Serum Levels Of AGEs Research Articles

Modulation of circulating levels of advanced glycation end products and its impact on intima-media thickness of both common carotid arteries: CORDIOPREV randomised controlled trial

BackgroundIncreasing evidence supports the role of advanced glycation end products (AGEs) in atherosclerosis in both diabetic and non-diabetic patients, suggesting that therapeutic strategies targeting AGEs may offer potential benefits in this population. The Mediterranean diet is associated with improved biomarkers and anthropometric measurements related with atherosclerosis in addition to its ability to modulate AGE metabolism. Our aim was to determine whether the reduction in atherosclerosis progression (measured by changes in intima-media thickness of both common carotid arteries (IMT-CC)), observed after consumption of a Mediterranean diet compared to a low-fat diet, is associated with a modulation of circulating AGE levels in patients with coronary heart disease (CHD).Methods1002 CHD patients were divided in: (1) Non-increased IMT-CC patients, whose IMT-CC was reduced or not changed after dietary intervention and (2) Increased IMT-CC patients, whose IMT-CC was increased after dietary intervention. Serum AGE levels (methylglyoxal–MG and Nε-Carboxymethyllysine-CML) and parameters related to AGE metabolism (AGER1 and GloxI mRNA and sRAGE levels) and reduced glutathione (GSH) levels were measured before and after 5-years of dietary intervention.ResultsThe Mediterranean diet did not affect MG levels, whereas the low-fat diet significantly increased them compared to baseline (p = 0.029), leading to lower MG levels following the Mediterranean diet than the low-fat diet (p < 0.001). The Mediterranean diet, but not the low-fat diet, produced an upregulation of AGE metabolism, with increased AGER1 and GloxI gene expression as well as increased GSH and sRAGE levels in Non-increased IMT-CC patients (all p < 0.05). Although the Mediterranean diet increased MG levels in Increased IMT-CC patients, this increment was lower compared to the low-fat diet (all p < 0.05).ConclusionsOur results suggest that an improvement in modulation of AGE metabolism, which facilitates better management of circulating AGE levels, may be one of the mechanisms through which the Mediterranean diet, compared to a low-fat diet, reduces the progression of atherosclerosis in patients with CHD.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT00924937, Clinicaltrials.gov number, NCT00924937.Graphical abstract

8421 The Effect of Dietary Glycotoxins on Insulin Resistance in Polycystic Ovary Syndrome

Abstract Disclosure: A. Weidner: None. K. Vann: None. J. Zhang: None. A. Roy: None. O. Astapova: None. Polycystic ovary syndrome (PCOS) is a chronic systemic disorder that affects both metabolism and reproduction. PCOS is characterized by hyperandrogenism and insulin resistance, which are closely intertwined in this disease pathophysiology. PCOS affects an estimated 10% of people with ovaries and increases risk of endometrial cancer, type 2 diabetes, and major cardiovascular events. Furthermore, treatment options are generally poorly tolerated. Despite its prevalence, severity, and enormous public health burden, the etiology of PCOS is not well-understood. Insulin resistance likely plays a central role in PCOS pathogenesis, and often leads to hyperinsulinemia as the pancreas attempts to compensate for insulin’s decreased efficacy in the body. Moreover, the Western diet is becoming increasingly rich in advanced glycation end products (AGEs): non-enzymatically modified biomolecules that have recently been found to have a harmful effect on insulin sensitivity and are associated with diabetes, aging, and oxidative stress. Serum AGE levels have been reported to be higher in both lean and obese PCOS patients, regardless of PCOS subtype. We have also found higher levels of AGE precursors in the serum of our chronic dihydrotestosterone-induced mouse model of PCOS. Using this mouse model, we have shown that ovarian granulosa cells (GCs) remain insulin-sensitive despite systemic insulin resistance and hyperinsulinemia, manifested by impaired glucose tolerance and increased HOMA-IR. To assess whether GCs respond to insulin through alternative receptor pathways, we knocked down insulin receptor in human granulosa-derived KGN cells and found that insulin-stimulated AKT phosphorylation was only minimally reduced, suggesting that insulin may signal in large part through the insulin-like growth factor 1 receptor (IGF1R) in these cells. Therefore, we believe that compensatory hyperinsulinemia plays a key role in chronic GC hyperstimulation, possibly by rerouting the insulin signal through IGF1R to overcome the resistance to insulin receptor activation, suggesting a mechanism for AGE toxicity in PCOS. We hypothesize that in PCOS, this results in impaired GC function and exacerbation of ovarian dysfunction. We will use our PCOS mouse model to study the effects of a reduced-AGE diet in ameliorating the reproductive and metabolic phenotype of an androgenized PCOS mouse. In preliminary experiments, we have found that a low-AGE diet results in lower fasting glucose in C57BL/6J mice after only 4 weeks. We expect that reproductive symptoms, such as estrous cyclicity, and metabolic symptoms, such as GTT and circulating insulin, will improve in our PCOS mouse model when mice are fed a low-AGE diet throughout development and adulthood. This project has significant clinical implications, as reducing dietary AGEs could provide an effective, tolerable, non-drug therapy option for patients with PCOS. Presentation: 6/3/2024

