File Name: advanced glycation end products and diabetes file.zip
Advanced glycation end products AGEs are proteins or lipids that become glycated as a result of exposure to sugars.
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There are substantial differences in the onset and severity of diabetes complications that are not fully explained by HbA1c levels and other risk factors. HbA1c is the gold standard for assessing metabolic control, but has limited value to identify patients at risk of developing diabetic complications.
The main disadvantage of HbA1c is that it does not provide information about glycemic variability and does not reflect long-term exposure to hyperglycemia.
One of the main pathogenetic mechanisms of diabetic complications is the generation and accumulation of advanced glycation end-products AGEs. Based on its fluorescence properties, AGEs may be measured in tissues such as the skin or lens. These non-invasive measurements of AGE accumulation may be considered as promising biomarkers of late diabetic complications, and our objective is to summarize the available evidence supporting this statement.
However, further translational research and prospective clinical trials are needed before these new biomarkers may be incorporated into clinical practice..
The prevalence of diabetes is increasing worldwide and if this trend continues by , million people will have diabetes especially in developing countries. The burden of diabetes mellitus for both patients and society comes from the vascular complications of the disease, cardiovascular disease being a major cause of death and disability in patients with type 2 diabetes. Moreover, diabetic retinopathy is still the leading cause of vision loss in working age adults, the prevalence of ESRD end-stage renal disease is also up to 10 times higher in people with diabetes as those without, and diabetes is the main cause non-traumatic amputation.
The measurement of HbA1c has been the gold standard for metabolic control. The reasons why HbA1c cannot be considered a good biomarker of diabetic complications are as follows:. Therefore, the use of new biomarkers that reflect the accumulated exposition to hyperglycemia could be useful to predict diabetes outcomes. HbA1c does not provide information about the intensity of fluctuations of blood glucose levels. Glycemic variability, and in particular hyperglycemic spikes could be high enough to activate complication-causing mechanisms but too brief to affect the HbA1c value.
Among the main metabolic pathways involved in the pathogenesis of late diabetic complications i. In addition, the different methods for determining the degree of oxidative stress or the inflammatory status inform us regarding the situation in real time rather than reflecting a sustained metabolic fingerprint. By contrast, AGEs have been implicated in the long-term nature of metabolic memory 4 and their assessment takes into account cumulative glycemia exposure and glycemic variability, 7 thus overcoming the limitations of HbA1c as a biomarker for diabetic outcomes.
The objective of this review is to summarize the evidence available regarding AGEs assessment as a biomarker for diabetic complications, focusing on non-invasive techniques for its measurement.
For this purpose, a comprehensive literature search of the electronic MEDLINE database was performed between August and November using Pubmed search service and the relevant articles both originals and reviews have been included.
The non-enzymatic glycation reaction is known to be one of the most significant mechanisms contributing to tissue damage that occurs in diabetes. It involves a series of chemical reactions that lead to the formation of early glycation products like HbA1c , alpha-dicarbonyls, which are directly toxic and precursors of AGEs.
Advanced glycation occurs over a prolonged period, affecting long-lived proteins, like structural components of the connective tissue matrix and basement membrane components. For example, Boehm et al. In addition, increased plasma levels of AGEs were found to predict incident cardiovascular disease and all-cause mortality in a population with type 1 diabetes with a Hazard Ratio of 1.
It should be mentioned, that they also found a positive association between 2-aminoipic acid, an oxidative stress product, and coronary artery calcification. At the same time, oxidative stress products accelerate AGE formation increasing the risk of presenting diabetic complications. In a small but very illustrative study, plasma levels of two AGEs nitrotyrosine and glyceraldehydes-derived AGE were correlated with the mean amplitude of glycemic excursions, which was associated with more severe coronary artery disease.
However, biochemical and immunochemical assays for circulating AGE determination are complex, time-consuming, expensive and have a low reproducibility. In recent years, tandem mass spectrometry has considerably facilitated the use and improved reproducibility of the assay for several AGEs.
Nevertheless, serum AGEs do not necessarily reflect tissue AGE levels, as they depend on the half-life of these proteins, and in those tissues where diabetic complications develop there are also those where long lived proteins are present. Based on the fluorescent property of some AGEs, new non-invasive methods for their detection have been developed: skin and lens autofluorescence. The detection of AGEs in these tissues adds an advantage to its plasma determination. This is because lens crystallins and skin collagen are long lived proteins as a result of a low turnover.
