant biomarkers that have been found to be associated with DN and that potentially may be used to predict the onset and/or monitor the progression of nephropathy. In particular, biomarkers of renal damage, inflammation, and oxidative stress may be useful tools for detection at an early stage or prediction of DN. Proteomic-based biomarker discovery represents a novel strategy to improve diagnosis, prognosis and treatment of DN; however, proteomics-based approaches are not yet available in most of the clinical chemistry laboratories. The use of a panel with a combination of biomarkers instead of urinary albumin alone seems to be an interesting approach for early detection of DN, including markers of glomerular damage (e.g., albumin), tubular damage (e.g., NAG and KIM-1), inflammation (e.g., TNF-α) and oxidative stress (e.g., 8-OHdG) because these mechanisms contribute to the development and outcomes of this disease.
Collapse
Affiliation(s)
- Rafael N Moresco
- Laboratório de Pesquisa em Bioquímica Clínica, Departamento de Análises Clínicas e Toxicológicas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil.
| | | | | | | | | |
Collapse
|
|
34
|
Shao N, Kuang HY, Wang N, Gao XY, Hao M, Zou W, Yin HQ. Relationship between Oxidant/Antioxidant Markers and Severity of Microalbuminuria in the Early Stage of Nephropathy in Type 2 Diabetic Patients. J Diabetes Res 2013; 2013:232404. [PMID: 23671859 PMCID: PMC3647557 DOI: 10.1155/2013/232404] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 12/29/2012] [Indexed: 01/08/2023] Open
Abstract
A wide range of microalbuminuria cutoff values are currently used for diagnosing the early stage of nephropathy in type 2 diabetes (T2D). This study analyzed the relationships between oxidant and antioxidant markers of nephropathy and the severity of microalbuminuria. The study included 50 healthy controls (Group 1), 50 diabetic patients with no nephropathy (Group 2), 50 diabetic patients with nephropathy and a urinary albumin excretion (UAE) of 30-200 mg/24 h (Group 3), and 50 diabetic patients with UAE 200-300 mg/24 h (Group 4). Serum nitrotyrosine, conjugated dienes, 8-hydroxy-2'-deoxyguanosine (8-OHdG), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) levels were determined. Oxidative stress is increased in the early stage of nephropathy in patients with T2D. There was a significant correlation between the extent of microalbuminuria and markers of oxidative stress. Multiple linear regression analysis identified lipid oxidative stress as a possible independent marker for evaluating the degree of renal damage in diabetic nephropathy. Stratifying microalbuminuria values during the early stage of nephropathy might be an important factor in facilitating earlier and more specific interventions.
Collapse
Affiliation(s)
- Ning Shao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Hong Yu Kuang
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
- *Hong Yu Kuang:
| | - Na Wang
- Department of Endocrinology, The Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, China
| | - Xin Yuan Gao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Ming Hao
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| | - Wei Zou
- Department of Neurology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China
| | - Hui Qing Yin
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China
| |
Collapse
|
|
35
|
Piarulli F, Lapolla A, Ragazzi E, Susana A, Sechi A, Nollino L, Cosma C, Fedele D, Sartore G. Role of endogenous secretory RAGE (esRAGE) in defending against plaque formation induced by oxidative stress in type 2 diabetic patients. Atherosclerosis 2012. [PMID: 23182189 DOI: 10.1016/j.atherosclerosis.2012.10.050] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
OBJECTIVES This study was conducted to examine the relationship between endogenous secretory receptors for advanced glycation end products (esRAGE) and oxidative stress in type 2 diabetic patients (T2DM) with/without advanced macro-angiopathy. METHODS Sixty-one T2DM were assessed for glycemic control, lipid profile, AGEs, carboxymethyl-lysine (CML), soluble receptor for advanced glycation end products (sRAGE), esRAGE and vitamin E levels, and underwent echo-color-Doppler of the abdominal aorta and aorto-iliac tree, carotid and lower limb arteries to check for evidence of plaques. RESULTS AGEs and CML levels were significantly higher in T2DM with plaques than in those without (P = 0.0156 and P = 0.007, respectively) despite a comparable metabolic control and history of disease. EsRAGE and vitamin E levels were lower in T2DM with than in those without plaques (P < 0.0001), while no differences were observed as regards sRAGE levels. Considering all T2DM, univariate regression analysis showed a positive correlation between esRAGE and vitamin E (r = 0.456, P < 0.001), and a negative correlation between esRAGE and AGEs (r = -0.284, P < 0.05). After dividing patients by the presence/absence of plaques, esRAGE only correlated directly with vitamin E (r = 0.563, P < 0.01) and CML (r = 0.479, P < 0.05) in patients without plaques. CONCLUSIONS This is the first study to establish a relationship between esRAGE and oxidative stress and/or antioxidant power, suggesting that esRAGE upregulation might be part of the cell's antioxidative defenses against plaque forming as a result of oxidative stress in the T2DM phenotype (cases with a more efficient esRAGE production being better protected).
