Serum Levels Of Carboxymethyl)lysine Research Articles

Lactococcus lactis KF140 Reduces Dietary Absorption of Nε - (Carboxymethyl)lysine in Rats and Humans via β-Galactosidase Activity.

Background and AimsExcessive intake of advanced glycation end products (AGEs), which are formed in foods cooked at high temperatures for long periods of time, has negative health effects, such as inflammatory responses and oxidative stress. Nε-(Carboxymethyl)lysine (CML) is one of the major dietary AGEs. Given their generally recognized as safe status and probiotic functionalities, lactic acid bacteria may be ideal supplements for blocking intestinal absorption of food toxicants. However, the protective effects of lactic acid bacteria against dietary AGEs have not been fully elucidated.Materials and MethodsWe investigated the effect of treatment with Lactococcus lactis KF140 (LL-KF140), which was isolated from kimchi, on the levels and toxicokinetics of CML. The CML reduction efficacies of the Lactococcus lactis KF140 (LL-KF140), which was isolated from kimchi, were conducted by in vitro test for reducing CML concentration of the casein-lactose reaction product (CLRP) and in vivo test for reducing serum CML level of LL-KF140 administered rats at 2.0 × 108 CFU/kg for14 days. In addition, 12 volunteers consuming LL-KF140 at 2.0 × 109 CFU/1.5 g for 26 days were determined blood CML concentration and compared with that before intake a Parmesan cheese.ResultsAdministration of LL-KF140 reduced serum CML levels and hepatic CML absorption in rats that were fed a CML-enriched product. In a human trial, the intake of LL-KF140 prevented increases in the serum levels of CML and alanine aminotransferase after consumption of a CML-rich cheese. LL-KF140 was determined to presence in feces through metagenome analysis. Furthermore, β-galactosidase, one of the L. lactis-produced enzymes, inhibited the absorption of CML and reduced the levels of this AGE, which suggests an indirect inhibitory effect of LL-KF140. This study is the first to demonstrate that an L. lactis strain and its related enzyme contribute to the reduction of dietary absorption of CML.

SERUM CARBOXYMETHYL-LYSINE AND SOLUBLE RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS IN HYPERTHYROID AND HYPOTHYROID PATIENTS.

The formation and accumulation of advanced glycation end products (AGEs) are enhanced with increased oxidative stress and inflammatory conditions. A hyperthyroid and hypothyroid state is associated with oxidative stress. This study aimed to evaluate skin AGE deposition, serum carboxymethyl-lysine (CML), and serum soluble receptor for AGEs (sRAGE) levels in hypothyroid and hyperthyroid patients. A total of 203 subjects were included in this cross-sectional study. After excluding diabetes mellitus, 103 newly diagnosed hypothyroid patients, 50 newly diagnosed hyperthyroid patients, and 50 control (euthyroid) subjects were enrolled. All tests were done before beginning the appropriate treatment. Accumulated AGEs in the skin collagen were measured by skin autofluorescence (SAF) using an AGE Reader. SAF measurements were 1.82 ± 0.04, 1.80 ± 0.40, and 1.63 ± 0.30 arbitrary units for the hypothyroid, hyperthyroid, and euthyroid groups, respectively (p = 0.04). Serum CML levels were 8.2 ± 2.8, 10.2 ± 2.0, and 8.0 ± 3.3 ng/mL for the hypothyroid, hyperthyroid, and euthyroid groups, respectively (p = 0.01). sRAGE levels were similar between the groups. Serum thyroid-stimulating hormone and SAF measurements were positively correlated (r = 0.25, p = 0.02) in the hypothyroid group and negatively correlated in the hyperthyroid group (r = -0.36, p = 0.04). There was no correlation between CML and sRAGE levels. SAF measurements are increased in both hypo- and hyperthyroid normoglycemic patients. Serum CML levels are increased in hyperthyroid patients. Hypo and hyperthyroid states might be associated with acceleration of AGE accumulation and may have a long term effect on metabolic memory.

