Advanced Glycation End Products In Patients Research Articles

Cardiovascular risks and endothelial dysfunction in reproductive-age women with endometriosis

Endometriosis is a prevalent gynecological condition, affecting around 10% of reproductive-age women. Inflammatory processes associated with endometriosis may contribute to endothelial dysfunction. Increased skin accumulation of advanced glycation end-products (AGEs), reflecting arterial stiffness, potentially links endometriosis with elevated risk of cardiovascular events. We hypothesized that patients with endometriosis have impaired endothelial function as well as increased arterial stiffness and AGE skin accumulation, compared to healthy controls. We compared endothelial function, arterial stiffness, and levels of AGEs in patients suffering from endometriosis and in healthy controls. The study included 45 women aged 20 to 40: 21 patients with endometriosis and 24 healthy controls, matched in terms of age, BMI, and blood pressure values. Endo-PAT 2000 device was used for non-invasive assessment of (i) endothelial function, expressed as Reactive Hyperemia Index (RHI), and (ii) arterial stiffness, expressed as Augmentation Index (AI) and Augmentation Index at 75 heart beats/min (AI@75). Endothelial dysfunction was defined as an RHI value ≤ 1.67. AGE Reader device was used for non-invasive evaluation of skin AGE level accumulation. Patients with endometriosis had lower mean RHI values (1.69 ± 0.54 vs. 2.02 ± 0.48, p = 0.037) and a higher prevalence of endothelial dysfunction, (52.4% vs. 20.8%, p = 0.027) compared to healthy controls. Skin AGE level was higher in patients with endometriosis, compared to controls (2.00 ± 0.57 vs. 1.70 ± 0.24, p = 0.013). There were no significant differences in AI and AI@75 between the two groups. Patients with endometriosis have impaired endothelial function and higher AGE skin accumulation, which are well-established preclinical manifestations of increased cardiovascular risk. There is a great need for comprehensive cardiovascular risk assessments in women with endometriosis to prevent the development of potential atherosclerotic-based complications.

Skin advanced glycation end-products as indicators of the metabolic profile in diabetes mellitus: correlations with glycemic control, liver phenotypes and metabolic biomarkers

IntroductionThe production of advanced glycation end-products (AGEs) is a key pathomechanism related to the complications of diabetes mellitus. The measurement of HbA1c as one of the AGEs is widely used in the clinic, but also other proteins undergo glycation in the course of diabetes. Here, we measure skin AGEs (SAGEs) in patients with diabetes type 1 (DM1) and type 2 (DM2) and correlate them with metabolic markers as well as non-invasively measured liver fibrosis and steatosis.Patients and methodsIn this cross-sectional study, a total of 64 patients with either DM1 or DM2 and 28 healthy controls were recruited. SAGEs were measured using autofluorescence (AGE Reader). Liver fibrosis and steatosis were quantified using transient elastography, which determines liver stiffness measurement (LSM) and controlled attenuation parameter (CAP). FGF19, FGF21 and GDF-15 were measured in blood samples using ELISA.ResultsSAGEs were elevated in both groups of patients with diabetes as compared to healthy controls (both p < 0.001) and were higher in patients with DM2 in comparison to DM1 (p = 0.006). SAGEs correlated positively with HbA1c (r = 0.404, p < 0.001), CAP (r = 0.260, p = 0.016) and LSM (r = 0.356, p < 0.001), and negatively with insulin growth factor binding protein 3 (p < 0.001). We also detected a positive correlation between GDF15 and SAGEs (r = 0.469, p < 0.001).ConclusionsSAGEs are significantly elevated in patients with both DM types 1 and 2 and correlate with metabolic markers, including HbA1c and GDF15. They might also help to detect patients with advanced liver injury in the setting of diabetes.

The Effect of Vitamin D Treatment on Advanced Glycation End-Products in Patients with Prediabetes and Type 2 Diabetes Mellitus

The Effect of Vitamin D Treatment on Advanced Glycation End-Products in Patients with Prediabetes and Type 2 Diabetes Mellitus

The Intake of Dicarbonyls and Advanced Glycation Endproducts as Part of the Habitual Diet Is Not Associated with Intestinal Inflammation in Inflammatory Bowel Disease and Irritable Bowel Syndrome Patients.

