The potential role of dietary advanced glycation endproducts in the development of chronic non-infectious diseases: a narrative review.

Increasing clinical and experimental evidence accumulated during the past few decades supports an important role for dietary advanced glycation endproducts (AGE) in the pathogenesis of many chronic non-infectious diseases, such as type 2 diabetes, CVD and others, that are reaching epidemic proportions in the Western world. Although AGE are compounds widely recognised as generated in excess in the body in diabetic patients, the potential importance of exogenous AGE, mostly of dietary origin, has been largely ignored in the general nutrition audience. In the present review we aim to describe dietary AGE, their mechanisms of formation and absorption into the body as well as their main mechanisms of action. We will present in detail current evidence of their potential role in the development of several chronic non-infectious clinical conditions, some general suggestions on how to restrict them in the diet and evidence regarding the potential benefits of lowering their consumption.

Premature loss of muscle mass and function in type 2 diabetes.

INTRODUCTION: Muscle mass and function are among the most relevant factors that contribute to an optimal quality of life, and are strong predictors of mortality in the elderly. Loss of lean tissues and deterioration of muscle function have been described as one of the many complications of type 2 diabetes mellitus (DM2), but most studies do not isolate age as an intervening factor. AIM: To study whether adult DM2 patients up to 60years of age have decreased muscle mass and function compared with healthy non-diabetic (ND) subjects of similar age. METHODOLOGY: Appendicular fat-free mass (ApFFM) by dual X-ray absorptiometry (DEXA), handgrip strength (HS), quadriceps strength (QS), 12 min walking capacity (12MW) and the Timed Up and Go test (TUG) were measured in 100 DM2 patients and 39 ND controls. Muscle quality, or the ratio between lean mass and muscle strength of upper and lower limbs, and the functional limitations associated with pain and stiffness assessed according to the Western Ontario and McMaster Universities Arthrosis Index (WOMAC) were also recorded. Specific tests were performed to rule out microvascular diabetic complications (retinal and peripheral nerves), metabolic control, kidney function and vitamin D status and examine their association with ApFFM and function. RESULTS: ApFFM was significantly higher among DM2 female patients and lower among diabetic men. However opposite results were obtained when individual values were corrected for body mass index (BMI), specifically among women, who were more likely to be obese. As for muscle strength and global functionality tests, significantly better performances in TUG, 12MW, QS and HS were observed among ND subjects of both sexes. These differences prevailed even after excluding diabetic patients with microvascular complications as well as those with more than 10years of diabetes. Muscle quality was also significantly better among ND women. Higher scores of pain and stiffness in the WOMAC scale correlated with 12MW and TUG in both groups but did not correlate with ApFFM. CONCLUSIONS: We found a clear deterioration of lean mass and muscle functions among adult DM2 patients of up to 60years old, independent of length of disease, metabolic control, vitamin D status and presence of microvascular complications and pain.

Effect of weight maintenance or gain in a 10 years period over telomere length, sirtuin 1 and 6 expression and carotid intima media thickness.

BACKGROUND: Lack of weight gain throughout adult life could mimic the beneficial effects of energy restriction in humans. The present study aimed to assess the effects of weight stability or gain, over a period of 10 years, on telomere length, sirtuin 1 and 6 expression, and carotid intima media thickness. METHODS: We studied 148 healthy adults (age range 20-59 years; 101 females) who had an objective record of their weight 10 years before. They were classified as weight losers, weight maintainers, weight gainers and extreme weight gainers. A fasting blood sample was obtained for routine laboratory and isolation of peripheral blood mononuclear cells, to extract DNA and RNA, and to measure telomere length and sirtuin 1 and 6 expression, respectively. Carotid intima media thickness was measured by ultrasound. Body composition was measured by Dual-energy X-ray absorptiometry. RESULTS: In the 10-year period, 24 participants lost weight (17 females), 65 maintained weight (41 females), 25 gained weight (15 females) and 34 were extreme weight gainers (28 females). Female weight gainers had a higher body mass index, waist circumference, total body fat and homeostatic model assessment insulin resistance. Male weight gainers had a higher hip circumference and total body fat. No differences in telomere length, sirtuin 1 expression and carotid intima media thickness were observed between weight gainers and maintainers. CONCLUSIONS: No effect of weight maintenance or gain was observed on metabolic and vascular markers of ageing.

