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The irreversible reaction of proteins, lipids, and nucleic acids with carbohydrates is called glycation.

Advanced glycation end products AGEs are proteins or lipids that become glycated as a result of exposure to sugars.

Advanced glycation end-product

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.

Besides, the BMI and other specific biomarkers showed a significant difference between the two groups indicating the high risk of developing long-standing type 2 diabetes and its complications in gestational diabetic women. Early detection of these biomarkers may play a pivotal role in controlling postpartum diabetic complications. Editor: Frank T. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Additional files are attached as supplements along with the manuscript. Competing interests: The authors have declared that no competing interests exist. According to the American Diabetes Association ADA , gestational diabetes mellitus GDM can be defined as glucose intolerance with onset during pregnancy and typically resolves itself postpartum.

It is treated as a major public health concern due to its adverse maternal and neonatal outcomes and a likelihood of developing type-2 diabetes later in the lives of the mothers and offsprings [ 1 ].

The genetic, epigenetic, and environmental factors may jointly contribute to the development of GDM. Hence, the underlying mechanisms involved in the pathogenesis of GDM remain complex and gradually evolving.

Available evidence indicated that chronic inflammation, oxidative stress, gluconeogenesis, and placental factors contribute to the pathology of GDM [ 2 ].

Even if pregnancy is normally considered as a state of oxidative stress, the presence of GDM heightens the oxidative state. The rise in the levels of reactive oxygen species ROS has been associated with non-enzymatic glycation of macromolecules which may partly play a role in the development of postpartum type 2 diabetes mellitus and maternal and neonatal complications [ 3 , 4 ].

Under favorable conditions, a series of non-enzymatic reactions occur between the amino groups of macromolecules and the carbonyl groups of reducing sugars, a process known as Maillard reaction. Such early glycation adducts undergo further rearrangement into final stable heterogeneous products called advanced glycation end products AGEs [ 5 , 6 ]. Such reactions alter the structure and function of macromolecules leading to pathological aging processes.

To this end, hyperglycemic and oxidative stress conditions accelerate this process [ 6 ]. N-carboxymethyl-lysine CML [ 7 ]. The formation of AGEs normally occurs both exogenously and endogenously.

The exogenous production of AGEs occurs when foods are processed with high temperature. It is evident that fried food items such as cookies, biscuits, and chips having one or more AGE-forming ingredients are overwhelmed with high levels of AGEs [ 5 , 8 — 10 ]. The contemporary lifestyle provides a conducive environment for thermally processed food items replete with pro-inflammatory and oxidative stress-inducing AGEs.

By stimulating appetite and causing overnutrition, such food items pose a risk for overweight and obesity [ 8 , 11 ]. A study indicated that a dietary quality index score was negatively correlated with the serum levels of some AGEs [ 12 ] emphasizing the quality of processed food items determines their AGE content.

Likewise, higher level of maternal consumption of fried fish and fried chicken just before conception was associated with an increased risk of GDM [ 13 ]. A case-control study conducted in Iran indicated that western dietary pattern was associated with an increased risk of GDM [ 14 ]. Therefore, wise dietary adjustment has a paramount importance for controlling an AGE load in the body. AGEs mediate inflammatory actions via protein kinases and the nuclear factor kappa B NF-kB signaling pathway in human gestational tissues [ 16 ].

The growing body of evidence has indicated AGEs-RAGE interaction elicits oxidative stress which in turn triggers proliferative, inflammatory, thrombotic, and fibrotic reactions. This evidence supports AGEs involvement in diabetes and age-related disorders [ 6 , 7 , 17 ]. In this regard, Dariya and Nagaraju summarized the role of AGE-RAGE interaction and downstream signaling pathways highly implicated for tumorigenesis and diabetic complications.

The generation of ROS, activation of NF-kB, and protein kinases play a pivotal role for downstream signaling processes. The authors also pointed out phytochemical constituents such as genistein and curcumin can sequester highly reactive dicarbonyl compounds such as methylglyoxal and glyoxalase thereby prevent the formation of AGEs and their interaction with RAGE [ 18 ].

Hence, we conducted this systematic review and meta-analysis to generate pooled estimates at global level. References of identified citations and Google Scholar were also searched to identify additional studies. Truncation was used when appropriate to fine-tune the search and increase the number of relevant findings.