Association of Dietary Fructose With Serum Advanced Glycation End Products in a Controlled Feeding Study of Healthy Adults

Abstract Objectives Sugars form advanced glycation end products (AGEs) through natural metabolism and interactions with proteins, lipids, and nucleic acids, which accumulate in tissues and have been implicated in the etiology of chronic diseases. Due to the increased consumption of fructose and its high ability to form AGEs, a further understanding of this association is important to clarify the role of sugars in disease. Our objective was to explore the association between usual fructose intake and serum levels of AGEs in healthy adults. Methods This is a secondary analysis of a 15-d controlled feeding study (n = 100) consuming their usual diet conducted in the Phoenix metropolitan area. Participants completed two 7-d food diaries, and custom 15-d menu plans were created to replicate their habitual diet. Forty participants (mean age: 42.5y, BMI: 27.8, gender: 55% male) were selected based on their 15-d mean total fructose intake for this analysis [top and bottom 20% of the sample distribution; high fructose (HF) =20 (76.3 ± 12.5 g/day), low fructose (LF) = 20 (27.3 ± 5.4 g/day)]. Fasting serum collected five weeks after the feeding period were analyzed for carboxymethyl-lysine (CML), a major AGE, using ELISA kits. A database of 549 common foods with known CML amounts was used to calculate exogenous CML intake. A general linear model was fitted to investigate the difference in serum CML between LF and HF groups while adjusting for age, gender, BMI, and exogenous CML intake. Results Exogenous CML intake was not significantly different between the HF and LF groups (P = 0.925). Participants in the HF group had significantly higher serum CML levels compared to participants in the LF group (37.3 ± 8.4 ng/mL versus 30.5 ± 8.0 ng/mL; P = 0.013). This difference remained statistically significant after adjusting for covariates [LF vs. HF: β = −6.4 (SE = 2.9); P = 0.036; Log10(age): β = −12.0 (10.6), P = 0.267; BMI: β = 0.4 (0.4), P = 0.352), male vs. female: β = 1.2 (3.6), P = 0.753; and exogenous CML intake: β = −8.5 (10.2), P = 0.411]. Conclusions Our findings suggest that endogenous CML formation may be an explanation for the significant difference in serum CML between HF and LF groups. This is significant in further understanding mechanisms of sugar intake and disease etiology and could have implications for at-risk populations consuming a high fructose diet. Funding Sources NIH/NCI and ASU

Association of dietary intake, medication and anthropometric indices with serum levels of advanced glycation end products, caspase-3, and matrix metalloproteinase-9 in diabetic patients.

Increased serum levels of advanced glycation end products (AGEs), caspase-3 (Cas-3) and matrix metalloproteinase-9 (MMP-9) have been reported in diabetic patients. This study aimed to evaluate association of anthropometric, dietary, and therapeutic factors with serum levels of methylglyoxal (MGO), carboxymethyl lysine (CML), pentosidine (Pen), Cas-3, and MMP-9 in diabetic patients. The current study included 36 diabetic subjects. Dietary intake of the participants was assessed using three-day 24-h recall survey and anthropometric indices were measured. Demographic factors and medication intake of every subject were obtained. Serum levels of CML, MGO, Pen, MMP-9, and Cas-3 were measured using ELISA method. Gliclazide consumption was positively correlated with MMP-9 and Cas-3, but not AGEs levels. Females had higher MGO level compared with males. Further, CML levels were negatively correlated with BMI and WHR. Dietary protein intake was positively correlated with MMP-9, Cas-3, and MGO levels. As well as dietary energy and fat intake had significant positive relationship with serum Cas-3 concentration. It is concluded that anthropometric characteristics, dietary intake, and therapeutic medications are possible factors that may determine the circulating levels of AGEs, MMP-9, and Cas-3 in patients with diabetes.

