Elevated Advanced Glycation End Products Research Articles

Antidiabetic Agents and Bone Quality: A Focus on Glycation End Products and Incretin Pathway Modulations.

Diabetes mellitus is associated with inadequate bone health and quality and heightened susceptibility to fractures, even in patients with normal or elevated bone mineral density. Elevated advanced glycation end-products (AGEs) and a suppressed incretin pathway are among the mechanisms through which diabetes affects the bone. Accordingly, the present review aimed to investigate the effects of antidiabetic medications on bone quality, primarily through AGEs and the incretin pathway. Google Scholar, Cochrane Library, and PubMed were used to examine related studies until February 2024. Antidiabetic medications influence AGEs and the incretin pathway directly or indirectly. Certain antidiabetic drugs including metformin, glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl-peptidase-4 (DDP-4) inhibitors, α-glucosidase inhibitors (AGIs), sodium-glucose co-transporter-2 inhibitors, and thiazolidinediones (TZDs), directly affect AGEs through multiple mechanisms. These mechanisms include decreasing the formation of AGEs and the expression of AGEs receptor (RAGE) in tissue and increasing serum soluble RAGE levels, resulting in the reduced action of AGEs. Similarly, metformin, GLP-1RA, DDP-4 inhibitors, AGIs, and TZDs may enhance incretin hormones directly by increasing their production or suppressing their metabolism. Additionally, these medications could influence AGEs and the incretin pathway indirectly by enhancing glycemic control. In contrast, sulfonylureas have not demonstrated any obvious effects on AGEs or the incretin pathway. Considering their favorable effects on AGEs and the incretin pathway, a suitable selection of antidiabetic drugs may facilitate more protective effects on the bone in diabetic patients.

Exosomal MALAT1 promotes the proliferation of esophageal squamous cell carcinoma through glyoxalase 1-dependent methylglyoxal removal

In previous study we characterized the oncogenic role of long non-coding RNA MALAT1 in esophageal squamous cell carcinoma (ESCC), but the detailed mechanism remains obscure. Here we identified glyoxalase 1 (GLO1) as the most possible executor of MALAT1 by microarray screening. GLO1 is responsible for degradation of cytotoxic methylglyoxal (MGO), which is by-product of tumor glycolysis. Accumulated MGO may lead to glycation of DNA and protein, resulting in elevated advanced glycation end products (AGEs), while glyoxalase 1 detoxify MGO to alleviate its cytotoxic effect to tumor cells. GLO1 interfering led to accumulation of AGEs and following activation of DNA injury biomarkers, which lead to cell cycle arrest and growth inhibition. In silico analysis based on online database revealed abundant enrichment of histone acetylation marker H3K27ac in GLO1 promotor, and acetyltransferase inhibitor C646 declined GLO1 expression. Acetyltransferase KAT2B, which was also identified as a target of MALAT, mediated histone lysine acetylation of GLO1 promotor, which was confirmed by ChIP-qPCR experiment. Shared binding sites of miR-206 were found on MALAT1 and KAT2B mRNA. Dual-luciferase reporter assays confirmed interaction within MALAT1-miR-206-GLO1. Finally, we identified MALAT1 encapsuled by exosome from donor cells, and transferred malignant behaviors to recipient cells. The secreted exosomes may enter circulation, and serum MALAT1 level combined with traditional tumor markers showed potential power for ESCC diagnosis.

Clinical Pathobiochemistry of Vitamin B12 Deficiency: Improving Our Understanding by Exploring Novel Mechanisms with a Focus on Diabetic Neuropathy.

Vitamin B12 (B12) is an essential cofactor of two important biochemical pathways, the degradation of methylmalonic acid and the synthesis of methionine from homocysteine. Methionine is an important donor of methyl groups for numerous biochemical reactions, including DNA synthesis and gene regulation. Besides hematological abnormalities (megaloblastic anemia or even pancytopenia), a deficiency in B12 may cause neurological symptoms, including symptoms resembling diabetic neuropathy. Although extensively studied, the underlining molecular mechanism for the development of diabetic peripheral neuropathy (DPN) is still unclear. Most studies have found a contribution of oxidative stress in the development of DPN. Detailed immunohistochemical investigations in sural nerve biopsies obtained from diabetic patients with DPN point to an activation of inflammatory pathways induced via elevated advanced glycation end products (AGE), ultimately resulting in increased oxidative stress. Similar results have been found in patients with B12 deficiency, indicating that the observed neural changes in patients with DPN might be caused by cellular B12 deficiency. Since novel results show that B12 exerts intrinsic antioxidative activity in vitro and in vivo, B12 may act as an intracellular, particularly as an intramitochondrial, antioxidant, independent from its classical, well-known cofactor function. These novel findings may provide a rationale for the use of B12 for the treatment of DPN, even in subclinical early states.