During the screening and eligibility assessments, there were predefined inclusion and exclusion criteria to include relevant studies. Restriction was not applied on the years of publication and geographical location, but only studies written in English language were considered for inclusion. Review papers, editorials, commentaries, opinions, and case reports were excluded during screening of titles and abstracts. Studies addressing the AGEs in women with GDM without control and animal-based preclinical studies were excluded during the selection process.

We also excluded cases mixed with other types of diabetes during eligibility assessment. Studies retrieved from various databases were combined. Duplicate records were removed with the help of ENDNOTE software followed by careful visual inspection by considering distinct referencing styles of sources which the software could not detect as duplicate.

Each record was independently assessed by two authors MS and TA using the predefined inclusion and exclusion criteria stated above. Following initial screening of records with their titles and abstracts, rigorous assessment of full texts was made by MS and DE. Disagreement raised among authors at any phase of the work was solved by discussion with the rest authors.

Important data were extracted from included studies using Excel sheet S2 Table. Following the assessment of eligible articles, two authors MS and AG independently assessed the methodological validity and analysis of outcome measures using the Joanna Briggs Institute JBI critical appraisal checklist for observational studies, University of Adelaide, Australia [ 24 ]. The assessment tool consisted of design-specific questions about the quality of the study based on the following responses: Yes, No, Unclear, and Not Applicable.

This critical appraisal was conducted to assess the internal and external validity of studies and to determine the extent to which each study has addressed the possibility of bias in its design, conduct, and analysis.

Subgroup analyses were performed based on trimester of pregnancy, geographic location, and type of samples. The extracted data were exported from Excel to Rev-Man 5. The heterogeneity of studies was assessed using I 2 statistics.

Influence analysis was conducted to evaluate whether a single study significantly affected the pooled SMD estimate [ 27 ]. The presence of publication bias was determined by using Egger's regression test and visualization of funnel plot asymmetry [ 28 , 29 ]. A total of studies were retrieved through visiting legitimate databases, indexing services, search engines, and repositories.

Then, records were retained for further screening using their titles and abstracts. Among which, a total of records studies by titles and studies by abstracts were excluded. The full texts of the remaining 37 studies were assessed for eligibility and 21 of which were excluded with various reasons. Finally, 16 studies were included for systematic review and meta-analysis Fig 1. Rigorous appraisal of included observational studies case-control and cross-sectional studies with and 9-point scales, respectively resulted in average quality scores ranging between 5 and Fortunately, all included studies fulfilled the minimum criteria and retained for systematic review and meta-analysis S3 Table.

A total of 16 studies with one study retained for specific AGE measures and metabolic biomarkers were included for systematic review and meta-analysis. The publication years of included studies ranged from to Regarding the geographical distribution, the review included seven studies from Europe [ 30 — 36 ], seven studies from Asia [ 37 — 43 ] and two studies from Latin America [ 44 , 45 ].

Thirteen of these studies employed case-control design [ 30 , 32 , 33 , 35 — 44 ] whereas the rest three studies were cross-sectional in design [ 31 , 34 , 45 ]. Specifically, the meta-analysis of AGEs involved cases and controls. The systematic review and meta-analysis involved studies that reported the outcome measures at both first and second trimesters [ 32 ], first and third trimesters [ 36 ], second trimester [ 30 , 31 , 34 , 41 , 44 ], second and third trimesters [ 38 , 42 ], and third trimester of pregnancy [ 33 , 35 , 37 , 39 , 40 ] whereas two studies did not specify gestational period during sample collection [ 43 , 45 ].

Blood sample was collected from 13 studies [ 30 , 31 , 33 , 35 — 40 , 42 — 45 ], skin sample from two studies [ 32 , 34 ], and placenta sample from one study [ 41 ] Table 1.

For analysis of specific AGEs and metabolic biomarkers, five and four studies were included to generate the pooled estimates of HOMA-IR [ 31 , 37 , 42 , 43 , 45 ], and HbA1c [ 31 , 33 , 37 , 43 ], respectively.

A without sensitivity analysis B with sensitivity analysis. For this, univariate meta-regression was run to identify potential covariates that likely affect the magnitude and direction of the overall SMD estimate. The bubble plots of SMD with sample size and publication year are presented in Figs 7 and 8 , respectively. Small studies with larger effect sizes are shown in the right lower side of the plot.