Pentosidine and carboxymethyl-lysine associate differently with prevalent osteoporotic vertebral fracture and various bone markers

Pentosidine (PEN) and carboxymethyl-lysine (CML) are well-recognized advanced glycation end products (AGEs). However, how these AGEs affect the pathophysiology of osteoporosis and osteoporotic fractures remains controversial. This cross-sectional study aimed to investigate the associations of PEN and CML with bone markers, bone mineral density (BMD), and osteoporotic fractures in postmenopausal women from the Nagano Cohort Study. A total of 444 Japanese postmenopausal outpatients (mean ± standard deviation age: 69.8 ± 10.2 years) were enrolled after the exclusion of patients with acute or severe illness or secondary osteoporosis. The relationships among urinary PEN and serum CML levels, various bone markers, lumbar and hip BMD, and prevalent vertebral and long-bone fractures were evaluated. PEN associated significantly with prevalent vertebral fracture after adjustment for other confounders (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.22–2.07; P < 0.001), but not with lumbar BMD. In contrast, a significant negative correlation was found between CML and lumbar BMD (r = − 0.180; P < 0.001), and this relationship was significant after adjustment for confounders (OR 0.84, 95% CI 0.76–0.93; P < 0.01). Although patients with prevalent vertebral fracture had significantly higher CML levels, the association between CML and prevalent vertebral fracture did not reach significance in the multivariate regression model. Both PEN and CML may play important roles in bone health for postmenopausal women, possibly via different mechanisms.

Dietary quality index is negatively associated with serum advanced glycation end products in healthy adults

In human, advanced glycation end products (AGEs) can endogenously formed or exogenously ingested from foods and tobacco. Dietary quality is an important factor to prevent many disorders. This study sought to determine any association between AGEs and diet quality. The participants were 90 healthy adults, aged higher than 20 years. Dietary intake of individuals was collected using two 24-h dietary recalls and quality of diets were determined by dietary quality index-International (DQI-I). Serum levels of pentosidine and carboxymethyl-lysine (CML) were examined by ELISA. Total DQI-I score was 62.3±1.3. Variety, adequacy, moderation, and the overall balance of diet scores in the study participants were 16.5±0.4, 25.8±0.5, 17.7±0.9, and 2.4±0.3, respectively. Participants with higher age (>40 years), higher education level, moderate calorie intake and married had significantly greater DQI-I score. Diet quality was positively associated with participants' education level (r=0.28, p=0.008). DQI-I score negatively correlated with serum levels of CML and pentosidine (r=-0.42, P<0.001 and r=-0.35, P<0.001, respectively). Dietary modification may be beneficial for controlling AGE accumulation in the body and subsequently in reduction of chronic diseases risk.

Ellisras Longitudinal Study 2017: elevated serum levels of carboxymethyl-lysine, an advanced glycation end-product, are associated with higher odds of developing endothelial dysfunction in black South African patients with type 2 diabetes mellitus (ELS 29).

This case-control study investigated the association between major types of serum advanced glycation end-products (AGEs) and selected serum/plasma markers of endothelial dysfunction in black patients with type 2 diabetes mellitus at Dr George Mukhari Academic Hospital. Serum AGEs were measured using either enzyme-linked immunosorbent assay (ELISA) or spectrofluoremetry. Serum markers of endothelial dysfunction were measured using either ELISA or calometry. The correlation and associations between major types of serum AGEs and markers of endothelial dysfunction were investigated using the Spearman correlation coefficient and bivariate logistic regression analysis, respectively. Although both serum total immunogenic AGEs and serum carboxymethyl-lysine (CML) were moderately and negatively associated with endothelial dysfunction, only serum CML was significantly associated with a higher odds for the development of endothelial dysfunction (low nitric oxide levels) in our diabetic subjects. It can therefore be concluded from this study that high serum levels of CML may predispose to endothelial dysfunction in black South Africans with type 2 diabetes.