Correlation between circulating advanced glycation end products and thioredoxin-interacting protein levels and renal fat content in type 2 diabetes mellitus patients

BackgroundThis study sought to explore the clinical relevance of the associations of serum levels of advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), and thioredoxin-interacting protein (TXNIP) with the renal fat fraction (RFF) in individuals with type 2 diabetes mellitus (T2DM).MethodsA total of 133 patients with T2DM were enrolled in the study. RFF, which represents the renal fat level, was determined utilizing Dixon magnetic resonance imaging (MRI). Serum levels of AGEs, sRAGE, TXNIP, and other biochemical parameters were measured in patients who fasted.ResultsRFF in T2DM patients was positively correlated with the fasting levels of C-peptide (CP), triglycerides (TG), AGEs, TXNIP, and sRAGE (P < 0.05) and negatively correlated with the high-density lipoprotein cholesterol (HDL-c) level (P < 0.05). Pearson’s correlation analysis indicated that the serum levels of AGEs, sRAGE, and TXNIP were interrelated and positively correlated (P < 0.05). Then, all patients were assigned to four groups according to the RFF quartile. The HC, CP, TG, AGEs, sRAGE, TXNIP, and DKD percentages tended to increase as the RFF quartiles increased, while the HDL-c level tended to decrease (p for trend < 0.05). Next, multiple linear regression analysis was performed using RFF as the dependent variable. After controlling for covariates related to RFF, the results showed that the serum levels of AGEs and TXNIP were still significantly correlated with RFF.ConclusionThese results suggest that circulating AGEs and TXNIP levels may be associated with ectopic fat accumulation in the kidneys of T2DM patients and may serve as indicators of the severity of renal fat deposition.

Advanced glycosylation end products promote the progression of CKD-MBD in rats, and its natural inhibitor, quercetin, mitigates disease progression.

Chronic kidney disease-mineral and bone metabolism disorder (CKD-MBD) is a common chronic kidney disease (CKD)-associated complication that increases the risk of metabolic bone diseases, fractures, osteoblastic trans-differentiation of vascular smooth muscle cells, and cardiovascular events. SD rats were randomised into five groups with six rats per group: sham, CKD, CKD + advanced glycosylation end products (AGEs), CKD + Quercetin, and CKD + AGEs + Quercetin. The protective effects of AGEs and quercetin on SD rats were assessed by renal function, renal pathology, bone metabolism, osteoblastic trans-differentiation of vascular smooth muscle cells, and the receptor for AGE (RAGE) expression. Compared with the control group, rats in the CKD and CKD + AGEs groups had significantly lower body weight, higher serum AGEs levels, impaired renal function, increased levels of oxidative stress in the kidney and bone marrow tissues, lower femoral bone mineral density (BMD), callus mineralised volume fraction (mineralised bone volume/total volume), abnormal serum bone metabolism levels, and increased renal tissue, bone tissue, and abdominal aorta RAGE expression levels, and the RAGE downstream NF-κB signalling pathway was upregulated. Quercetin significantly improved renal dysfunction, attenuated serum AGE levels, reduced oxidative stress levels in the kidney and bone marrow tissues, and downregulated RAGE expression in the kidney, bone, and abdominal aorta and the RAGE downstream NF-κB signalling pathway in rats with CKD. AGEs are involved in the pathogenesis of CKD-MBD by promoting osteoblastic trans-differentiation of vascular smooth muscle cells and abnormal bone metabolism. Quercetin plays a role in the prevention and treatment of CKD-MBD by reducing the production of AGEs.

Reduction of circulating methylglyoxal levels by a Mediterranean diet is associated with preserved kidney function in patients with type 2 diabetes and coronary heart disease: From the CORDIOPREV randomized controlled trial

AimAdvanced glycation end products (AGEs) play a role in kidney disease in type 2 diabetes mellitus (T2DM). However, there have been no prior controlled clinical trials examining the effects of specific diets on AGE metabolism and their impact on kidney function. Our aim was to assess whether modulating AGE metabolism resulting in reduced AGEs levels, after consumption of two healthy diets, could delay kidney function decline in patients with T2DM and coronary heart disease (CHD). MethodsT2DM patients (540 out of 1002 patients from the CORDIOPREV study), with estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2, were classified based on their baseline kidney function: normal eGFR (≥ 90 ml/min/1.73 m2), mildly decreased eGFR (60- < 90 ml/min/1.73 m2) and moderately decreased eGFR (<60 ml/min/1.73 m2). Serum AGE levels, methylglyoxal (MG) and N-carboximethyllysine (CML), and gene expression related to AGE metabolism (AGER1, RAGE, and GloxI mRNA) were measured before and after 5-years of dietary intervention (a Mediterranean diet or a low-fat diet). ResultsMediterranean diet produced a lower declined of eGFR compared to the low-fat diet only in patients with mildly decreased eGFR (P = 0.035). Moreover, Mediterranean diet was able to decrease MG levels and increase GloxI expression in normal and mildly decreased eGFR patients (all P < 0.05). One standard deviation increment of MG levels after dietary intervention resulted in a 6.8-fold (95 % CI 0.039;0.554) higher probability of eGFR decline. ConclusionOur study showed that lowering circulating AGE levels, specifically MG, after following a Mediterranean diet, might be linked to the preservation of kidney function, evidenced by a decreased decline of eGFR in T2DM patients with CHD. Patients with mildly decreased eGFR could potentially benefit more from AGE reduction in maintaining kidney function.