A Western diet comprises high levels of dicarbonyls and advanced glycation endproducts (AGEs), which may contribute to flares and symptoms in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). We therefore investigated the intake of dietary dicarbonyls and AGEs in IBD and IBS patients as part of the habitual diet, and their association with intestinal inflammation. Food frequency questionnaires from 238 IBD, 261 IBS as well as 195 healthy control (HC) subjects were used to calculate the intake of dicarbonyls methylglyoxal, glyoxal, and 3-deoxyglucosone, and of the AGEs Nε-(carboxymethyl)lysine, Nε-(1-carboxyethyl)lysine and methylglyoxal-derived hydroimidazolone-1. Intestinal inflammation was assessed using faecal calprotectin. The absolute dietary intake of all dicarbonyls and AGEs was higher in IBD and HC as compared to IBS (all p < 0.05). However, after energy-adjustment, only glyoxal was lower in IBD versus IBS and HC (p < 0.05). Faecal calprotectin was not significantly associated with dietary dicarbonyls and AGEs in either of the subgroups. The absolute intake of methylglyoxal was significantly higher in patients with low (<15 μg/g) compared to moderate calprotectin levels (15−<50 μg/g, p = 0.031). The concentrations of dietary dicarbonyls and AGEs generally present in the diet of Dutch patients with IBD or IBS are not associated with intestinal inflammation, although potential harmful effects might be counteracted by anti-inflammatory components in the food matrix.

Adherence to Mediterranean diet and advanced glycation endproducts in patients with diabetes.

BACKGROUNDIn recent years, American Diabetes Association started to strongly advocate the Mediterranean diet (MD) over other diets in patients with diabetes mellitus (DM) because of its beneficial effects on glycemic control and cardiovascular (CV) risk factors. Tissue levels of advanced glycation endproducts (AGEs) emerged as an indicator of CV risk in DM. Skin biopsy being invasive, the use of AGE Reader has been shown to reflect tissue AGEs reliably.AIMTo examine the association between adherence to MD and AGEs in patients with DM type II.METHODSThis cross-sectional study was conducted on 273 patients with DM type II. A survey questionnaire was composed of 3 separate sections. The first part of the questionnaire included general data and the habits of the participants. The second part aimed to assess the basic parameters of participants’ diseases and associated conditions. The third part of the questionnaire was the Croatian version of the 14-item MD service score (MDSS). AGEs levels and associated CV risk were measured using AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands).RESULTSA total of 27 (9.9%) patients fulfilled criteria for adherence to MD, with a median score of 8.0 (6.0-10.0). Patients with none/limited CV risk had significantly higher percentage of MD adherence in comparison to patients with increased/definite CV risk (15.2% vs 6.9%, P = 0.028), as well as better adherence to guidelines for nuts (23.2% vs 12.6%, P = 0.023) and legumes (40.4% vs 25.9%, P = 0.013) consumption. Higher number of patients with glycated hemoglobin (HbA1c) < 7% adhered to MD when compared to patients with HbA1c > 7% (14.9% vs 7.3%, P = 0.045). Moreover, those patients followed the MDSS guidelines for eggs (33.0% vs 46.8%, P = 0.025) and wine (15.6% vs 29.8%, P = 0.006) consumption more frequently. MDSS score had significant positive correlation with disease duration (r = 0.179, P = 0.003) and negative correlation with body mass index (BMI) values (r = -0.159, P = 0.008). In the multiple linear regression model, BMI (β ± SE, -0.09 ± 0.04, P = 0.037) and disease duration (β ± SE, 0.07 ± 0.02, P < 0.001) remained significant independent correlates of the MDSS score. Patients with HbA1c > 7% think that educational programs on nutrition would be useful for patients in significantly more cases than patients with HbA1c < 7% (98.9% vs 92.6%, P = 0.009).CONCLUSIONAlthough adherence to MD was very low among people with diabetes, we demonstrated that adherence to MD is greater in patients with lower CV risk, longer disease duration, and well-controlled glycaemia.