MON-261 DECREASED RENAL FUNCTION AFFECTS BIOLOGYCAL CALBONYL STRESS STRONGER THAN SERUM BLOOD GLUCOSE IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Intermediate carbonyls and advanced glycation end products (AGEs) are thought to be related to the development of complications of patients with chronic kidney diseases. Especially, Nε-(carboxymethyl) lysine (CML) has been primarily studied in persons with diabetes or end-stage renal disease as a modifiable risk factor of renal disease. However, each AGE is known to contribute to the different pathology, and the pathophysiology of another AGE is still unclear. The objective is to characterize the relationship between AGEs and renal function, especially in terms of Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) level as a biomarker of carbonyl stress. The total of 50 patients who admitted in our hospital between April and November 2014 was enrolled in this study (33 men and 17 women, average age: 60.9 years; range 19-88 years). Patients who received corticosteroid and renal replacement therapies were excluded from the analysis. Serum levels of CML and MG-H1, the predominant AGEs, were measured by using liquid chromatography - tandem mass spectrometry, and subjected to a cross-sectional analysis to determine their correlation correlated with renal function. CML and MG-H1 levels were correlated with renal dysfunction status (Spearman rank correlation coefficient: CML vs. estimated glomerular filtration rate [eGFR], r = -0.784, p < 0.01; MG-H1 vs. eGFR, r = -0.691, p < 0.01). In the multivariate logistic regression analysis, advanced renal failure (eGFR < 30mL/min/1.73m2) was associated with higher serum CML levels (higher than the median; odds ratio [OR], 54.43; 95% confidence interval [CI], 5.83-446.55; p < 0.01) after adjusting for age, diabetes mellitus (DM), and systolic blood pressure. Advanced renal failure was also associated with higher serum MG-H1 levels (higher than the median; OR, 20.44; 95% CI, 3.89-107.49; p < 0.01) after adjusting for age, DM, systolic blood pressure, and a history of cardiovascular disease. Renal dysfunction is strongly associated with serum MG-H1 as well as serum CML. In future, we attempt to clarify what clinical condition MG-H1 is linked to in patients with chronic kidney disease.

A Short-term Diet High in Carboxymethyl-lysine (CML) Increases Urinary Excretion but Not Serum CML Levels (P12-012-19)

ObjectivesDietary advanced glycation end products (AGEs) are a group of compounds formed by the Maillard reaction. Carboxymethyl-lysine (CML), a marker of AGEs in foods, may contribute to cardiometabolic diseases. However, CML health effects and its absorption and excretion in healthy individuals remained controversial. For this reason, the aim of this study was to evaluate serum and urinary excretion CML levels in healthy adults after a short-term diet high in CML. MethodsA randomized clinical trial was conducted in 30 healthy adults (18–35 years old). After signing the informed consent, subjects were randomly assigned to a low or a high CML diet. All participant followed a diet with low CML content for seven days (washing period) before the 5-days intervention. During the 5 days participants received all the foods according to their group. Blood and 24-hour urine samples were collected before and after the intervention to evaluate serum and urinary CML levels. CML measurement in foods, serum, and urine was carried out by HPLC-ESI-ITMS/MS. Comparison between groups was carried out by a t-test. The research was approved by the Institutional Review Board and the clinical trial registration number NCT03208946. ResultsBiochemical and anthropometric variables were similar between groups (P > 0.05). The average consumption of CML was 1.93 ± 1.47 mg/day for the low CML diet and 5.03 ± 2.22 mg/day for the high CML diet, whereas caloric, protein and fat intake were similar. Serum levels decreased significantly in both groups (low diet: basal 488.1 ± 135.4 μg/L, final 383.2 ± 78.6 μg/L (P = 0.007)) (high diet: basal 463.5 ± 90.3 μg/L, final 390.3 ± 99.1 μg/L (P = 0.02)). No significant difference was found when comparing the final CML levels between groups (P = 0.47). The excretion of CML in urine was adjusted by creatinine (mg) and the high CML group had a greater excretion (4.5 ± 8.0 ug CML/mg) when compared to the low CML group (–1.5 ± 7.2 ug CML/mg) (P = 0.04). ConclusionsA high CML diet increases urinary CML excretion levels in healthy adults when compared to a low CML diet. There were no significant differences in serum CML levels between both groups. However, a greater decrease was observed in the subjects who followed a diet with a low content of AGEs. Funding SourcesUniversity of Guanajuato. CONACYT.

Exploring the role of body mass index in relationship of serum nitric oxide and advanced glycation end products in apparently healthy subjects.