THU336 Correlation Between Dietary Advanced Glycation End-products (Ages) And Skin Ages In Adults With Longstanding T1D

Abstract Disclosure: A.B. Murthy: None. B.E. Gray: None. M. Cote: None. B. Zahedi: None. E.W. Yu: Grant Recipient; Self; Amgen Inc. Background: Advanced glycation end products (AGEs) are involved in the pathophysiology of diabetic complications, and are thought to accrue with aging, hyperglycemia, and through diet. Despite the postulated impact of dietary intake on circulating AGE levels, there is currently no validated methodology for dietary AGE (dAGE) assessment. Thus, we sought to develop a crosswalk algorithm to calculate AGE intake from the commonly utilized Block Food Frequency Questionnaire (FFQ), and to validate our algorithm by correlating dAGE to skin AGE values within a cohort of adults with Type 1 Diabetes (T1D). Methods: We performed preliminary analysis of 50 study participants from the ongoing Type 1 Diabetes Bone Health Connection (T1D BEACON) study evaluating postmenopausal women and men older than 50 years with T1D. Dietary AGE intake was quantified using a novel algorithm we developed to associate items from the 2014 Block FFQ with their AGE content as determined by ELISA in a published data set (Urribarri, et al. 2014). Mean daily dAGE intake (kU/day) was correlated with autoflourescent skin AGE values (AGE Reader, DiagnOptics Technologies) using multivariate linear regression, after adjusting for age and gender. Diabetic characteristics and complications were assessed through questionnaires, physical exams (mTCNS, DPNCheck), chart review, and urine/serum tests. Results: The average age of the T1D cohort was 62.7 ± 6.8 years, 50% were female, the average duration of diabetes was 45 ± 9.4 years, with average A1c of 7.2 ± 1.1. Regarding diabetic complications, 70% had retinopathy, 30% had microalbuminuria (urine albumin-creatinine ratio &amp;gt; 30 mcg/mg), and 33% had neuropathy (mTCNS score &amp;gt; 5). Using our novel algorithm, the mean daily dAGE intake was calculated as 13178 ± 4455 kU/day. Mean daily dAGE intake was significantly higher for men (15279 ± 6337 kU/day) compared to women (11628 ± 3699 kU/day) (p = 0.016). Importantly, dAGEs were significantly correlated with skin AGEs (r = 0.409, p = 0.004), an association that persisted after adjusting for age and gender (p = 0.005). Additionally, dAGEs were correlated with current A1c values (r=0.37, p = 0.009, adj. p = 0.042) and with BMI (r = 0.32, p = 0.024, adj. p = 0.020), even after adjusting for age and gender. No associations were found between dAGEs and retinopathy, microalbuminuria, or neuropathy. Additional analysis of the full planned cohort is ongoing, along with assessments of serum AGE levels. Conclusion: We have developed and validated a novel dietary AGE algorithm that quantifies dAGE intake using the Block FFQ and is correlated with skin AGEs and glycemic control among adults with T1D. If further validated in larger cohorts, we hope this dAGE tool will facilitate future investigation of the impact of dietary AGEs on diabetic complications. Presentation: Thursday, June 15, 2023

Differences in AGEs and hs-CRP between Type 2 Diabetes Mellitus with and without Complications

Background: Diabetes mellitus is a metabolic disease that can lead to macrovascular and microvascular complications that can cause death and reduce the quality of life. The level of serum AGEs increases with diabetes or a state of hyperglycemia. Increased AGEs in patients with diabetes mellitus can increase the risk of macrovascular and microvascular complications and increase the formation of hs-CRP. This study aims to assess the differences in AGEs and hs-CRP between type 2 diabetes mellitus patients with and without complications and the relationship between AGEs and hs-CRP. Methods: A cross-sectional study was conducted with 30 subjects of type 2 diabetes mellitus with complications and 30 subjects of diabetes mellitus without complications. Data were collected from September to December 2022. AGEs were measured using ELISA and hs-CRP using the turbidimetric method. Data were statistically processed to determine the difference and relationship between AGEs and hs-CRP. Results: AGEs and hs-CRP values in patients with type 2 diabetes mellitus with complications were 0.671±0.194 ng/ mL and 2.08(0.98-15.3) mg/L. In patients with uncomplicated type 2 diabetes 0.561±0.127 ng/mL and 1.69(0.22-9.25) mg/L. Differences in AGEs and hs-CRP between the two subject groups had significant results (AGEs p=0.012, hs-CRP p=0.038). The relationship between AGEs and hs-CRP in each subject group showed no significant results (With complications r=0.659 p=0.659, Without complications r=0.253 p=0.253). Conclusion: There are differences in AGEs and hs-CRP values between patients with type 2 diabetes mellitus with and without complications and there is no relationship between AGEs and hs-CRP values in each subject.