Impact of Dietary Advanced Glycation End-Product Restriction on Insulin Resistance and Anthropometric Indices in Coronary Artery Patients Treated with Percutaneous Coronary Intervention: A Randomized Controlled Trial.

Insulin resistance (IR), even in its subclinical state, is a significant risk factor for the onset and progression of coronary artery disease (CAD). IR is a multifactorial condition, and dietary composition is a factor associated with its development. Elevated advanced glycation end products (AGEs) in the body, secondary to highly processed food consumption, can impair glucose metabolism. The present study investigated whether a restricted AGE diet could affect insulin sensitivity and anthropometric indices reflecting visceral adipose tissue in nondiabetic CAD patients. This trial randomly allocated 42 angioplasty-treated patients to follow either low-AGE or control diets based on the AHA/NCEP guidelines for 12 weeks. Serum levels of total AGEs, insulin, HbA1c, and fasting blood sugar, as well as anthropometric measurements, were evaluated before and after the intervention. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and anthropometric indices were calculated according to the proposed formula. The patients' health status was assessed using the Seattle Angina Questionnaire (SAQ) at baseline and after the intervention. Our study showed a significant reduction in anthropometric indices in the low-AGE group after 12 weeks. Insulin levels and IR decreased during the low-AGE diet. No significant changes were observed in the other serum biochemical markers. All SAQ domains significantly decreased in both groups, except for Treatment Satisfaction. A low-AGE diet for 12 weeks had beneficial effects on HOMA-IR and insulin levels in patients with CAD. Regarding the fundamental role of AGE in IR development and body fat distribution, AGE restriction may positively affect these patients.

D-galactose-induced aging aggravates obesity-induced bone dyshomeostasis

We aimed to compare the time-course effect of D-galactose (D-gal)-induced aging, obesity, and their combined effects on bone homeostasis. Male Wistar rats were fed with either a normal diet (ND; n = 24) or a high-fat diet (HFD; n = 24) for 12 weeks. All rats were then injected with either vehicle or 150 mg/kg/day of D-gal for 4 or 8 weeks. Blood was collected to measure metabolic, aging, oxidative stress, and bone turnover parameters. Bone oxidative stress and inflammatory markers, as well as bone histomorphometry were also evaluated. Additionally, RAW 264.7 cells were incubated with either D-gal, insulin, or D-gal plus insulin to identify osteoclast differentiation capacity under the stimulation of receptor activator of nuclear factor κB ligand. At week 4, D-gal-induced aging significantly elevated serum malondialdehyde level and decreased trabecular thickness in ND- and HFD-fed rats, when compared to the control group. At week 8, D-gal-induced aging further elevated advanced glycation end products, increased bone inflammation and resorption, and significantly impaired bone microarchitecture in HFD-fed rats. The osteoclast number in vitro were increased in the D-gal, insulin, and combined groups to a similar extent. These findings suggest that aging aggravates bone dyshomeostasis in the obese condition in a time-dependent manner.

Elevated advanced glycation end products are associated with subfoveal ellipsoid zone disruption in diabetic macular edema.

Purpose:Advanced glycation end products (AGEs), due to increased production and a slow turnover rate, serve as mediators of “metabolic memory” even after the resolution of hyperglycemia. A prospective study was undertaken to evaluate the association of AGEs with subfoveal ellipsoid zone (EZ) disruption in diabetic macular edema (DME).Methods:A tertiary-care-center-based cross-sectional study included 40 consecutive cases with DME and 20 healthy controls in the age group of 40–65 years. All the study subjects underwent spectral-domain optical coherence tomography (SD-OCT) for cross-sectional imaging of the retina. The EZ was defined as a hyperreflective band below the external limiting membrane. The disruption of EZ was graded as intact EZ and disrupted EZ. Serum AGEs were assessed by assay of Nε-carboxymethyl-lysine (Nε-CML) using the standard protocol. Data were analyzed statistically.Results:Subfoveal EZ disruption was noted in 80% (32/40) of the cases of DME. In the cases without EZ disruption, visual acuity (LogMAR VA) was 0.60 ± 0.52, whereas in cases with EZ disruption, LogMAR VA was 0.96 ± 0.56 (P < 0.001). In the cases without EZ disruption, Nε-CML was 94.31 ± 57 ng/mL, whereas in cases with EZ disruption Nε-CML was 120.64 ± 71.98 ng/mL (P < 0.001).Conclusion:In DME, increased levels of AGEs are significantly associated with EZ disruption on SD-OCT.