This study aimed to identify any association of serum nitric oxide (NO) and advanced glycation end products (AGEs) with body mass index (BMI) in apparently healthy subjects. In this cross-sectional study, participants were 90 apparently healthy subjects, categorized into three BMI groups as follows: BMI≤19.5 (n = 21), 19.6≤BMI≤24.9 (n = 35), and BMI≥25 (n = 34). Serum levels of NO were measured by griess reaction method. Determination of serum pentosidine and carboxymethyllysine (CML) was done using ELISA. Median (95% confidence interval [CI]: lower- upper) of serum NO in subjects with BMI≥25 were 68.94 (CI: 55.01–70.56) μmol/L, which was higher compared with 19.6≤BMI≤24.9 and BMI≤19.5 groups (22.65 (CI: 19.29–28.17) μmol/L and 8.00 (CI: 9.12–29.58) μmol/L, respectively). Serum NO positively correlated with BMI in total subjects (r = 0.585, p<0.001), which this correlation was significant in both male and female groups (r = 0.735, p<0.001 and r = 0.476, p = 0.001, respectively). Serum pentosidine and CML were significantly lower in subjects with higher BMI. Further, BMI showed negative correlations with pentosidine and CML (r = -0.363, p<0.001 and r = -0.484, p<0.001, respectively). There were not any significant differences in serum NO, pentosidine, and CML levels between sex groups. After adjusting the effects of confounders (BMI, sex, age, and waist to hip ratio), serum NO significantly correlated with serum pentosidine and CML (r = -0.319, p = 0.003 and r = -0.433, p<0.001, respectively). It is concluded that higher BMI is accompanied by increased serum NO and suppressed pentosidine and CML.

Skin autofluorescence and serum carboxymethyllysine levels in hypothyroid and hyperthyroid patients

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Serum Carboxymethyl-Lysine, Disability, and Frailty in Older Persons: The Cardiovascular Health Study

Advanced glycation endproducts are biologically active compounds that accumulate in disordered metabolism and normal aging. Carboxymethyl-lysine (CML), a ubiquitous human advanced glycation endproduct, has been associated with age-related conditions and mortality. Our objective was to ascertain the relationship between CML and geriatric outcomes (disability and frailty) in a large cohort of older men and women. In 1996-1997, serum CML was measured in 3,373 Cardiovascular Health Study participants (mean age 78.1 ± 4.8 years). Disability, defined as difficulty in any of six activities of daily living, was assessed every 6-12 months for 14 years. Frailty was defined according to five standard criteria at the 1996-1997 visit. Cox proportional hazard models estimated the relationship between CML and incident disability (N = 2,643). Logistic regression models estimated the relationship between CML and prevalent frailty. Adjusting for multiple potential confounders, higher CML was associated with incident disability (hazard ratio per standard deviation [225 ng/mL] increase: 1.05, 95% CI 1.01-1.11). In men, odds of frailty increased with higher CML values (odds ratio = 1.30 per standard deviation, 95% CI 1.14-1.48), but the relationship was attenuated by adjustment for cognitive status, kidney function, and arthritis. CML was not associated with frailty in women. Higher serum CML levels in late life are associated with incident disability and prevalent frailty. Further work is needed to understand CML's value as a risk stratifier, biomarker, or target for interventions that promote healthy aging.

Evaluation of N-(carboxymethyl)lysine and lipid peroxidation in multiethnic Malaysian subjects with type 2 diabetes mellitus