Unveiling the molecular basis of inflamm-aging induced by advanced glycation end products (AGEs)-modified human serum albumin (AGE-HSA) in patients with different immune-mediated diseases

Increased serum advanced glycation end products (AGEs) are commonly found in the patients with Diabetes mellitus (DM), aging-related diseases, and immune-mediated diseases. These diseases are notorious for vasculopathy, immune dysfunctions, and low-grade inflammation mimicking inflamm-aging. However, the molecular basis of inflamm-aging related to AGEs remains elucidation. In this study, we incubated human serum albumin (HSA) and glucose at 37 °C in 5% CO2 incubator for 0–180 days to generate AGE-HSA. We found the mixture gradually changing the color from transparancy to brown color and increased molecular weight during incubation. The pH value also gradually decreased from 7.2 to 5.4 irrelevant to ionic charge or [Ca2+] concentration, but dependent on gradual glycation of the alkaline amino acids, lysine and arginine. Functionally, 40 μg/mL of AGE-HSA decreased IL-2 production from human Jurkat T cell line via suppressing p-STAT3, p-STAT4, and p-STAT6 with an increased tendency of senescence-associated β-galactosidase (SA-βgal) expression but irrelevant to change of Th1/Th2/Treg subpopulations. In contrast, AGE-HSA enhanced CC motif chemokine ligand 5 (CCL-5), IL-8, macrophage migration inhibitor factor (MIF), and interleukin 1 receptor antagonist (IL-1Ra) but suppressed SA-βgal expression by human macrophage-like THP-1 cells. Interestingly, AGE-HSA abrogated the HSA-induced soluble intercellular adhesion molecules 1 (sICAM-1), sE-selectin and endothelin release from human coronary artery endothelial cells (HCAEC) and enhanced SA-βgal expression. The accelerated and increased HSA glycations by individual inflammation-related cytokine such as IL-2, IL-6, IL-17, TGF-β, or TNF-α in the in vitro study reflect increased serum AGE levels in patients with immune-mediated diseases. In conclusion, AGE-HSA can exert immunosuppresive, inflammatory and vasculopathic effects mimicking inflamm-aging in these patients.

Advanced glycation end products and their soluble receptor (sRAGE) in patients with Hashimoto's thyroiditis on levothyroxine substitution.

Advanced glycation end products (AGEs) are heterogenous group of irreversible chemical moieties originated from non-enzymatic glycation and oxidation of proteins, nucleic acids, and lipids. The engagement of AGEs with their chief cellular receptor (RAGE) activates a myriad of signaling pathways contributing to the progression of chronic diseases like autoimmune thyroiditis, type 2 diabetes mellitus and its complications. Soluble RAGE (sRAGE) prevents AGE-RAGE interaction in a competitive manner. We investigated the association between serum AGE, sRAGE and thyroid function in 73 Hashimoto thyroiditis patients (HT) on levothyroxine substitution, and in 83 age, BMI and gender-matched healthy controls. The serum AGEs levels were determined by autofluorescence on a multi-mode microplate reader, and the serum sRAGE levels by ELISA method. Mean AGE level was lower (10.71 vs 11.45 AU/µg protein; p=0.046), while mean sRAGE level was higher (923 vs 755 pg/mL; p<0.0005) in the serum of HT patients than the controls. AGE correlated with age, while sRAGE correlated negatively with BMI in both groups. We found negative correlation between AGE and fT3 levels (r=-0.32; p=0.006) and sRAGE and TSH levels (r=-0.27; p=0.022) in HT patients, while we failed to find association between AGE, sRAGE and parameters of thyroid function in the control group. Median AGE/sRAGE ratio was lower in HT patients than in controls (2.4, IQR 1.9 - 3.1 vs 3.3, IQR 2.3 - 4.1 AU/pg; p < 0.001). In HT patients, the AGE/sRAGE ratio correlated positively with BMI and correlated negatively with fT3. According to our results in HT patients lower TSH and higher fT3 levels within the reference range is accompanied by a favorable AGE/RAGE balance. Further investigations are needed to confirm these results.

Correlation of serum IGF-1, AGEs and their receptors with the risk of colorectal cancer in patients with type 2 diabetes mellitus.