Erectile dysfunction in diabetes mellitus: A review

The International Diabetes Federation estimates that globally there are 425 million people with diabetes. Estimates of the prevalence of erectile dysfunction (ED) in men with diabetes range from 20% to 85% in different studies. Among men with ED, those with diabetes are likely to experience the problem 10–15 years earlier than men without diabetes. This review aims to provide an update of the epidemiology, pathophysiology and management of ED in diabetes patients in India. The proposed mechanisms of ED in diabetic patients include elevated advanced glycation end-products and increased levels of oxygen-free radicals, impaired nitric oxide (NO) synthesis, increased endothelin B receptor binding sites and ultrastructural changes, upregulated RhoA/Rho-kinase pathway, NO-dependent selective nitrergic nerve degeneration and impaired cyclic guanosine monophosphate-dependent kinase-1. Modifiable risk factors for ED include smoking, lack of physical activity, wrong diets, overweight or obesity, metabolic syndrome and excessive alcohol consumption. Therefore, the promotion of healthful lifestyles would yield great benefits in reducing the burden of ED. The treatment of diabetic ED is multimodal. The treatment of the underlying hyperglycaemia and comorbidities is of utmost importance to prevent the progression of the disease. The peripherally acting oral phosphodiesterase type 5 inhibitors are the mainstay of oral medical treatment of ED in diabetics. Vacuum erection devices are an additional a non-invasive treatment option. The local administration of vasoactive medication through urethral suppository or intracorporal injection can be effective with minimal side-effects.

Glucose Lowering Effect of Basil Leaves in Diabetic Rats.

BACKGROUND:The incidence of diabetes and its complications has risen since the last decades, and it has been predicted that the prevalence of diabetes will be double in the coming year. Chronic hyperglycemia marked as elevated advanced glycation end products plays an important role in complications of diabetes. Basil leaves (Ocimum basilicum) originating from India and commonly found in Southeast Asia, is widely used empirically to decrease the blood sugar in diabetic patients.AIM:The purpose of the study was to investigate the effect of extract ethanol of Basil leaves in diabetic rats.METHODS:This is an experimental study; Streptozotocin was used to induce type 2 diabetic rats. Thirty Wistar male rats were divided into six groups (normal group, group treated with metformin 45 mg/kg body weight, group treated with Basil leaves 100 mg/kg body weight, 200 mg/kg body weight, 400 mg/kg body weight, control diabetic group). The blood glucose level was measured before induction and after treatment at week 1 and 4. Advanced glycation end products were measured in all groups at week 4.RESULTS:Extract ethanol of basil leaves 100, 200, 400 mg/body weight all showed significant lowering blood glucose level (p < 0.001) compared to diabetic group without treatment, but did not show superior to metformin group (p = 0.17), advanced glycation end products did not show statistical significance between group with normal rats and group of diabetic rats treated with basil leaves 100 mg/kg, 200 mg/kg, 400 mg/kg (p = 0.12, p = 0.33, p = 0.26).CONCLUSION:Extract ethanol of basil leaves showed good results in lowering blood glucose and advanced glycation end products in diabetic rats.

Advanced Glycation End Products Stimulate Angiotensinogen Production in Renal Proximal Tubular Cells

Elevated advanced glycation end products (AGE) in diabetes mellitus (DM) are implicated in the progression of DM-associated tissue injury, including diabetic nephropathy. The intrarenal renin-angiotensin system, in particular augmentation of angiotensinogen (AGT) in proximal tubular cells (PTC), plays a crucial role in the development of diabetic nephropathy. This study investigated hypothesis that AGE stimulates AGT production in PTC. Urinary AGT and AGE levels in streptozotocin-induced DM mice were measured by enzyme-linked immunosorbent assays. AGT expression and secretion were evaluated in cultured rat PTC receiving 0-200 µg/ml AGE-BSA treatments for 24 hours. Furthermore, intracellular signaling pathways activated by AGE were elucidated. DM mice exhibited greater urinary AGT and AGE levels compared to control mice (AGT: 21.6 ± 5.5 ng/day vs. 190.1 ± 57.8 ng/day, AGE: 139.1 ± 21.6 μg/day vs. 332.8 ± 102.7 μg/day). In cultured PTC, treatment with AGE-BSA enhanced AGT mRNA expression (3.43 ± 0.11-fold compared to control), intracellular AGT protein levels (3.60 ± 0.38-fold), and secreted AGT levels (2.11 ± 0.18-fold). On the other hand, AGT levels were not altered in PTC receiving nonglycated BSA. Recombinant soluble AGE receptor, which competes with endogenous AGE receptor, diminished the AGE-induced AGT upregulation, suggesting that AGE-BSA stimulates AGT expression via activation of the AGE receptor. Enhanced phosphorylation of ERK1/2 and c-Jun, but not p38 MAP kinase, were observed in AGE-BSA-treated PTC. AGE-induced AGT augmentation was attenuated by an ERK inhibitor. The findings indicate that AGE enhances proximal tubular AGT expression via ERK1/2, which can exacerbate the development of diabetic related kidney injury.