Collapse
Affiliation(s)
- Francesco Piarulli
- Department of Medicine - DIMED, University of Padova, Via dei Colli 4, 35143 Padova, Italy.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Hegab Z, Gibbons S, Neyses L, Mamas MA. Role of advanced glycation end products in cardiovascular disease. World J Cardiol 2012; 4:90-102. [PMID: 22558488 PMCID: PMC3342583 DOI: 10.4330/wjc.v4.i4.90] [Citation(s) in RCA: 238] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2012] [Revised: 04/04/2012] [Accepted: 04/10/2012] [Indexed: 02/06/2023] Open
Abstract
Advanced glycation end products (AGEs) are produced through the non enzymatic glycation and oxidation of proteins, lipids and nucleic acids. Enhanced formation of AGEs occurs particularly in conditions associated with hyperglycaemia such as diabetes mellitus (DM). AGEs are believed to have a key role in the development and progression of cardiovascular disease in patients with DM through the modification of the structure, function and mechanical properties of tissues through crosslinking intracellular as well as extracellular matrix proteins and through modulating cellular processes through binding to cell surface receptors [receptor for AGEs (RAGE)]. A number of studies have shown a correlation between serum AGE levels and the development and severity of heart failure (HF). Moreover, some studies have suggested that therapies targeted against AGEs may have therapeutic potential in patients with HF. The purpose of this review is to discuss the role of AGEs in cardiovascular disease and in particular in heart failure, focussing on both cellular mechanisms of action as well as highlighting how targeting AGEs may represent a novel therapeutic strategy in the treatment of HF.
Collapse
Affiliation(s)
- Zeinab Hegab
- Zeinab Hegab, Stephen Gibbons, Ludwig Neyses, Mamas A Mamas, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester M13 9WL, United Kingdom
| | | | | | | |
Collapse
|
|
37
|
Bigagli E, Raimondi L, Mannucci E, Colombi C, Bardini G, Rotella CM, Lodovici M. Lipid and protein oxidation products, antioxidant status and vascular complications in poorly controlled type 2 diabetes. ACTA ACUST UNITED AC 2012. [DOI: 10.1177/1474651411435588] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The inter-relationships between glycaemic control, the progression of diabetes-related vascular complications, oxidative/antioxidative status and inflammation, have not been fully understood. We measured malondialdehyde (MDA) and carbonyl residues, C-reactive protein (CRP) and antioxidant systems by means of ferric reducing ability of plasma (FRAP) and superoxide dismutase (SOD) activity, in well controlled and poorly controlled type 2 diabetic patients without complications (NC) and in poorly controlled patients with microvascular (MicroVC) and with both micro- and macrovascular complications (Micro+Macro VC). All poorly controlled diabetic patients showed higher MDA and carbonyl residues compared to well controlled NC, as did those with Micro+Macro VC compared to poorly controlled NC. The higher CRP and SOD activity levels reached significance in Micro VC and Micro+Macro VC groups. FRAP decreased only in poorly controlled NC compared to well controlled NC (p<0.05). Glycated hamemoglobin (HbA1c) levels were positively correlated with MDA (p<0.05) and CRP (p<0.001) and inversely associated with FRAP (p<0.05) and SOD (p=0.06). An increase in MDA or carbonyl residues could be a marker of high risk for complications in patients with poorly controlled diabetes and they should be considered for monitoring the effectiveness of drug treatment.