According to epidemiological evidence, people with type 2 diabetes mellitus have a higher risk of developing colorectal cancer. To examine the relationship between colorectal cancer (CRC) and serum levels of IGF-1, IGF-1R, AGEs,RAGE and sRAGE in patients with type 2 diabetes. By using RNA-Seq data of CRC patients from The Cancer Genome Atlas (TCGA) database, we divided the patients into normal group(58 patients)and tumor group(446 patients), and analyzed the expression and prognostic value analysis of IGF-1,IGF1R and RAGE. Cox regression and the Kaplan-Meier method were used to determine the predictive value of target gene on clinical outcomes in CRC patients. In order to further combine CRC with diabetes research,one hundred forty-eight patients hospitalized in the Second Hospital of Harbin Medical University from July 2021 to July 2022 were enrolled and divided into CA and control groups. There were 106 patients in the CA group, including 75 patients with CRC and 31 patients with CRC+T2DM; the control group comprised 42 patients with T2DM. Circulating levels of IGF-1, IGF-1R, AGEs, RAGE, and sRAGE in the serum of the patients were measured using Enzyme-Linked Immunosorbnent Assay(ELISA) kits, and other clinical parameters were also measured during hospitalization. Statistical methods used were χ² test, independent samples t-test and Pearson correlation analysis were. Finally, we controlled for confounding factors and used logistic multi-factor regression analysis. Bioinformatics analysis showed that IGF-1, IGF1R and RAGE were highly expressed in CRC patients, and the patients with high expression also showed significantly lower overall survival rate. Through Cox regression analysis, IGF-1 can be used as an independent influencing factor of CRC. In the ELISA experiment, serum AGE, RAGE, IGF-1, and IGF-1R levels were higher in the CRC and CRC+T2DM groups than in the T2DM group, but the serum sRAGE concentrations in these groups were lower than those in the T2DM group (P < 0.05). Serum AGE, RAGE, sRAGE, IGF1, and IGF1R levels were higher in the CRC+T2DM group than in the CRC group (P < 0.05). In CRC+T2DM patients, serum AGEs were correlated with age (p = 0.027), and the serum AGE levels in these groups were positively correlated with RAGE and IGF-1 levels (p < 0.001) and negatively correlated with sRAGE and IGF-1R levels (p < 0.001). After correcting for confounding factors based on logistic multiple regression analysis, the effects of age, serum IGF-1 and IGF-1R on the development of CRC in patients with T2DM were statistically significant (p<0.05). Serum IGF-1 and IGF-1R levels independently influenced the development of CRC in patients with T2DM. Furthermore, IGF-1 and IGF-1R were correlated with AGEs in CRC patients who also had T2DM, suggesting that AGEs may influence the development of CRC in T2DM patients. These findings suggest that we may be able to lower the risk of CRC in the clinic by regulating AGEs through the regulation of blood glucose levels, which will affect IGF-1 and its receptors.

Advanced Glycation End Products and Bone Metabolism in Patients with Chronic Kidney Disease.

Advanced glycation end products (AGEs) accumulation may be involved in the progression of CKD-bone disorders. We sought to determine the relationship between AGEs measured in the blood, skin, and bone with histomorphometry parameters, bone protein, gene expression, and serum biomarkers ofbone metabolism in patients with CKD stages 3 to 5D patients. Serum levels of AGEs were estimated by pentosidine, glycated hemoglobin (A1c), and N-carboxymethyl lysine (CML). The accumulation of AGEs in the skin was estimated from skin autofluorescence (SAF). Bone AGEs accumulation and multiligand receptor for AGEs (RAGEs) expression were evaluated by immunohistochemistry; bone samples were used to evaluate protein and gene expression and histomorphometric analysis. Data are from 86 patients (age: 51 ± 13 years; 60 [70%] on dialysis). Median serum levels of pentosidine, CML, A1c, and SAF were 71.6pmol/mL, 15.2ng/mL, 5.4%, and 3.05 arbitrary units, respectively. AGEs covered 3.92% of trabecular bone and 5.42% of the cortical bone surface, whereas RAGEs were expressed in 0.7% and 0.83% of trabecular and cortical bone surfaces, respectively. AGEs accumulation in bone was inversely related to serum receptor activator of NF-κB ligand/parathyroid hormone (PTH) ratio (R=-0.25; p=0.03), and RAGE expression was negatively related to serum tartrate-resistant acid phosphatase-5b/PTH (R=-0.31; p=0.01). Patients with higher AGEs accumulation presented decreased bone protein expression (sclerostin [1.96 (0.11-40.3) vs. 89.3 (2.88-401) ng/mg; p=0.004]; Dickkopf-related protein 1 [0.064 (0.03-0.46) vs. 1.36 (0.39-5.87) ng/mg; p=0.0001]; FGF-23 [1.07 (0.4-32.6) vs. 44.1 (6-162) ng/mg; p=0.01]; and osteoprotegerin [0.16 (0.08-2.4) vs. 6.5 (1.1-23.7) ng/mg; p=0.001]), upregulation of the p53 gene, and downregulation of Dickkopf-1 gene expression. Patients with high serum A1c levels presented greater cortical porosity and Mlt and reduced osteoblast surface/bone surface, eroded surface/bone surface, osteoclast surface/bone surface, mineral apposition rate, and adjusted area. Cortical thickness was negatively correlated with serum A1c (R=-0.28; p=0.02) and pentosidine levels (R=-0.27; p=0.02). AGEs accumulation in the bone of CKD patients was related to decreased bone protein expression, gene expression changes, and increased skeletal resistance to PTH; A1c and pentosidine levels were related to decreased cortical thickness; and A1c levels were related to increased cortical porosity and Mlt. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A Cross-Sectional Analysis of Receptor for Advanced Glycation End Products in Human Skeletal Muscle: A Comparative Analysis between Patients with and without Sarcopenia