The Effect of a &lt;em&gt;Phaseolus vulgaris&lt;/em&gt; and Dietary Fiber Based Supplement on Advanced Glycation End Products: An Open-label Trial

Elevated Advanced Glycation End product (AGE) levels are associated with certain impaired health states. As these are disruptive to the function of healthy tissues, due to their protein cross-linking ability, AGEs are significant contributors to the aging process. In fact, population studies have revealed that AGE levels tend to increase as we get older. Certain lifestyle and dietary factors may accelerate AGE accumulation. Therefore, strategies intended to modify these factors, or mitigate their effects, may be useful in controlling the aging process. In an 11 week open-label clinical trial, 30 adult volunteers consumed daily a commercially available combination of white kidney bean extract, dietary fibers, &beta-carotene and noni ( Morinda citrifolia ) fruit pulp, in combination with calorie restriction and exercise. During the course of the trial, participants experienced significant weekly declines in average body weight and fat mass. The average AGE score, as measured by skin auto-fluorescence, had also decreased significantly. In terms of AGE associated years, the change in AGE scores corresponded to an average decrease of 8.83 years. The results indicate that the intervention contributed to improved health and exhibited anti-aging properties.

-374 T/A RAGE Polymorphism Is Associated with Chronic Kidney Disease Progression in Subjects Affected by Nephrocardiovascular Disease

BackgroundChronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease.Methods174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6–9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease.ResultsCarriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p = 0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p = 0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square = 6.84, p = 0,03). Cox regression showed that -374 T/A RAGE polymorphism (p = 0.037), albuminuria (p = 0.01) and LDL cholesterol (p = 0.038) were directly associated with CKD progression. HDL cholesterol (p = 0.022) and BMI (p = 0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline.Conclusions-374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression.

Diabetes Mellitus Activates Signal Transduction Pathways Resulting in Vascular Endothelial Growth Factor Resistance of Human Monocytes

Monocytes are cellular components of wound repair, arteriogenesis, and atherogenesis. Vascular endothelial growth factor (VEGF)-A and placental growth factor recruit monocytes to sites of arteriogenesis via stimulation of VEGF receptor-1 (VEGFR-1). The chemotactic response of monocytes to VEGF-A is attenuated in individuals with diabetes mellitus (DM). This VEGF resistance correlates with impaired collateral growth. The aim of this study is to elucidate the molecular basis of VEGF resistance and impaired monocyte response in DM. Phosphorylation of Akt, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) could be stimulated with either placental growth factor-1 or VEGF-A in monocytes from non-DM but not DM individuals. In contrast, formyl-methionyl-leucyl-phenylalanine caused a comparable activation of these molecules in both DM and non-DM monocytes. Baseline phosphorylation of Akt, p38, and ERK1/2 was significantly elevated in monocytes from DM compared with non-DM subjects. Of note, H(2)O(2) activated Akt, p38, and ERK1/2 in non-DM monocytes ex vivo. Protein tyrosine phosphatases had stronger oxidative modifications in monocytes from DM than from non-DM individuals, which reflects functional protein tyrosine phosphatase inhibition, similar to that seen after H(2)O(2) challenge. Overall, protein tyrosine phosphatase and protein tyrosine phosphatase-1B activity were reduced in DM monocytes. DM monocytes revealed higher expression of the receptor for advanced glycation end products. Stimulation with advanced glycation end products ligands resulted in activation of non-DM monocytes and inhibition of VEGFR-1-mediated chemotaxis. The elevated baseline phosphorylation/activation of Akt, p38, and ERK1/2 in DM monocytes likely causes the resistance to further stimulation with specific stimuli such as VEGF-A, revealing a molecular explanation of the DM-related signal transduction defect. We propose that elevated advanced glycation end products expression and increased oxidative stress in diabetic monocytes lead to activation of VEGFR-1-related signaling pathways and to desensitization of VEGFR-1 responses. These data establish VEGF resistance as a novel molecular concept for DM-related cellular dysfunction.