P0951THE DIETARY TREATMENT EFFECTIVENESS IN HEMODIALYSIS PATIENTS WITH DIABETES MELLITUS TYPE 2 AND FEATURES OF PROTEIN-ENERGY WASTING

Abstract Background and Aims The percentage of patients receiving RRT for ESRD secondary to diabetes mellitus (DM) is equal to 20-30% nowadays and is trending upward. Unfavourable changes in nutrition and body composition is highly prevalent in patients with chronic kidney disease (CKD) undergoing dialysis. DM type 2 (DM2) coupled with CKD is an additional factor for nutrition abnormalities in dialysis patients due to more prominent inflammatory status and insulin resistance. Resting energy expenditure is significantly higher in hemodialysis patients with DM2 than in those without it. Daily energy intake as usual is substantially less than required in the most dialysis patient, suggesting that patients could develop protein-calorie wasting and sarcopenia. The aims of our study were to compare of nutritional status in hemodialysis patients with and without DM2 and to treat revealed nutritional abnormalities by correction of the protein and energy intake. Method 79 hemodialysis patients (aged 50 to 70 years) were divided in two groups: 40 with DM2 and 39 without DM2. The groups didn’t distinguish by age, gender, comorbidity, dialysis duration and adequacy. In the DM2 group there were no patients with severe diabetes complications or decompensation. All patients kept a 3-days food diary for assessment of protein and other nutrients and energy intake. The examination, which included anthropometry, measurement of body composition by bioimpedance analysis, biochemical parameters (serum albumin, transthyretin, C-reactive protein (CRP), interleukins 1 and 6 (IL1 and IL6), advanced glycation endproducts (AGE)), was performed at baseline, and then after 6 and 12 weeks of the dietary treatment. The pattern of the diet for every patient was based on the individual parameters of nutrient and energy intake obtained from the food diary. The aim of the diet was to make good the deficit of protein and energy intake. Results Baseline BMI and degree of abdominal obesity were significantly higher in DM2 group, but lean mass (LM), hand grip strength and gait velocity were significantly less. The significantly more decreased level of transthyretin was identified in DM2 group. Levels of AGE and CRP were not different between the groups, but were twice higher of normal range. IL6 was significantly higher in DM2 group. Protein and energy intake were under dietary recommendations for dialysis patients in DM2 group. We identified positive association between protein intake and levels of albumin and transthyretin and negative with IL1, IL6 and AGE in patients with DM2. In patients without DM2 we revealed negative correlation between LM and CRP. The dynamic of the main anthropometric and biochemical parameters are represented in the table. Conclusion A degree of persistent inflammation and sarcopenia more prominent in hemodialysis patients with DM2. Absence of appetite due to inflammation is a probable cause of low protein and energy intake in those patients. Balanced diet based on individual nutritional requirements can effectively improve nutritional status of the dialysis patients with DM2 and decrease inflammation.

Phytate Decreases Formation of Advanced Glycation End-Products in Patients with Type II Diabetes: Randomized Crossover Trial

Myo-inositol hexaphosphate (phytate; IP6) is a natural compound that is abundant in cereals, legumes, and nuts and it has the ability to chelate metal cations. The binding of IP6 to transition metals suggests that it could be used for the treatment of metal-catalyzed protein glycation, which appears to trigger diabetes-related diseases. Our in vitro studies showed that IP6 reduced the formation of Fe3+-catalyzed advanced glycation end-products (AGEs). This led us to perform a randomized cross-over trial to investigate the impact of the daily consumption IP6 on protein glycation in patients with type 2 diabetes mellitus (T2DM; n = 33). Thus, we measured AGEs, glycated hemoglobin (HbA1c), several vascular risk factors, and urinary IP6 at baseline and at the end of the intervention period. Patients who consumed IP6 supplements for 3 months had lower levels of circulating AGEs and HbA1c than those who did not consume IP6. This is the first report to show that consumption of IP6 inhibits protein glycation in patients with T2DM. Considering that AGEs contribute to microvascular and macrovascular complications in T2DM, our data indicates that dietary supplementation with IP6 should be considered as a therapy to prevent the formation of AGEs and therefore, the development of diabetes-related diseases in patients with T2DM.