The glycoxidation product, Ne-(carboxymethyl)lysine (CML), is formed during reaction of glucose with protein under oxidative conditions. The aim of the study was to evaluate the levels of the most common glycoxidation product; Ne-(carboxymethyl)lysine (CML) and the most advanced lipoxidation product, malondialdehyde (MDA) in type 2 diabetic Malay, Indian, and Chinese ethnic groups in the Malaysian population. Studies were performed on age-matched Malay, Indian, and Chinese subjects with type 2 diabetes mellitus. Different biochemical parameters including serum levels of CML, MDA, lipid profile, glucose, and hemoglobin A1c (HbA1c) were measured by standard methods. The relationships between circulating CML and lipids, HbA1c, and MDA, were examined. Correlation studies between CML, lipids, HbA1c, and lipid peroxidation were performed. CML and MDA levels were significantly higher in Malay subjects than in Indian or Chinese patients (p <0.005). A significant difference was also observed in the levels of serum total cholesterol and LDL-cholesterol (p <0.05) between the groups in the study. A positive correlation was observed between serum levels of CML and MDA in Malay diabetic patients, but no such correlation was seen in either the Chinese or Indian populations. The results of this study demonstrate that ethnicity affects CML and MDA circulating levels in Malaysian subjects with type 2 diabetes mellitus. Key words: Type 2 diabetes mellitus, Ne-(carboxymethyl) lysine, lipoxidation, multiethnic Malaysian subjects.

Infusion fluids contain harmful glucose degradation products

PurposeGlucose degradation products (GDPs) are precursors of advanced glycation end products (AGEs) that cause cellular damage and inflammation. We examined the content of GDPs in commercially available glucose-containing infusion fluids and investigated whether GDPs are found in patients’ blood.MethodsThe content of GDPs was examined in infusion fluids by high-performance liquid chromatography (HPLC) analysis. To investigate whether GDPs also are found in patients, we included 11 patients who received glucose fluids (standard group) during and after their surgery and 11 control patients receiving buffered saline (control group). Blood samples were analyzed for GDP content and carboxymethyllysine (CML), as a measure of AGE formation. The influence of heat-sterilized fluids on cell viability and cell function upon infection was investigated.ResultsAll investigated fluids contained high concentrations of GDPs, such as 3-deoxyglucosone (3-DG). Serum concentration of 3-DG increased rapidly by a factor of eight in patients receiving standard therapy. Serum CML levels increased significantly and showed linear correlation with the amount of infused 3-DG. There was no increase in serum 3-DG or CML concentrations in the control group. The concentration of GDPs in most of the tested fluids damaged neutrophils, reducing their cytokine secretion, and inhibited microbial killing.ConclusionsThese findings indicate that normal standard fluid therapy involves unwanted infusion of GDPs. Reduction of the content of GDPs in commonly used infusion fluids may improve cell function, and possibly also organ function, in intensive-care patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-010-1873-x) contains supplementary material, which is available to authorized users.

Advanced Glycation End Products and Their Circulating Receptors and Level of Kidney Function in Older Community-Dwelling Women

Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) are implicated in the pathogenesis of kidney disease; however, their relation with level of kidney function has not been well characterized. Cross-sectional and prospective. 548 moderately to severely disabled community-dwelling women in the Women's Health and Aging Study I in Baltimore, MD. Serum carboxymethyl-lysine (CML), a dominant AGE; total soluble RAGE (sRAGE); and endogenous secretory RAGE (esRAGE). Glomerular filtration rate (GFR), prevalent and incident decreased GFR (GFR < 60 mL/min/1.73 m(2)). Serum CML, sRAGE, and esRAGE. Of 548 women, 283 (51.6%) had decreased GFR at baseline. Serum CML level was associated with decreased GFR (OR [all expressed per 1 SD], 1.98; 95% CI, 1.41 to 2.76; P < 0.001) in a multivariate logistic regression model adjusting for age, race, hemoglobin A(1c) level, and chronic diseases. Serum sRAGE and esRAGE levels (both in nanograms per milliliter) were associated with decreased GFR (OR, 1.42; 95% CI, 1.12 to 1.79; P = 0.003; OR, 1.42; 95% CI, 1.14 to 1.77; P = 0.001, respectively) in separate multivariate logistic regression models adjusting for potential confounders. Of 230 women without decreased GFR at baseline, 32 (13.9%) developed decreased GFR by the follow-up visit 12 months later. Serum CML (in micrograms per milliliter), sRAGE, and esRAGE levels at baseline were associated with the prevalence of decreased GFR 12 months later (OR, 1.80; 95% CI, 1.19 to 2.71; P = 0.005; OR, 1.32; 95% CI, 1.01 to 1.74; P = 0.05; and OR, 1.33; 95% CI, 1.01 to 1.77; P = 0.05, respectively) in separate multivariate logistic regression models adjusting for potential confounders. Small number of incident cases, limited follow-up, creatinine values not standardized. AGE and circulating RAGE levels are independently associated with decreased GFR and seem to predict decreased GFR. AGEs are amenable to interventions because serum AGE levels can be decreased by change in dietary pattern and pharmacological treatment.