Dietary intake increases serum levels of carboxymethil-lysine (CML) in diabetic patients.

INTRODUCTION: Advanced glycation end products are produced endogenously, in association with hyperglycemia and oxidative stress. They can also be generated during cooking or food processing and, once absorbed, alter protein function and promote inflammation. METHODS: We selected 40 healthy male subjects, 17 patients with type 2 diabetes of both sexes and 15 patients with type 1 diabetes of both sexes. Each participant underwent both a food frequency questionnaire (FFQ) and 24-hour dietary recall specially adapted for measuring CML intake, anthropometry, measurement of blood pressure and biochemical parameters in blood and urine. RESULTS: Serum CML levels were significantly higher in patients with diabetes compared to healthy subjects (p 0.04), showing a direct relationship between dietary intake and serum levels of CML in T2D patients (r 0.53 p 0.03). sCML levels correlated positively with length of diabetes mellitus, and inversely with body mass index (BMI). The most important dietary factor contributing to raise CML levels in these patients with diabetes was the consumption of milk powder. CONCLUSION: Serum levels of CML were found to be higher among diabetic subjects, associated to length of diabetes as expected, but also with the ingestion of foods containing higher amounts of ML. The consumption of milk powder in this group is a major determinant of increased serum levels.

Proliferation and differentiation of human adipocyte precursor cells: differences between the preperitoneal and subcutaneous compartments.

Human adipocyte precursor cells (APC) have been characterized in their proliferation and differentiation potential from subcutaneous, omental, and mesenteric depots, mostly from morbidly obese patients. Cells from the preperitoneal adipose compartment have not been characterized yet, least of all when obtained from normal weight subjects. The aim was to compare proliferation and differentiation of subcutaneous (SC) and preperitoneal (PP) APC derived from adipose tissue in healthy subjects with different body mass. SC and PP adipose tissue was obtained during surgery of inguinal hernias in five healthy non-obese subjects and three obese otherwise healthy men. APC, obtained by collagenase digestion, were cultured. Proliferation was assayed by cell counting and differentiation by oil red O staining and flow cytometry using Nile Red staining. Proliferation of SC was higher than PP APC. Such differences between both compartments were even higher in APC obtained from obese patients. Conversely PP APC differentiated earlier in vitro compared with SC cells. These results agree with published data on fat cell proliferation. However regarding differentiation, our data show that APC from deeper depots (in this case PP) differentiate earlier than subcutaneous APC. This is different to previous studies performed in mesenteric or omental adipose tissue.

Fluorescent serum and urinary advanced glycoxidation end-products in non- diabetic subjects

Introduction: Advanced glycoxidation end-products (AGEs) are involved in age-related conditions and diabetic complications. Diet intake contributes to their circulating concentrations. Aim: To measure serum and urinary AGEs in non-diabetic volunteers and relate their concentration to body composition, blood chemistry and dietary ingesti¢n. Methods: We studied 41 adult men (31 middle-aged adults and 10 elderly). A nutritional assessment including a dietary recall designed for detection of AGE ingesti¢n (specifically carboxymethyl-lysine(CML)), and anthropometric measurements were performed. Also serum lipoproteins, insulin, glucose, leptin and C reactive protein (CRP). AGEs were measured in serum and urine samples using size exclusion chromatography and flow injection assay (FIA); the technical procedures were first employed in 11 heterogeneous diabetics, as positive controls for this methodology. Results: Serum and urinary chromatograms indicated that areas under the curve were not different in younger compared with elderly adults. AGEs did not correlate with dietary intake, body composition, nor metabolic parameters, however they correlated significantly with renal function and CRP concentration. Discussion: In these non-diabetic volunteers, with low CML intake, serum and urinary concentration of AGEs were not related to dietary intake. AGEs were related to renal function and CRP, but not to body composition, lipoproteins, insulin and glucose.