Elevated Advanced Glycation Endproducts (AGEs) in Rat Models

It is reported that plasma AGEs are elevated in patients with diabetes mellitus (DM) and in rats with STZ‐induced DM, where non‐enzymatic formation of AGEs causes crosslink of proteins, lipids and DNA. We examined in this study the plasma AGEs fluorescence (ex. 360nm, em. 450nm) in 3 rat models. (1) Male SD rats were given STZ (i.p. 60mg/kg), and continuously drank water or 5% fructose or sucrose water. Addition of fructose in drinking water caused higher mortality (92%) in rats, compare to controls (p&lt;0.001). Addition of sucrose did not increase plasma AGEs in STZ‐induced DM rats (p&gt;0.05). (2) In alloxan‐induced (i.v. 40mg/kg) DM rats, plasma AGEs were increased by 41%, 108% and 239% at Wks 4, 8 and 12, respectively, compared to normal rats (p&lt;0.05). Carboxymethyl lysine (CML) and HbA1c were also increased at Wk 8 by 673% and 239%, respectively (p&lt;0.01). (3) In a high‐calorie diet‐induced Metabolic Syndrome model in male SD rats, plasma AGEs were increased by 12% at Wk 12, as compared to normal rats (p&lt;0.05). In summary, the alloxan‐induced DM rats and diet‐induced Syndrome X rats may serve as animal models for AGEs research, in addition to the STZ model. Fructose or sucrose drinks are not options of increasing plasma AGEs in the STZ‐induced DM rats. It is to be studied if fructose drinks would accelerate plasma AGEs elevation in diet‐induced Syndrome X rats.

Plasma advanced glycation endproduct, methylglyoxal-derived hydroimidazolone is elevated in young, complication-free patients with Type 1 diabetes

Objectives Elevated advanced glycation endproducts (AGEs) are implicated in diabetic complications. Methylglyoxal-derived hydroimidazolone (MG-H) is one of the most abundant AGEs in vivo. Our objective was to develop a time-saving, specific method to measure free MG-H in plasma and determine its levels in complication-free young individuals with Type 1 diabetes (T1DM). The relationship of plasma free MG-H to hemoglobin A1C (A1C) and plasma methylglyoxal levels was also determined. Design and methods A solid phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed, and free plasma MG-H levels were measured in 40 T1DM patients (DM group), aged 6–21 years, and 11 non-diabetics (ND group), 6–22 years. Methylglyoxal was measured using LC-MS/MS and A1C by a Tosoh G7 high-performance liquid chromatograph. Results Our method showed high recovery, sensitivity and short run-time. Plasma free MG-H (nmol/L) was higher ( p < 0.001) in the DM group (1318 ± 569; mean ± standard deviation) as compared to the ND group (583 ± 419). Within the DM group, plasma free MG-H did not correlate with plasma methylglyoxal or A1C. Conclusions Our LC-MS/MS method to measure free MG-H in plasma may be useful for future clinical application. The increased levels of free MG-H observed in individuals with TIDM are not merely the result of short term changes in glucose or methylglyoxal, but may reflect long-term alterations to tissue proteins.

Pathophysiology and treatment of diabetic erectile dysfunction

The pathophysiology of diabetes is multifactorial and no single etiology is at the forefront. The proposed mechanisms of erectile dysfunction (ED) in diabetic patients includes elevated advanced glycation end-products (AGEs) and increased levels of oxygen free radicals, impaired nitric oxide (NO) synthesis, increased endothelin B receptor binding sites and ultrastructural changes, upregulated RhoA/Rho-kinase pathway, NO-dependent selective nitrergic nerve degeneration and impaired cyclic guanosine monophosphate (cGMP)-dependent kinase-1 (PKG-1). The treatment of diabetic ED is multimodal. Treatment of the underlying hyperglycemia and comorbidities is of utmost importance to prevent or halt the progression of the disease. The peripherally acting oral phosphodiesterase type 5 (PDE5) inhibitors are the mainstay of oral medical treatment of ED in diabetics. Vacuum erection devices are an additional treatment as a non-invasive treatment option. Local administration of vasoactive medication via urethral suppository or intracorporal injection can be effective with minimal side-effects. Patients with irreversible damage of the erectile mechanism are candidates for penile implantation. Future strategies in the evolution of the treatment of ED are aimed at correcting or treating the underlying mechanisms of ED. With an appropriate vector, researchers have been able to transfect diabetic animals with agents such as neurotrophic factors and nitric oxide synthase (NOS). Further studies in gene therapy are needed to fully ascertain its safety and utility in humans.