Notwithstanding the presence of several reports that demonstrate the relationship between AGEs, hyperglycemia, and oxidative stress, the underlying mechanism of causal relationship between body AGEs and GDM remains equivocal. Thus, AGEs can partly contribute to chronic stress conditions in diabetes [ 46 ].

In turn, the formation of some AGEs is induced by states of oxidative stress which plays a more important role in the formation of AGEs in type 2 diabetes in which unhealth weight gain is commonly observed [ 47 , 48 ]. Sustained load of these oxidants may surmount host defense mechanisms and lead to unopposed oxidative stress and chronic inflammation. Moreover, hyperglycemia is a major driving force for AGE formation, especially when there is a pre-existing oxidative stress.

It is becoming increasingly vivid that the contemporary diets are loaded with preformed AGEs, which may catalyze oxidative stress [ 11 ]. There are several research reports that link the high level of AGEs in the body with metabolic syndrome, type 2 diabetes, and cardiovascular diseases [ 49 , 50 ], diabetic macrovascular diseases [ 51 ], greater cognitive decline in older adults [ 52 ], and new or worsening nephropathy [ 53 ].

Even though much is yet to be investigated, studies suggested that interaction of AGEs with RAGE alters downstream signaling pathways and results in gene expression, release of pro-inflammatory molecules and free radicals [ 7 ]. Hence, blockade of AGEs formation or interaction with RAGE and suppressing downstream signaling pathways have become viable targets in the treatment of diabetes and metabolic syndrome [ 55 , 56 ]. There is increasing evidence that supports the role of RAGE in the pathogenesis of type 1 diabetes.

Hence, blockade of RAGE, its ligands or signal transduction presents a viable target for the secondary prevention of diabetes [ 58 ]. In line with this, in HIT-T15 cell lines cultured with AGEs, a reduced expression and nuclear localization of pancreatic and duodenal homeobox-1 PDX-1 gene, a decreased phosphorylation, and an increased acetylation of transcription factor FoxO1 was observed.

Consequently, AGEs decrease insulin content through unbalancing the transcription factors and regulating insulin gene expression [ 59 ]. AGEs can also promote insulin resistance and hence trigger diabetes by depleting the antioxidant defenses such as AGE receptor-1 and a survival factor sirtuin-1 [ 8 ].

AGEs can undergo post-translational modification of insulin molecule and impair its function [ 60 , 61 ]. Tan et al. Likewise, measurement of HbA1c, at the end of pregnancy was associated with adverse pregnancy outcomes [ 65 ].

Piuri et al also observed a positive correlation between methylglyoxal MGO levels, the major precursor in the formation of AGEs, and HbA1c both at diagnosis and after 12 weeks of gestation.

MGO levels were also positively correlated with both the pregestational and gestational weight of women [ 19 ].

The Role of Advanced Glycation End Products in Diabetic Vascular Complications

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. Besides, the BMI and other specific biomarkers showed a significant difference between the two groups indicating the high risk of developing long-standing type 2 diabetes and its complications in gestational diabetic women.

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.

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.

Advanced Glycation End Products

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Advanced glycation end-product

In cases of chronic hyperglycemia, advanced glycation end-products AGEs are actively produced and accumulated in the circulating blood and various tissues. AGEs also accelerate the expression of receptors for AGEs, and they play an important role in the development of diabetic vascular complications through various mechanisms. Active interventions for glucose and related risk factors may help improve the clinical course of patients by reducing AGEs. This review summarizes recent updates on AGEs that have a significant impact on diabetic vascular complications. The Sulwon Award for Scientific Achievement is the Korean Diabetes Association's highest scientific award and honors an individual who has excellently contributed to the progress in the field of diabetes and metabolism.

Diabetic nephropathy DN is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease ESRD. Degenerative changes such as glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubulointerstitial fibrosis, glomerulosclerosis and podocytopathy manifest in various degrees of proteinuria in DN. AGE modification of client proteins from the extracellular matrix induces crosslinking, which is often associated with thickening of the basement membrane. Elevated levels of both serum and tissue AGEs are associated with adverse renal outcome. This review provides insights of NEG, discusses the cellular and molecular events triggered by AGEs, which manifest in the pathogenesis of DN including renal fibrosis, podocyte epithelial-mesenchymal transition and activation of renin-angiotensin system. Proteins and polypeptides are routinely subjected to several post-translational modifications during their lifetime, which includes phosphorylation, glycosylation, deamination, ubiquitination and sumoylation.

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