Introduction: Animal studies suggest that advanced glycation end products (AGEs) and their interaction with receptor for AGEs (RAGE) are involved in sarcopenia, but their relationship in human skeletal muscles has yet to be elucidated. We aimed to determine whether RAGE expression in human skeletal muscle is associated with serum AGE levels and sarcopenia-related changes. Methods: We retrospectively reviewed 33 consecutive women (mean age, 65 years) with distal radius fracture who had consented to donate a sample of forearm muscle for research purposes, which was taken during surgical fracture repair. The muscle RAGE expression was measured with immunohistochemistry staining and serum AGE levels using ELISA method. We compared RAGE expression and AGE levels in patients with and without sarcopenia. We also correlated RAGE expression with such clinical parameters as demographic factors, as well as sarcopenia-related changes, including grip strength, appendicular skeletal muscle mass, and muscle cross-sectional area (CSA) ratios. Results: Twelve patients (36%) were diagnosed with sarcopenia. They had a significantly higher RAGE expression (p = 0.044) and AGE level (p < 0.001) than those without sarcopenia. The RAGE expression correlated significantly with a high AGE level (r = 0.510, p = 0.011) and correlated inversely with a muscle CSA ratio (r = −0.696, p < 0.001). Discussion: This study shows that RAGE expression increases in sarcopenic patient skeletal muscles. This expression also correlates positively with serum AGE levels and inversely with muscle CSA ratios. Further studies are necessary to determine whether targeting RAGEs can be a therapeutic option for sarcopenia.

Fluorescent advanced glycation end products in type 2 diabetes and its association with diabetes duration, hemoglobin A1c, and diabetic complications.

Fluorescent advanced glycation end products (fAGEs) are generated through the Maillard reaction between reducing sugars and amino compounds. fAGEs accumulation in human bodies have been confirmed to be related to many chronic diseases. To date, the correlations between serum fAGEs levels and clinical parameters or carotid intima media thickness (CIMT) in patients with T2DM remain unclear. Thus, this study aimed to investigate the relationship between serum AGEs levels and clinical parameters or CIMT in patients with T2DM. A total of 131 patients with diabetes and 30 healthy controls were enrolled. Patients were divided into three groups according to diabetes duration, including ≤5, 5-10, and ≥10 years. Serum fAGEs, protein oxidation products, clinical parameters, and CIMT were determined. The result showed that levels of fAGEs and protein oxidation products increased with the increasing duration of diabetics. Pearson correlation coefficients of fAGEs versus hemoglobin A1c (HbA1c) were >0.5 in patients with diabetes duration ≥10 years. A continued increase in fAGEs might cause the increase of HbA1c, urinary albumin/creatinine ratio (UACR) and CIMT in patients with T2DM. Our study suggested that levels of fAGEs could be considered as an indicator for duration of diabetics and carotid atherosclerosis. Diabetes duration and smoking might have a synergistic effect on the increment of fAGEs levels, as evidence by the results of correlation analysis in patients with long-duration diabetics (≥10 years) and smoking. The determination of fAGEs might be helpful to advance our knowledge on the overall risk of complications in patients with T2DM.

Plantamajoside attenuates cardiac fibrosis via inhibiting AGEs activated-RAGE/autophagy/EndMT pathway.

Advanced glycation end products (AGEs) have been identified to transduce fibrogenic signals via inducing the activation of their receptor (RAGE)-mediated pathway. Recently, disrupting AGE-RAGE interaction has become a promising therapeutic strategy for chronic heart failure (CHF). Endothelial-to-mesenchymal transition (EndMT) is close to the cardiac fibrosis pathological process. Our previous studies have demonstrated that knockout RAGE suppressed the autophagy-mediated EndMT, and thus alleviated cardiac fibrosis. Plantamajoside (PMS) is the major bioactive compound of Plantago Asiatica, and its activity of anti-fibrosis has been documented in many reports. However, its effect on CHF and the underlying mechanism remains elusive. Thus, we tried to elucidate the protective role of PMS in CHF from the viewpoint of the AGEs/RAGE/autophagy/EndMT axis. Herein, PMS was found to attenuate cardiac fibrosis and dysfunction, suppress EndMT, reduce autophagy levels and serum levels of AGEs, yet did not affect the expression of RAGE in CHF mice. Mechanically, PMS possibly binds to the V-domain of RAGE, which is similar to the interaction between AGEs and RAGE. Importantly, this competitive binding disturbed AGEs-induced the RAGE-autophagy-EndMT pathway in vitro. Collectively, our results indicated that PMS might exert an anti-cardiac fibrosis effect by specifically binding RAGE to suppress the AGEs-activated RAGE/autophagy/EndMT pathway.

High chitotriosidase and AGE levels in acromegaly: a case-control study.

Acromegaly is associated with oxidative stress and inflammation parameters. Chitotriosidase (CHITO) is a marker of macrophage activation and plays a pivotal role in the activation of inflammatory and immunological responses. Our study aimed to determine CHITO,YKL-40, advanced glycation end product (AGE), and high-sensitivity C-reactive protein (hsCRP) levels to investigate malondialdehyde (MDA), catalase, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities and to evaluate any association of these parameters with carotid intima media thickness (cIMT) in patients with controlled acromegaly. Thirty controlled acromegaly patients and 41 age- and sex-matched control cases were studied. We obtained demographic data, hormonal and metabolic parameters, and cIMT. CHITO activity was measured with the fluorometric method of Chamoles et al. YKL-40 and hsCRP levels were measured using ELISA. AGEs were measured based on spectrofluorimetric detection. GSH-Px activity was determined by a colorimetric assay. MDA, SOD, and catalase activities were determined in hemolysis. Higher CHITO, AGE, and hsCRP concentrations were observed in patients with acromegaly compared to controls. SOD levels were non-significantly higher in the acromegaly group, while catalase activities were lower in patients with acromegaly. Correlation analyses of CHITO, AGEs, YKL-40, hsCRP, MDA, catalase, GSH-Px, and SOD with metabolic, anthropometric, and laboratory parameters did not demonstrate any significant correlation (p > 0.05). There was no significant difference between groups with regard to cIMT levels. This is the first study investigating CHITO and AGE levels in patients with acromegaly. Serum CHITO, AGE, and hsCRP levels in acromegalic patients were significantly increased. It may be important to evaluate CHITO, AGE, and hsCRP levels in acromegalic patients who are already under cardiometabolic surveillance due to risk of developing cardiovascular disease.