Unchanged serum levels of advanced glycation endproducts in patients with liver disease

Advanced glycation end products (AGEs), e.g., carboxymethyllysine (CML) or imidazolone are involved in several age-related disorders. Concerning their accumulation, the importance of hepatic and renal function is controversially discussed. To test whether impairment of hepatic or renal function will affect their accumulation, both AGEs have been measured in various populations, such as 52 patients with liver disease [viral hepatitis C without (n = 19) and with (n = 10) fatty liver; nonalcoholic fatty liver (n = 13), nonalcoholic steatohepatitis (n = 10)]. Serum concentrations of both AGEs have been compared to those in 20 healthy controls and 24 patients with moderate renal impairment (creatinine clearance 23-55 ml/min). Concerning CML (95% C.I. 803-1200 ng/ml), no differences between the various groups could be observed. Likewise, serum levels of imidazolone (95% C.I. 1.3-5.6 units) were similar in all populations. In conclusion, moderate impairment in hepatic or in renal function did not affect serum levels of CML and imidazolone. Apparently, any increase observed in severe cirrhosis or renal failure seems to be rather a consequence than a cause of both disorders.

Role of N-(carboxymethyl)lysine in the development of ischemic heart disease in type 2 diabetes mellitus.

This study aims to determine the levels of Nε-(carboxymethyl)lysine (CML) in patients with Type 2 diabetic patients with and without ischemic heart disease (IHD) and to find for a possible association between circulating CML and a number of clinical parameters including lipids, hemoglobin A1c (HbA1c) and malondialdehyde (MDA) in Type 2 diabetic IHD patients. Serum CML levels were measured by enzyme-linked immunosorbent assay using polyclonal anti-CML antibodies. Serum levels of CML and MDA were assessed in 60 IHD patients with Type 2 diabetes, 43 IHD patients without Type 2 diabetes, 64 Type 2 diabetics without IHD, and 80 sex- and age-matched healthy subjects. Correlations studies between CML levels and lipids, HbA1c, and lipid peroxidation were performed in Type 2 diabetes patients with and without IHD. A statistical significance was observed in the levels of serum glucose, lipids (triglyceride, total cholesterol, HDL-cholesterol), MDA, HbA1c, CML and LDL-cholesterol (p<0.05) between the groups of the study. CML levels were significantly increased in diabetic IHD patients compared with Type 2 diabetes patients but without IHD (537.1 ± 86.1 vs 449.7 ± 54.9, p<0.001). A positive correlation was observed between serum levels of CML and MDA, r = 0.338 (p = 0.008) in Type 2 diabetes patients with IHD. However, age, HbA1c and lipids had no significant influence on CML levels among diabetics (p>0.05). In conclusion, this study demonstrates the effect of both diabetes and oxidative stress on the higher levels of circulating CML. These results showed that increased serum levels of CML are associated with the development of IHD in Type 2 diabetes mellitus.