Sickle Cell Disease is Associated With Elevated Levels of Skin Advanced Glycation Endproducts

Sickle cell disease (SCD) is associated with increased oxidative stress which potentially enhances generation of advanced glycation endproducts (AGEs). We estimated skin accumulation of AGEs in SCD patients and assessed their relationship with hemolysis and nephropathy. Skin intrinsic fluorescence (SIF), an estimate of AGEs, was assessed in African American patients with and without SCD. After skin excitation with light at 375, 405, and 420 nm, raw autofluorescence was adjusted using specific intrinsic corrections. Group differences in SIF were evaluated by multiple variable regression using chronological age and sex as covariates. The relationship of SIF with reticulocyte count, serum lactate dehydrogenase, estimated glomerular filtration rate (GFR), plasma creatinine, bilirubin, and urine microalbumin was assessed. There were 48 SCD patients (29 male/19 female, age=13.4±3.6 y) and 51 controls (25 male/26 female, age=10.4±5.0 y). SIF375(1.0,0.0), SIF405(0.5,0.5), and SIF420(0.5,0.5) were significantly higher in SCD patients. There was no difference in SIF between SCD patients with and without microalbuminuria. SIF 420(0.5,0.5) was correlated with reticulocyte count (r=0.33; P=0.03). Skin AGEs as estimated by SIF were higher in children with SCD and weakly associated with 1 measure of hemolysis. Further study is needed to determine whether chronic increased deposition of AGEs is associated with development of complications of SCD.

Diverging effects of diabetes mellitus in patients with peripheral artery disease and abdominal aortic aneurysm and the role of advanced glycation end-products: ARTERY study — protocol for a multicentre cross-sectional study

IntroductionDiabetes mellitus is a well-defined risk factor for peripheral artery disease (PAD), but protects against the development and growth of abdominal aortic aneurysm (AAA). Diabetes mellitus is associated with arterial...

Protective role of soluble receptor for advanced glycation end-products in patients with non-alcoholic fatty liver disease

BackgroundSoluble receptor for advanced glycation end-products (sRAGE) exerts protective metabolic effects. AimsTo identify if sRAGE plays a protective role in NAFLD. MethodssRAGE (n=55) and Nε-(Carboxymethyl) lysine (CML) (n=36) serum levels were measured in NAFLD patients. Liver steatosis and fibrosis were non-invasively quantified by the hepatorenal index and the NAFLD fibrosis score (NFS). ResultssRAGE levels were lower in NAFLD patients compared to controls (1207±439 vs. 1596±562ng/l, P<0.001) and were lower among subjects with moderate-severe steatosis compared with mild (1043±287 vs. 1378±506, P=0.005). Higher sRAGE was associated with lower steatosis with adjustment for age, gender, BMI and fasting insulin (OR=0.998, 0.996–0.999 95%CI, P=0.018). CML was not correlated with liver steatosis (r=0.07, P=0.683), but was positively correlated with AST (r=0.34, P=0.04), GGT (r=0.38, P=0.023) and HbA1C (r=0.37, P=0.027). sRAGE tended to be higher in subjects with NFS<−1.455 compared with NFS>−1.455 (1287±450 n=36 vs. 1051±364 n=13, P=0.08). While sRAGE was positively correlated with vegetables consumption (r=0.268, P=0.05), CML levels were not associated with sRAGE or dietary intake. sRAGE increased following a 3 month-lifestyle intervention (1194±446 vs. 1367±440 n=31, P<0.001) and change in sRAGE levels was negatively correlated with change in ALT levels (r=−0.37, P=0.041). ConclusionsRAGE plays a protective role in NAFLD and it is influenced by lifestyle.