Diagnostic Values of Advanced Glycation End Products and Homocysteine in Patients with Alzheimer's Disease and Sarcopenia.

This study is aimed at exploring the diagnostic value of advanced glycation end products (AGEs) and homocysteine (Hcy) in Alzheimer's disease (AD) complicated with sarcopenia (SP) and to analyze the risk factors related to AD complicated with SP. A total of 168 patients admitted to our hospital from November 2019 to December 2021 were enrolled. Patients were divided into the NC (no SP and AD) group with 29 cases, the AD group with 39 cases, the AD+SP group with 35 cases, and the SP group with 65 cases. The general information, Mini-Mental State Examination (MMSE) scores, and serum levels of AGEs and Hcy among the four groups were compared. Unordered logistic regression was used to analyze the influencing factors of SP patients complicated with dementia. The AGE level was higher in the AD or AD+SP group than the NC or SP group (P < 0.05). There was no significant difference between the SP group and the NC group or between the AD group and the AD+SP group (P > 0.05). The Hcy level was higher in the SP or AD group than the NC group (P < 0.05). There were no significant differences between the AD group and NC group or between the SP group and AD+SP group (P > 0.05). The ROC curve of serum AGEs and Hcy for the diagnosis of AD showed that the area under curve (AUC) was 0.887, P < 0.05 (95% CI: 0.821-0.954, sensitivity: 80.95%, specificity: 73.81%) and 0.7423, P < 0.05 (95% CI: 0.6382-0.8465, sensitivity: 60.42%, specificity: 57.59%), respectively. The ROC curve of serum AGEs and Hcy for the diagnosis of SP showed that the AUC was 0.5533, P > 0.05 (95% CI: 0.4294-0.6771) and 0.8744, P < 0.05 (95% CI: 0.8006-0.9483). Age (P < 0.001), depression (P = 0.001), malnutrition (P = 0.002), and BMI (P < 0.001) were independent influencing factors of SP complicated with AD in elderly inpatients. In conclusion, combined serum AGEs and Hcy had a good diagnostic value for AD combined with SP, which may be helpful for early detection of patient condition.

Involvement of AGE and Its Receptors in the Pathogenesis of Hypertension in Elderly People and Its Treatment.

Both systolic and diastolic blood pressures increase with age up to 50 to 60 years of age. After 60 years of age systolic pressure rises to 84 years of age but diastolic pressure remains stable or even decreases. In the oldest age group (85-99 years), the systolic blood pressure (SBP) is high and diastolic pressure (DBP) is the lowest. Seventy percent of people older than 65 years are hypertensive. This paper deals with the role of advanced glycation end products (AGE) and its cell receptor (RAGE) and soluble receptor (sRAGE) in the development of hypertension in the elderly population. Plasma/serum levels of AGE are higher in older people as compared with younger people. Serum levels of AGE are positively correlated with age, arterial stiffness, and hypertension. Low serum levels of sRAGE are associated with arterial stiffness and hypertension. Levels of sRAGE are negatively correlated with age and blood pressure. Levels of sRAGE are lower in patients with arterial stiffness and hypertension than patients with high levels of sRAGE. AGE could induce hypertension through numerous mechanisms including, cross-linking with collagen, reduction of nitric oxide, increased expression of endothelin-1, and transforming growth factor-β (TGF-β). Interaction of AGE with RAGE could produce hypertension through the generation of reactive oxygen species, increased sympathetic activity, activation of nuclear factor-kB, and increased expression of cytokines, cell adhesion molecules, and TGF- β. In conclusion, the AGE-RAGE axis could be involved in hypertension in elderly people. Treatment for hypertension in elderly people should be targeted at reduction of AGE levels in the body, prevention of AGE formation, degradation of AGE in vivo, downregulation of RAGE expression, blockade of AGE-RAGE interaction, upregulation of sRAGE expression, and use of antioxidants.