[The importance of folic acid in current medicine]. / Importancia del ácido fólico en la medicina actual.

Lately, folic acid deficiency is gaining a predominant role in the pathogenesis of congenital malformations and cardiovascular diseases in adults. The planning of individual and population preventive strategies for these diseases must consider this deficiency. This paper reviews the anatomical, biochemical and molecular bases of neural tube defects and cardiovascular diseases in adults. In these two frequent diseases, folic acid supplementation has shown a clear cut protective effect.

[New pieces in the puzzle of atherogenesis]. / Nuevas piezas en el puzzle de la aterogénesis.

The contribution of high serum levels of cholesterol to atherogenesis has been widely recognized, but the mechanisms are not completely clear. Numerous publications have emphasized that oxidized, but not native low-density lipoproteins, are the particles incorporated into the arterial wall. A group of receptors generically called "scavenger" (SR), actively bind these modified lipoproteins and incorporate them into monocytes-macrophages, in the arterial intima. SR are not down regulated by intracellular concentrations of cholesterol, thus accumulating huge amounts of lipids, transforming monocyte-macrophages into foam cells, predominant cell type of the fatty streak. The simultaneous cytokine production and migration of other cellular types progressively transform this initial lesion into the organized atherosclerotic plaque. In this setting SR, which are up-regulated by oxidized LDL, play a central promoting role. Its presence has been demonstrated in arterial plaques both in human and animal models, and its blockade protects animals from development or progression of atherosclerosis. In humans, elevated antibody titers to oxidized LDL in patients with coronary stenosis, and increased SR activity, in pro-atherogenic conditions such as haemodialysis, indicate that this model may operate as well, but the evidences are still not solid enough to definitively conclude that the oxidized-LDL-SR hypothesis is a finished puzzle.

Lipid turnover in alcoholics before and after an ethanol load.

Alcohol ingestion decreases plasma free fatty acids (FFAs) and lipid oxidation. This study was conducted to determine palmitate turnover in alcoholics during a short abstinence period and after an ethanol load and in a group of nonalcoholic control subjects, looking for correlations between palmitate turnover, FFA, acetate, and acetoacetate/beta hydroxybutyrate ratio (AKBR). Palmitate C14 turnover was studied in five alcoholics during early abstinence and after a 0.8 g/kg ethanol load, and in five nonalcoholic normal controls. Plasma levels of FFA, acetate, acetoacetate, and beta hydroxybutyrate were measured before and during the ethanol load. A needle hepatic biopsy was performed in alcoholics. FFA levels, palmitate flux, oxidation, and nonoxidative disposal were similar in alcoholics compared with control subjects, decreasing significantly after the ethanol load in both groups. AKBR and ketone bodies were similar in both groups in the basal period. After the alcohol infusion, AKBR decreased significantly. Acetoacetate levels did not change, and beta hydroxybutyrate and total ketone bodies increased significantly in alcoholics and control subjects. A positive correlation was found between FFA levels and palmitate flux. Liver biopsies showed mild changes in the patients studied. The similar inhibition of lipid turnover, FFA release, and the drop in AKBR observed after an alcohol load in alcoholics and control subjects suggest that this effect is mediated by alcohol metabolism and not by metabolic alterations present in alcoholics.

[Markers of hepatic fibrogenesis in alcoholic patients]. / Marcadores de fibrogénesis hepática en pacientes alcohólicos.