Sputum–plasma ratio of soluble receptor for advanced glycation end-products in patients with chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is associated with systemic inflammatory consequences. Receptor for advanced glycation end products (RAGE) acts as an important progression factor amplifying the immune and inflammatory responses in several pathophysiological conditions. The soluble form of RAGE (sRAGE) acts as a decoy for the receptor ligands and is thus thought to protect against excessive inflammation. Conflicting reports exist about sRAGE value in stable and exacerbating COPD. ObjectiveTo assess the sputum to plasma ratio of sRAGE in stable COPD patients. Subjects and methodsThe study included 44 adult patients of both sexes who were presented to Alexandria Main University Hospital between March and July 2015. Patients were categorized into three groups; 15 stable COPD patients (Group I), 15 smokers without COPD (Group II), and 14 healthy non-smokers (Group III). Measurement of sRAGE level in induced sputum and plasma was performed using ELISA technique. ResultsThe study included 38 male patients and 6 female patients, whose median ages were 50, 42 and 35.5years in Groups I, II, and III respectively (p<0.001). Median FEV1% predicted were 35, 96, and 105% in Groups I, II, and III respectively (p<0.001). No statistical significant difference was found among all groups regarding sRAGE level in induced sputum, plasma or sputum/plasma ratio (p=0.092, 0.372, 0.154, respectively). Although levels of sRAGE is apparently higher in induced sputum rather than in plasma, it lacked significance (r=0.27, p=0.08). Furthermore, no significant correlation was found between either plasma or sputum sRAGE level and predicted FEV1% (r=−0.11, p=0.48 and r=−0.12, p=0.28, respectively). ConclusionssRAGE level either in induced sputum, plasma or sputum plasma ratio is not significantly different between stable COPD patients, smokers and healthy controls. Thus, sRAGE cannot be considered as a marker of either diagnosis or severity of COPD.

Association between intraoperative ventilator settings and plasma levels of soluble receptor for advanced glycation end-products in patients without pre-existing lung injury.

The soluble form of the receptor for advanced glycation end-products (sRAGE) is elevated and correlated with severity in patients with acute respiratory distress syndrome (ARDS). The impact of ventilator settings on plasma levels of sRAGE, in patients with or without pre-existing lung injury, remains under-investigated to date. Our objective was to assess the effects of a lung-protective ventilation strategy (combining low tidal volume, positive end-expiratory pressure and recruitment maneuvers), as compared with a non-protective approach (with high tidal volume and zero end-expiratory pressure), on plasma levels of sRAGE in patients without lung injury undergoing major abdominal surgery. Plasma samples were obtained from 95 patients enrolled in a large randomized controlled trial of lung-protective ventilation for major abdominal surgery. Plasma levels of sRAGE were measured in duplicate with an enzyme-linked immunoassay on day 1, immediately after surgery, and on postoperative days 1, 3 and 7. Early postoperative plasma levels of sRAGE were significantly lower in the lung-protective ventilation group (n = 47) than in the non-protective ventilation group (n = 48) (mean (standard deviation), 1782 (836) vs 2171 (1678) pg/mL, respectively, P = 0.03). Intraoperative changes in plasma sRAGE were associated with postoperative hypoxemia and ARDS. A lung-protective ventilation strategy decreased plasma sRAGE in patients without lung injury undergoing major abdominal surgery compared with the patients with non-protective ventilation. This intraoperative decrease could reflect a lesser degree of epithelial injury.

Soluble receptor of advanced glycation end-products in patients with acute myocardial infarction treated with remote ischaemic conditioning.

Several studies have demonstrated that soluble receptor of advanced glycation end-products (sRAGE) is a valuable inflammatory biomarker in cardiovascular disease (CVD). Remote ischaemic conditioning may rescue myocardial tissue during acute myocardial infarction (AMI). In the present study, we evaluate whether sRAGE is a helpful biomarker in patients with AMI receiving remote ischaemic conditioning. Plasma sRAGE levels were measured in 191 patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous intervention (pPCI) of which 97 patients were randomised to receive remote ischaemic conditioning. The sRAGE levels were not different when compared to the randomised controls. In 122 patients, measurement of myocardial salvage index (SI) was obtained. Patients who received remote ischaemic conditioning had significantly higher SI compared to the controls (p < 0.03), although this effect was not seen in sRAGE concentrations. However, sRAGE levels increased with higher New York Heart Association (NYHA) classification after 30 days of follow-up. sRAGE levels do not reflect increased SI in AMI patients who received remote ischaemic conditioning prior to hospital admission.