Therefore, AGEs accumulation in these proteins represents cumulative long-term glycaemia exposure. The accumulation of AGEs in the skin measured in skin biopsies predicted the progression of microvascular complications in type 1 diabetic patients in a year prospective study. It is worth mentioning that the predictive effect of HbA1c disappeared after adjustment for AGE levels. In type 1 diabetic subjects SAF has been associated in cross-sectional studies with the presence of subclinical atherosclerosis, coronary artery disease OR 3.
Schleicher et al. Moreover, in a cross-sectional study, 56 non-diabetic subjects with carotid artery stenosis age and sex matched with healthy control presented significantly elevated values of SAF measurement 2.
The difference was higher in patients with both carotid stenosis and peripheral artery occlusive disease. This evidence suggests that SAF could be an indicator of macrovascular risk in both diabetic and non-diabetic patients. One possible explanation is that in some patients, AGEs formation starts before the diagnosis of diabetes at least when it is made by the classical methods HbA1c and glycemic values. When interpreting the results of SAF, it should be taken into account that they are influenced by the presence of renal impairment.
This has been demonstrated in both diabetic 30 and non-diabetic patients. On the other hand, in non-diabetic patients, subjects with mild to moderate decrease in GFR showed significantly higher levels of SAF compared to subjects without chronic kidney disease 2.
However, when the presence of subclinical atherosclerosis was taken into account, the difference only remained in the group of patients with subclinical atherosclerosis. Lens autofluorescence LAF measurement is also a non-invasive technique for determining AGE accumulation in the lens which is simple, rapid and does not need pupil dilation. Moreover, a higher LAF value at baseline was associated with the development of diabetic complications during follow-up.
It is worth mentioning that Koefoed Theil et al. Regarding diabetic complications, in a cross-sectional study among type 2 diabetic patients, LAF was associated with the presence of diabetic retinopathy: in a logistic regression model adjusting for age, sex and diabetes status, the OR for the presence of retinopathy was 4.
The most important limiting factor of LAF is that it is not reliable when cataracts are present and cannot be performed in those subjects who have had cataract surgery. The assessment of HbA1c is currently used for determining the risk of the development of diabetic related long-term complications. However, its inability to reflect the cumulative long-term exposure to hyperglycemia and glycemic variability explains why its measurement fails to predict diabetic outcomes. Because of their capacity to give us integrative information on cumulative life-exposure to hyperglycemia, LAF and SAF measurements are two promising biomarkers of diabetic outcomes.
However, the following scientific gaps need to be covered: 1 Although LAF and SAF assessments have been correlated with skin and lens AGE content, these measurements have not been validated by measuring the AGE content in the tissues affected by diabetic complications.
The inter-individual variability in the capacity of tissue glycation is a limiting factor that should be taken into account when analyzing the results of LAF and SAF measurements. As previously mentioned, SAF measurement was found elevated in non-diabetic subjects with atherosclerosis. Furthermore, RAGEs are not expressed homogenously in all tissues and there is evidence that the AGE's accumulation pattern change with age, 37 thus adding more complexity to the analysis of the results.
Apart from AGEs formed as a consequence of the glycation of endogenous proteins, it is worth mentioning that AGEs also exist in significant amount in several foods and their quantity also depends on the type of cooking. In the same direction, in healthy subjects dietary AGEs directly correlate with circulating AGEs as well as with markers of oxidative stress.
Furthermore, in patients with diabetes, restriction of dietary AGEs reduces markers of oxidative stress and inflammation. In summary, the assessment of AGEs by means of non-invasive methods such as LAF and SAF is a promising strategy for a better identification of diabetic patients at risk of developing late diabetic complications.
This would provide a rational basis to implement a patient-centered approach in the setting of personalized medicine, which would reduce the huge economic burden associated with diabetes. The authors declare that they have no conflicts of interest.
Assessment of advanced glycation end-products as a biomarker of diabetic outcome ISSN: Previous article Next article. Issue 9. Pages November Assessment of advanced glycation end-products as a biomarker of diabetic outcomes.