Serum Carboxymethyllysine Predicts Mortality in Hemodialysis Patients

Hemodialysis patients show markedly elevated serum levels of advanced glycation end products (AGEs). AGEs have been implicated in the pathogenesis of vascular damage and are regarded as a class of uremic toxins. However, to date, serum AGE level could not be identified as an independent predictor of mortality. The aim of the present study is to test whether serum level of the AGE carboxymethyllysine (CML) predicts all-cause or cardiovascular mortality in hemodialysis patients. Serum total CML concentration was measured by means of enzyme-linked immunosorbent assay in 154 patients receiving long-term hemodialysis. Patients were divided into groups with serum CML levels less and greater than the median (23.8 ng/mg protein). All-cause and cardiovascular mortality were registered during a follow-up of 51 months. The relationship between serum CML level and mortality was tested by using Kaplan-Meier and Cox regression analyses. In the group with low serum CML levels, 38% of patients died during the follow-up period; 23% had a cardiovascular cause of death. However, in the group with high CML levels, 58% died (P < 0.01) and 36% had a cardiovascular cause of death (P < 0.05). The following parameters proved to be independent risk factors of all-cause mortality: age (hazard ratio, 1.056; P < 0.001), preexisting vascular disease (hazard ratio, 2.53; P < 0.05), smoking (hazard ratio, 3.03; P < 0.005), high serum CML level (hazard ratio, 1.776; P < 0.05), and C-reactive protein level (hazard ratio, 1.017; P < 0.001). The AGE CML may contribute to increased mortality in patients with uremia.

Elevation of Nε-(carboxymethyl)lysine-modified advanced glycation end products in chronic liver disease is an indicator of liver cirrhosis

Objectives: Progression of liver fibrosis to cirrhosis is a dire consequence of chronic liver diseases (CLD). Nε-(carboxymethyl)lysine (CML)-modified advanced glycation end products (AGEs) in patients with CLD could reflect the degree of severity of the disease. Design and methods: In 110 patients with CLD and 124 healthy controls, CML serum levels and their diagnostic sensitivity and specificity were determined and compared to hyaluronan (HA). Results: Serum levels of CML were significantly affected by the stage of liver cirrhosis and were closely associated with liver function capacity. CML correlated positively with HA ( r = 0.639, P < 0.0001). In ROC analysis, the diagnostic sensitivity and specificity in distinguishing healthy controls from liver disease patients for CML (AUC 0.908; 95%-CI 0.863–0.942, cut-off 640 ng/mL, sensitivity 74.5% and specificity 97.6%) resembled HA (AUC 0.948; 95%-CI 0.907–0.974; cut-off 50 ng/mL, sensitivity 80.7% and specificity 97.9%). The combination of CML and HA shows an AUC of 0.932; 95%-CI 0.888–0.962; sensitivity 82.6%; and specificity 95.8%. Conclusions: Our data suggest that serum levels of CML could provide a supplementary diagnostic marker for advanced stages of liver cirrhosis. However, the quality of interaction needs further investigation.

Clinical implications of Nε‐(carboxymethyl)lysine, advanced glycation end product, in children and adolescents with type 1 diabetes

The aim of this study was to investigate the relationship between serum levels of the glycoxylation product N(epsilon)-(carboxymethyl)lysine (CML) and development of chronic diabetic complications and degree of diabetic control in children and adolescents with type 1 diabetes. The serum levels of CML were measured in 87 patients with uncomplicated type 1 diabetes mellitus (12.7 +/- 4.6 years of age) and in seven patients with background retinopathy, microalbuminuria or neuropathy (18.2 +/- 5.2 years of age) and compared with those in 64 normal control subjects (12.6 +/- 5.2 years of age). The mean durations of diabetes in uncomplicated and complicated patients were 5.0 +/- 3.4 years (0.1-14 years), and 8.6 +/- 5.0 years (3.1-18 years), respectively. The serum levels of CML were measured by enzyme-linked immunosorbent assay using a monoclonal anti-CML antibody (6D12). The serum levels of CML were significantly higher in the patient group than those in the control group; 0.85 +/- 0.37 (0.37-1.93) U/ml vs. 0.56 +/- 0.23 (0.15-1.05) U/ml (p < 0.001) and significantly higher in the patient group with chronic complications than those in patient group without chronic complications; 1.06 +/- 0.39 (0.72-1.78) U/ml vs. 0.83 +/- 0.36 (0.37-1.93) U/ml (p < 0.05). Weak, but statistically significant relationship between CML levels and haemoglobin A(1c) levels at the measurement of CML was observed (r = 0.29, p < 0.05). Our data are suggesting that higher serum levels of CML are involved in the development of chronic diabetic complications, and serum levels of CML reflect the degree of diabetic control for a long duration in type 1 diabetic children and adolescents.