Increased Levels of Circulating Advanced Glycation End-Products in Menopausal Women with Osteoporosis

Background: Advanced glycation end-products (AGEs) can accumulate in organs and tissues during ageing and diabetes. Increased levels of AGEs are found in the bone tissue of patients with osteoporosis. The purpose of this study was to evaluate circulating AGEs in patients with osteoporosis.Methods: We evaluated plasma AGEs, osteoporosis-related biomarkers, and bone mass in 82 menopausal women with osteoporosis or osteopenia, 16 young women with osteopenia, and 43 healthy women without osteoporosis or osteopenia.Results: Higher levels of serum AGEs were found in the osteoporosis or osteopenia group compared to healthy women (P < 0.0001). A negative correlation was observed between serum AGEs and lumbar spine bone density (BMD of lumbar spine, r = -0.249, P = 0.028; T-score of lumbar spine, r = -0.261, P = 0.021). Women with a increased level of serum AGEs (> 8.12 U/mL) had a 5.34-fold risk of osteopenia regarding lumbar spine T-score and a 3.31-fold risk of osteopenia regarding the hip T-score.Conclusion: Serum AGEs could be used to monitor the severity and progression of osteoporosis. An increased serum level of AGEs was associated with impaired bone formation and was a risk factor for the development of osteoporosis. Targeting AGEs may represent a novel therapeutic approach for primary or secondary osteoporosis.

Statins modulate feedback regulation mechanisms between advanced glycation end-products and C-reactive protein: Evidence in patients with acute myocardial infarction

ObjectiveHigh sensitivity C-reactive protein (hsCRP) and advanced glycation end-products (AGEs) have been proposed as mediators in inflammation and atherosclerosis. Therefore, we studied the relation between AGE and hsCRP in patients with acute myocardial infarction (AMI). MethodsPatients with AMI diagnosis and satisfying our inclusion criteria were included during 2009–2011 in an unicentre registry of AMI patients for a cross-sectional study. The final cohort was composed of 156 patients (46.2% STEMI and 27.6% with type-2 diabetes). AGE and hsCRP were measured in plasma. ResultsDiabetic patients were older than non-diabetics (68.6±10.6 vs. 60.4±13.9years; p<0.05), presented more incidence of hypertension (62.8 vs. 36.3%; p<0.05) and were in a higher Killip class (p<0.05). The mean values of fluorescent AGE and hsCRP levels were 61.3±49.8 AU and 2.4±4.0mg/L, respectively, and there were no differences in these parameters between diabetic and non-diabetic patients. A direct association between AGE and hsCRP levels was observed, mainly in diabetic patients (r=0.258; p=0.018). Importantly, this association disappeared in patients who had been treated with statins before their AMI (r=−0.055; p=0.845), but it was maintained in non-diabetic patients naïve for statins treatment (r=0.634; p<0.001), independently of other treatments and confounding parameters. ConclusionsThis is the first evidence in humans of a feedback regulation mechanism between CRP and the AGE–RAGE axis modulated by statins.