Download PDF. Corresponding author. This item has received. Article information. However, further translational research and prospective clinical trials are needed before these new biomarkers may be incorporated into clinical practice. Palabras clave:. Introduction The prevalence of diabetes is increasing worldwide and if this trend continues by , million people will have diabetes especially in developing countries.
HbA1c does not provide information on glycemic variability HbA1c does not provide information about the intensity of fluctuations of blood glucose levels. AGEs as potential biomarkers of diabetes outcomes The non-enzymatic glycation reaction is known to be one of the most significant mechanisms contributing to tissue damage that occurs in diabetes.
Assessment of AGE accumulation in accessible tissues Based on the fluorescent property of some AGEs, new non-invasive methods for their detection have been developed: skin and lens autofluorescence. Future perspectives and concluding remarks The assessment of HbA1c is currently used for determining the risk of the development of diabetic related long-term complications.
Conflict of interest The authors declare that they have no conflicts of interest. IDF diabetes atlas. Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial.
Am J Cardiol, 75 , pp. The relationship of glycemic exposure HbA1c to the risk of development and progression of retinopathy in the diabetes control and complications trial.
Diabetes, 44 , pp. Ceriello, M. Ihnat, J. J Clin Endocrinol Metab, 94 , pp.
About million people worldwide had diabetes in The global figure of people with diabetes is projected to increase to million in As the prevalence of diabetes has risen to epidemic proportions worldwide, diabetic nephropathy has become one of the most challenging health problems. Therapeutic options such as strict blood glucose and blood pressure controls are effective for preventing diabetic nephropathy, but are far from satisfactory, and the number of diabetic patients on end-stage renal disease is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. There is accumulating evidence that advanced glycation end products AGEs , senescent macroprotein derivatives formed at an accelerated rate under diabetes, play a role in diabetic nephropathy via oxidative stress generation. Diabetic nephropathy is the most common cause of end-stage renal disease in the world, and could account for disability and high mortality rate in patients with diabetes.
Hyperglycemia is considered as a major teratogenic factor for congenital malformation, although other associated factors such as ketone bodies, branched amino acids, and triglycerides have also been shown to exert adverse effects on the developing embryo Eriksson et al. However, it is not yet clear in which way maternal hyperglycemia affects prenatal embryo development. There is upcoming evidence that advanced glycation end products AGEs might play a critical role in diabetic pregnancies. AGEs are a complex group of compounds formed via non-enzymatic reactions between reducing sugars and N-terminal amino groups on proteins, lipids, and nucleic acids. Formation and accumulation of AGEs are related to aging as well as to prolonged hyperglycemia and oxidative stress resulting from DM Sell et al. The post-translational modification of proteins by reducing sugars alters their biological structure and function and leads not only to a loss of molecular function but also to a reduced degradation of these damaged proteins.
Gestational Diabetes Mellitus GDM is a condition in which women without history of diabetes experience hyperglycemia during pregnancy, especially at the second and third trimesters. In women who have had GDM, an elevated body mass index BMI may have a substantial impact for persistent hyperglycemia in their lives after gestation. Beyond hyperglycemia, increased local oxidative stress directly promotes the formation of Advanced Glycation End-products AGEs. Following screening and eligibility evaluation, relevant data were extracted from included studies and analyzed using Rev-Man 5. Besides, meta-regression, meta-influence, and publication bias analyses were conducted. A total of 16 original studies were included for the systematic review and meta-analysis.
Download PDF Flyer. DOI: Frontiers in Clinical Drug Research — Diabetes and Obesity is an eBook series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of two metabolic diseases — diabetes and obesity. The scope of the eBook series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs affecting endocrine and metabolic processes linked with diabetes and obesity.
It is the best journal to keep up to date with endocrine pathophysiology both in the clinical and in the research field. It publishes the best original articles of large research institutions, as well as prestigious reviews. The Impact Factor measures the average number of citations received in a particular year by papers published in the journal during the two receding years.
The irreversible reaction of proteins, lipids, and nucleic acids with carbohydrates is called glycation. Glycated reaction products are termed advanced glycation end products AGEs. It is essentially fructose, galactose, and as well glucose that react with endogenous structures in an uncontrolled manner.
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PDF | Advanced glycation end products (AGEs) are formed in vivo by a non-enzymatic reaction of proteins with carbohydrates and accumulate.