Collapse
Affiliation(s)
- E Bigagli
- University of Florence, Florence, Italy
| | | | - E Mannucci
- Diabetes Agency, Careggi Teaching Hospital, Florence, Italy
| | - C Colombi
- Diabetes Agency, Careggi Teaching Hospital, Florence, Italy
| | - G Bardini
- Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | - CM Rotella
- Department of Clinical Physiopathology, University of Florence, Florence, Italy
| | | |
Collapse
|
|
38
|
Nin JW, Jorsal A, Ferreira I, Schalkwijk CG, Prins MH, Parving HH, Tarnow L, Rossing P, Stehouwer CD. Higher plasma levels of advanced glycation end products are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study. Diabetes Care 2011; 34:442-7. [PMID: 21270199 PMCID: PMC3024364 DOI: 10.2337/dc10-1087] [Citation(s) in RCA: 169] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate the associations of plasma levels of advanced glycation end products (AGEs) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunction, low-grade inflammation, and arterial stiffness. RESEARCH DESIGN AND METHODS We prospectively followed 169 individuals with diabetic nephropathy and 170 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of N(ε)-(carboxymethyl)lysine, N(ε)-(carboxyethyl)lysine, pentosidine and other biomarkers were measured at baseline. The median follow-up duration was 12.3 (interquartile range 7.6-12.5) years. RESULTS During the course of follow-up, 82 individuals (24.2%) died; 85 (25.1%) suffered a fatal (n = 48) and/or nonfatal (n = 53) CVD event. The incidence of fatal and nonfatal CVD and of all-cause mortality increased with higher baseline levels of AGEs independently of traditional CVD risk factors: hazard ratio (HR) = 1.30 (95% CI = 1.03-1.66) and HR = 1.27 (1.00-1.62), respectively. These associations were not attenuated after further adjustments for markers of renal or endothelial dysfunction, low-grade inflammation, or arterial stiffness. CONCLUSIONS Higher levels of AGEs are associated with incident fatal and nonfatal CVD as well as all-cause mortality in individuals with type 1 diabetes, independently of other risk factors and of several potential AGEs-related pathophysiological mechanisms. Thus, AGEs may explain, in part, the increased cardiovascular disease and mortality attributable to type 1 diabetes and constitute a specific target for treatment in these patients.
Collapse
Affiliation(s)
- Johanna W Nin
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
O'Keefe JH, Abuannadi M, Lavie CJ, Bell DSH. Strategies for optimizing glycemic control and cardiovascular prognosis in patients with type 2 diabetes mellitus. Mayo Clin Proc 2011; 86:128-38. [PMID: 21270290 PMCID: PMC3031437 DOI: 10.4065/mcp.2010.0434] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Type 2 diabetes mellitus (DM) is a major cardiovascular (CV) risk factor and, as such, is considered a coronary artery disease risk equivalent. Although glycemic control is associated with decreased CV events epidemiologically, many prospective clinical trials have failed to conclusively demonstrate that aggressive glycemic control improves the CV prognosis of patients with type 2 DM, especially those with long-standing DM. Many therapies for type 2 DM with widely divergent mechanisms of action are available. Some of these drugs, in addition to their glucose-lowering actions, have properties that may reduce or increase CV events. Agents that lower both insulin resistance and postprandial hyperglycemia while at the same time avoiding hypoglycemia may be beneficial for CV health. This article reviews the evidence regarding the use of these agents and appropriate glycemic control targets for improving the adverse CV prognosis associated with type 2 DM. We conducted a systematic review of English articles using MEDLINE and the Cochrane Controlled Trials Register (1970-2010) using the following search terms: cardiovascular disease, randomized trials, hypoglycemia, and insulin resistance.