BACKGROUND: An elevation of serologic markers of hepatic fibrogenesis has been reported in liver diseases of different etiologies. Among these, the N-terminal type III procollagen (P-III-P) and the P1 proteolytic fragment of laminin (P1 laminin) increase in alcoholic liver damage, in proportion to the progression of this condition. AIM: To study serum levels of P-III-P and P1 laminin in asymptomatic alcoholics with and without liver damage and decompensated alcoholic cirrhotics, compared to normal controls. METHODS: Serum P-III-P and laminin levels were measured in asymptomatic alcoholics during detoxification treatment. Liver biopsies were obtained, in order to detect liver damage, which was graded with a numeric score, considering values over 6 as severe damage. Serum fibrogenesis markers were also measured in a group of decompensated alcoholic cirrhotics. RESULTS: P-III-P levels were significantly higher in cirrhotic patients compared to alcoholics with or without liver damage and to normal controls. Laminin was not different between groups. P-III-P did not correlate with histologic score in asymptomatic patients. CONCLUSIONS: In this study P-III-P and P1 laminin were not usefull discriminators of severe liver damage among asymptomatic alcoholics; their levels were found to rise significantly only when liver disease has become clinically evident.

Fatty acid composition of liver total lipids in alcoholic patients with and without liver damage.

Alcohol ingestion may promote lipid peroxidation, and the presence of polyunsaturated fatty acids in liver lipids may be essential for the generation of liver damage through this mechanism. The aim of this study is to examine fatty acid composition of liver lipids in chronic alcoholics with and without histological liver damage. A percutaneous liver biopsy was performed to 28 patients hospitalized for treatment of their alcoholism. Liver total lipids were extracted from a portion of the tissue sample and fatty acid composition was measured by gas chromatography. Another piece of the sample was sent for histological study. Six patients had histological cirrhosis or alcoholic hepatitis in their biopsies, the rest of the patients had minimal changes. Patients with liver damage had higher levels of oleic acid and total monoenoic fatty acids, a higher 18:1/18:0 ratio, lower levels of polyunsaturated fatty acids, a lower 20:4/18:2 ratio, and a lower peroxidability index in liver total lipids, than patients without liver damage. Alcoholic patients with asymptomatic liver damage have less unsaturated fatty acids in liver total lipids than their counterparts with normal livers.

[Major histocompatibility system as a risk factor for alcoholic liver disease]. / El sistema mayor de histocompatibilidad como factor de riesgo de la enfermedad hepática alcohólica.

Several associations between alleles of the major histocompatibility system and alcoholic liver disease have been described. However, these are weak and change from one population to another. The aim of this work was to search for a possible genetic risk factor for alcoholic liver disease among Chilean alcoholics. We studied blood groups, serum proteins and HLA antigens in 39 alcoholic cirrhotics, 104 asymptomatic alcoholics and 44 non alcoholic controls. Asymptomatic alcoholics were also subjected to a percutaneous liver biopsy that showed moderate to severe histological liver damage in 46 subjects (44%). No differences in the studied genetic markers, were found among the four groups. It is concluded that this study does not confirm previously reported associations between genetic markers and alcoholic liver disease.

Ventricular mass in hypertensive and normotensive obese subjects.

Two-dimensional echocardiography was performed in 29 normotensive obese subjects and 21 hypertensive obese subjects representative of the Chilean population. The left ventricular mass (LVM) did not correlate with height or body surface area (BSA) in these patients, but positively correlated with body mass index (BMI), tricipital skinfold thickness and blood pressure (BP). The LVM/BSA ratio was significantly higher in the hypertensive subjects and was correlated with BP only. Left ventricular hypertrophy (LVM/BSA > 120 or 150 g/m2 in women or men, respectively) was found in 28% of normotensive and 58% of hypertensive subjects (P = 0.036). No statistical differences were found in relative wall thickness (RWT) between both groups. Posterior wall thickness was independently associated with BP while interventricular septum thickness was positively associated with the waist/hip ratio. Systolic function, evaluated through fractional shortening and end systolic diameters, was negatively and independently associated with body fat area. Left ventricular hypertrophy is a prevalent condition in these obese subjects. Hypertension seems to exert an additive effect, mainly increasing posterior wall thickness. Fat accumulation was negatively related to systolic function in this sample, irrespective of blood pressure.