Exploration of Noninvasive Detection of Advanced Glycation End Products in the Lens to Screen for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a complication of diabetes, which is the most common cause of end-stage renal disease (dialysis). DKD has a high mortality rate, and only early detection can nip this disease in the bud. Advanced glycation end products (AGEs)are generally believed to be involved in the occurrence of DKD. Studies have shown that the lens AGEs fluorescence for noninvasive detection has high consistency with the gold standard OGTT, has high sensitivity and specificity, and could be used as a practical tool for the early screening of type 2 diabetes mellitus (T2DM).Therefore, we speculated that the noninvasive lens AGEs fluorescence detection method can be used to predict the occurrence of DKD. This study detected levels of AGEs in multiple cellular and tissues and analyzed the relationships between AGEs and lens, eyeballs, peripheral blood mononuclear cell (PBMC), serum, and kidney. Additionally, we examined the possible role of lens AGEs fluorescence in DKD screening. Our preexperimental study found that lens AGE levels in patients with T2DM were positively correlated with PBM and serum AGE levels. Lens AGE levels in patients with T2DM were negatively correlated with eGFR and positively correlated with urinary ACR. The animal and cell experiments showed that the AGE levels in the eyeballs of DM mice were also positively correlated with those in the serum and kidney. To increase the reliability of the experiment, we increased the sample size. In our results, lens AGEs levels were positively correlated with the occurrence of DKD, and the incidence of DKD in the high lens AGEs group was 2.739 times that in the low lens AGEs group. The receiver operating characteristic (ROC) curves showed that patients with T2DM with a lens AGEs value ≥ 0.306 were likely to have DKD. The area under the ROC curve of the noninvasive technique for identifying DKD was 0.757 (95% Cl: 0.677-0.838, p<0.001), and the sensitivity and specificity were 70.0% and 78.7%, respectively. These results suggest that noninvasive lens AGEs detection technology has certain clinical value in diagnosing whether patients with T2DM have DKD.

Increased serum levels of advanced glycation end products are negatively associated with relative muscle strength in patients with type 2 diabetes mellitus

BackgroundIn this study, we investigated whether serum levels of advanced glycation end products (AGEs) independently correlated with relative muscle strength after adjustment for clinical variables including diabetic peripheral neuropathy in patients with type 2 diabetes. Relative muscle strength was defined as muscle strength (in decinewtons, dN) divided by total muscle mass (in kg).MethodsWe enrolled 152 ambulatory patients with type 2 diabetes. Each participant underwent measurements of muscle strength and total muscle mass. Serum levels of AGEs were determined. The Michigan Neuropathy Screening Instrument Physical Examination (MNSI-PE) was performed to assess diabetic peripheral neuropathy.ResultsThe participants were divided into three groups on the basis of tertiles of serum AGEs levels. Significant differences were observed among the three groups in relative handgrip strength (71.03 ± 18.22, 63.17 ± 13.82, and 61.47 ± 13.95 dN/kg in the low-tertile, mid-tertile, and high-tertile groups, respectively, P = 0.005). The relative muscle strength of the ankle plantar flexors was higher in the low-tertile group than in the mid-tertile and high-tertile groups (107.60 ± 26.53, 94.97 ± 19.72, and 94.18 ± 16.09 dN/kg in the low-tertile, mid-tertile, and high-tertile groups, respectively, P = 0.002). After adjustment for MNSI-PE score and other clinical variables in partial correlation analysis, the correlations between serum levels of AGEs and the relative muscle strength of handgrip, ankle dorsiflexor, and ankle plantar flexor remained significant. Serum AGEs level was the only variable that remained significantly related to the relative muscle strength of handgrip, ankle dorsiflexor, and ankle plantar flexor when AGEs level, fasting plasma glucose, and glycated hemoglobin (HbA1c) were entered into multiple regression models simultaneously.ConclusionsAfter adjustment for multiple factors including diabetic peripheral neuropathy, this study demonstrated that increased serum levels of AGEs were independently associated with decreased relative muscle strength in patients with type 2 diabetes. Compared with fasting plasma glucose and HbA1c, serum level of AGEs is more strongly associated with relative muscle strength.

Advanced glycation end products promote osteoporosis by inducing ferroptosis in osteoblasts.

Advanced glycation end products (AGEs) have been widely reported to play an important role in osteoporosis (OP), particularly in diabetes-related OP. The aim of the present study was to investigate the effect of AGEs on osteoblast function and the underlying mechanisms. The level of bone mineral density (BMD), serum AGEs and fasting blood glucose (FBG) was measured in patients with OP and healthy individuals, and the correlation between AGE levels and BMD or FBG was then analyzed. For the in vitro experiments, the hFOB1.19 osteoblast cell line was cultured in medium containing AGEs and serum from healthy individuals or patients with OP, and with or without type-2 diabetes mellitus (T2DM). Cell proliferation, differentiation, mineralization, apoptosis and ferroptosis were evaluated using Cell Counting Kit-8 and alkaline phosphatase (ALP) assays, Alizarin red and TUNEL staining, iron indicator, lipid peroxidation tests and western blot analysis, respectively. In a separate set of experiments, the ferroptosis inhibitor, deferoxamine (DFO), was also added to the culture medium of cells treated with AGEs and serum from patients with OP and T2DM. The results demonstrated that patients with OP had a higher level of serum AGEs and FBG compared with that in healthy individuals. The level of serum AGEs in patients with OP was negatively correlated with BMD, but was positively correlated with FBG. In addition, AGEs and serum from patients with OP markedly inhibited hFOB1.19 cell proliferation, ALP production and mineralized nodule formation. Apoptosis and ferroptosis were significantly promoted by AGEs and serum from patients with OP. Moreover, serum from OP patients with T2DM caused stronger effect than that from OP patients with normal FBG. However, DFO reversed the effects induced by AGEs and serum from patients with OP and T2DM on hFOB1.19 cells. Collectively, AGEs could disrupt the functions of osteoblasts by inducing cell ferroptosis, thus contributing to OP.