Collapse
Affiliation(s)
| | | | | | - David S. H. Bell
- Individual reprints of this article are not available. Address correspondence to David S. H. Bell, MD, University of Alabama and Southside Endocrinology, 1020 26th St S, Room 204, Birmingham, AL 35205 ()
| |
Collapse
|
|
40
|
Advanced glycation end-products in myocardium-supported vessels: effects of heart failure and diabetes mellitus. J Heart Lung Transplant 2011; 30:558-64. [PMID: 21212000 DOI: 10.1016/j.healun.2010.11.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2010] [Revised: 11/11/2010] [Accepted: 11/12/2010] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Disturbed glucose metabolism, particularly in diabetes, is an important but not the sole factor leading to advanced glycation end-product (AGE) formation. The AGE amount and its distribution in cardiopathic myocardial tissues in the presence or absence of diabetes are not well documented. The aim of this study was to assess AGE deposition in unaffected myocardial vessels in heart failure patients with and without diabetes mellitus type 2 (DM2) undergoing transplantation. METHODS The following groups were established: 14 hearts harvested from subjects with ischemic cardiopathy and DM2; 8 hearts from subjects with dilated cardiopathy with DM2; 67 hearts from subjects with ischemic cardiopathy; 47 hearts from subjects with dilated cardiopathy; and 14 hearts from autopsy cases with diagnosed DM2. A control group consisted of 20 heart donors. AGE localization was determined immunohistochemically in tissue sections. A semi-quantitative scale was used to assess reaction intensity in arteries, arterioles, capillaries, venules and veins. RESULTS Both types of cardiomyopathy increased AGE accumulation in intramyocardial veins more than in arteries. The presence of DM2 significantly increased AGE in arterioles and capillaries, especially when coexisting with cardiomyopathy. The type of cardiopathy did not influence the pattern of AGE accumulation in myocardial vessels. CONCLUSION Both chronic heart failure and DM2 intensified AGE pathology and changed the susceptibility of myocardial vasculature to glycation. However, chronic heart failure increases AGE deposition mostly in veins, whereas DM2 predisposes arterioles to AGE accumulation.
Collapse
|
|
41
|
Protein oxidation biomarkers in plasma of type 2 diabetic patients. Clin Biochem 2009; 43:508-11. [PMID: 19941844 DOI: 10.1016/j.clinbiochem.2009.11.011] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Revised: 10/22/2009] [Accepted: 11/10/2009] [Indexed: 11/24/2022]
Abstract
OBJECTIVES To evaluate oxidative stress and the extent of oxidation of plasma proteins in type 2 diabetic patients. DESIGN AND METHODS Study was carried out on blood from 31 diabetic patients of both sexes (mean age = 58 + or - 7; duration of diabetes 12 + or - 5 years) and healthy age and sex matched normal subjects. Biomarkers of protein oxidation; plasma protein carbonyls (PCO), advanced oxidation protein products (AOPPs) and -SH group and free radical scavenging capacity of plasma was measured. RESULTS PCO and AOPPS levels were significantly (P<0.005) higher in diabetic patients in comparison to healthy volunteers. Reduced free radical scavenging capacity (P<0.001) and -SH group (P<0.05) was observed in plasma of type 2 diabetic patients. CONCLUSIONS Our data suggest that diabetics are susceptible to protein oxidation. Oxidative modulation of proteins due to reduced radical scavenging activity of plasma patients may be one of the reasons of altered physiological processes in type 2 diabetic patients.
Collapse
|