Skin Autofluorescence Relates to Soluble Receptor for Advanced Glycation End-Products and Albuminuria in Diabetes Mellitus

The aim of this study was to compare skin autofluorescence caused by advanced glycation end-products (AGEs) with biochemical markers of endothelial dysfunction and soluble receptor for AGEs (sRAGE) in patients with diabetes. Skin autofluorescence (AF) assessed by AGE-Reader was evaluated with sRAGE and other biochemical parameters in 88 patients with diabetes (47 Type 1/T1DM/ and 41 Type 2/T2DM/) and 20 controls. Skin AF was significantly higher in T1DM and T2DM in comparison to controls (2.39 ± 0.54, 2.63 ± 0.73 versus 1.96 ± 0.33 AU; P < 0.0001). Positive correlation of AF with sRAGE was detected in T1DM and T2DM (r = 0.37, P < 0.02 and r = 0.60, P < 0.0001), but not in controls. Significantly higher AF values were found in patients with positive albuminuria as compared to those with normal albuminuria. Similarly, higher AF was detected in patients with endothelial dysfunction expressed by vWF, ICAM-1, and VCAM-1. Multiple regression analysis revealed independent association of skin AF with age, sRAGE, and albumin-creatinine ratio in patients with diabetes (R 2 = 0.38). Our study confirms that AF is elevated in patients with diabetes, especially with positive albuminuria and endothelial dysfunction. The strong and independent relationship between AF and sRAGE supports the idea that AF may reflect AGEs/RAGE interactions. The exact mechanism remains to be established.

Effects on post-prandial glucose and AGE precursors from two initial insulin strategies in patients with Type 2 diabetes uncontrolled by oral agents

ObjectiveProgressive β-cell dysfunction in Type 2 diabetes results in the need for insulin therapy in many patients. Yet the best regimen to prescribe to patients transitioning from oral anti-hyperglycemic drugs (OADs) is not clear. We sought to compare the effects of two standard initial insulin strategies (basal insulin alone versus premixed insulin) on post-prandial glucose metabolism and precursors of advanced glycation end-products in patients with type 2 diabetes suboptimally controlled on OADs. Research Design and MethodsThis was a 6-month, open-label, single-center study using a cross-over design. 14 subjects were randomized to one of two protocols: once daily insulin glargine or twice-daily 75%/25% neutral protamine lispro/lispro mix. At 12 weeks, the subjects were crossed-over to the opposite protocol. During each period, insulin doses were titrated to target fasting blood glucose of 90–110mg/dL. At baseline and after the two 12-week treatment periods, subjects were studied in the Clinical Research Center; they consumed three liquid mixed isocaloric meals at 4-h intervals, and glucose, free fatty acids (FFA), lipids, and α-dicarbonyls (3-deoxyglucosone [3-DG] and methylglyoxal [MG]) were measured before and after each meal. Patient data were analyzed in the context of their assigned insulin strategy groups. ResultBoth insulin regimens led to a significant improvement in glycemic profiles, including fasting glucose and HbA1c, compared to baseline. However, mean post-prandial glucose was lower with lispro mix than with glargine (153±36 vs. 199±49 mg/dL, respectively; P=0.001). Likewise, there was a reduction in both fasting (48±13 vs. 57±19, P=0.047) and post-prandial (53±19 vs. 63±23; P=0.007) 3DG levels with lispro mix as compared to glargine. No differences were noted in MG concentrations. ConclusionIn type 2 diabetes patients failing OAD therapy, an initial insulin regimen of twice daily premixed insulin results in significantly improved post-prandial glucose levels as well as a reduction in a precursor of AGEs. The effect of these two initial insulin regimens on long-term diabetic complications requires further study.

Productos de glicación avanzada: nuevo marcador de disfunción renal en pacientes con insuficiencia cardíaca crónica

Background and objectives Advanced glycation end-products (AGE) are implicated in the physiopathology and prognosis of heart failure (HF) and they accumulate in situations such as kidney failure (KF). Our objective was to analyze the relation between AGE and KF in patients with chronic HF. Materials and methods 102 consecutive patients of our medical center were included. Clinical and analytical data were obtained, with measurement of glycated haemoglobin, brain natriuretic peptide, cystatin C and fluorescent AGE. Glomerular filtration rate (GFR) was estimated for each patient. Results 40.2% of patients presented GFR < 60 mL/min/1.73m 2 and 11.7% had hidden kidney disease (HKD). AGE correlated positively with creatinine (r = 0.685, p < 0.001) and cystatin C (r = 0.682, p < 0.001) and negatively with GFR (r = −0.720, p < 0.001). Medium value of fluorescent AGE in patients with KF was higher than those without KF (83.4 [3.3] URF vs 56.8 [2.1] URF, p < 0.001). With regard to the diagnostic value for HKD, fluorescent AGE presented an area under the ROC curve higher than other parameters for KD such as cystatin C. In the multivariate analysis, fluorescent AGE were an independent biomarker of KD (OR 1.060; 95% CI 1.024-1.097; p = 0.001). Conclusions AGE act as a biomarker of KD in patients with chronic HF, both diabetics and non diabetics, being better than cystatin C in the detection of HKD.

Atorvastatin decreases serum levels of advanced glycation endproducts (AGEs) in nonalcoholic steatohepatitis (NASH) patients with dyslipidemia: clinical usefulness of AGEs as a biomarker for the attenuation of NASH

Advanced glycation endproducts (AGEs), final reaction products of protein with sugars, are known to contribute to various disorders, including diabetes, aspects of aging, and neurodegenerative diseases. Recently, we reported elevated levels of serum AGEs in patients with nonalcoholic steatohepatitis (NASH); further, we found that AGEs induced the generation of reactive oxygen species followed by the proliferation and activation of hepatic stellate cells, a major contributor to liver fibrosis. In this study, to explore the clinical usefulness of AGEs as a biomarker for the attenuation of NASH, we investigated whether the treatment of NASH with dyslipidemia could decrease serum levels of AGEs. This study included 43 patients with biopsy-proven NASH with dyslipidemia. Serum glyceraldehyde-derived AGE measurements and clinical laboratory tests were performed periodically during an open-label study of atorvastatin (10 mg daily) for 12 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance tests and liver density assessment by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 22 patients. All 43 patients had dyslipidemia. The body mass indexes and serum glucose levels did not change during the treatment. After the treatment, NASH-related metabolic parameters were significantly improved. Serum glyceraldehyde-derived AGE levels were significantly decreased (10.4 +/- 3.8 and 2.5 +/- 1.1 IU/mL before and after treatment, respectively). The steatosis grade and nonalcoholic fatty liver disease (NAFLD) activity score were significantly improved. The present data demonstrated that atorvastatin decreased the serum levels of AGEs in NASH patients with dyslipidemia and suggest the usefulness of AGEs as a biomarker for the attenuation of NASH.

High plasma levels of the soluble receptor for advanced glycation endproducts in patients with symptomatic carotid atherosclerosis

Advanced glycation endproducts (AGEs), particularly carboxymethyl(lysine)-adducts (CML), exert part of their cellular effects by binding to a receptor, named receptor for AGEs (RAGE). The soluble form of this receptor (sRAGE) has been shown to have an athero-protective role. We hypothesized the existence of a relationship between the AGE-RAGE axis and the occurrence of symptoms related to carotid atherosclerosis in nondiabetic conditions. We evaluated plasma levels of CML and sRAGE (by ELISA), and tissue levels (tAGEs and tRAGE, semiquantitatively, by immunohistochemistry) in endarterectomy carotid plaque tissue in 29 nondiabetic patients. At the time of surgery, 10 patients were asymptomatic and 19 were symptomatic. Plasma levels of sRAGE were higher in symptomatic patients than in asymptomatic patients [median (interquartile range): 676 (394-858) pg mL(-1) vs. 347 (284-479) pg mL(-1), P = 0.009]. In symptomatic patients, plasma levels of sRAGE correlated positively with CML (r = 0.60, P < 0.01), C-reactive protein (CRP) (r = 0.618, P < 0.01) and fibrinogen (r = 0.522, P<0.005), while in asymptomatic patients, no correlation was observed. Although tissue and plasma levels of AGEs and RAGE did not correlate between each other, tAGEs and tRAGE were also positively correlated only in symptomatic patients (chi(2) = 8.93, P = 0.003). Plasma levels of sRAGE are higher in symptomatic than asymptomatic carotid atherosclerosis. Higher levels of sRAGE in symptomatic patients may be markers of a higher degree of vascular inflammation in such patients.