[Prediction of histological liver damage in asymptomatic alcoholic patients by means of clinical and laboratory data]. / Predicción del daño histológico hepático en pacientes alcoholicos asintomáticos mediante datos clínicos y de laboratorio.

Looking for a noninvasive method to predict liver histologic alterations in alcoholic patients without clinical signs of liver failure, we studied 187 chronic alcoholics recently abstinent, divided in 2 series. In the model series (n = 94) several clinical variables and results of common laboratory tests were confronted to the findings of liver biopsies. These were classified in 3 groups: 1. Normal liver; 2. Moderate alterations; 3. Marked alterations, including alcoholic hepatitis and cirrhosis. Multivariate methods used were logistic regression analysis and a classification and regression tree (CART). Both methods entered gamma-glutamyltransferase (GGT), aspartate-aminotransferase (AST), weight and age as significant and independent variables. Univariate analysis with GGT and AST at different cutoffs were also performed. To predict the presence of any kind of damage (Groups 2 and 3), CART and AST > 30 IU showed the higher sensitivity, specificity and correct prediction, both in the model and validation series. For prediction of marked liver damage, a score based on logistic regression and GGT > 110 IU had the higher efficiencies. It is concluded that GGT and AST are good markers of alcoholic liver damage and that, using sample cutoffs, histologic diagnosis can be correctly predicted in 80% of recently abstinent asymptomatic alcoholics.

[Controlled study of the effect of silymarin on alcoholic liver disease]. / Estudio controlado sobre el efecto de la silimarina en la enfermedad hepática alcohólica.

A controlled trial on the use of Silymarin in patients with alcoholic liver disease was performed. Seventy two patients were admitted to the trial and randomly assigned to an experimental or controls group. Experimentals received 280 mg/day of Silymarin and controls an equal number of placebo tablets. Three patients on placebo and nine on Silymarin were lost from control (p = 0.035), remaining in control 34 patients receiving placebo and 25 patients receiving the drug. Both groups did not differ in their initial laboratory assessment and were followed up for an average of 15 months. Ten patients died during the follow up (5 in placebo and 5 in Silymarin); life table analysis did not show significant differences in mortality. Patients who died had lower serum albumin and prothrombin time and higher total bilirubin, alkaline phosphatases and CCLI on the initial clinical and laboratory assessment. Final laboratory values and their changes in those who survived did not differ between Silymarin and placebo. Twenty two patients on placebo (65%) and 14 on Silymarin (58%) recognized alcohol ingestion or had a positive urine sample analysis for alcohol during follow up. Those who abstained from alcohol had a significant fall in gamma glutamyl transferase during follow up. No other significant differences were observed between these two groups. It is concluded that in this trial, Silymarin did not change the evolution or mortality of alcoholic liver disease.

[Muscular strength: an indicator of nutritional status]. / Fuerza muscular: un indicador de estado nutritivo.

A hand dynamometer was used to measure muscle strength in 207 patients admitted to the Gastroenterology service of a general hospital. Validation of international standards in a normal population of both sexes and different ages revealed that our normals perform at the 25% percentile of international values. Results were correlated with other measurements of nutritional status, namely anthropometric measurements, serum albumin level and tuberculin test. Compared to normals, muscle strength was significantly (p < 0.01) lower in patients with body mass index under 19, cutaneous tricipital folding < 85%, brachial circumference < 85%, and serum albumin < 3.5 g/dl. No difference in muscle strength between tuberculin positive or negative subjects was observed. None of the nutritional parameter was helpful to predict complications in patients submitted to surgery. Thus, muscle strength is a useful parameter to evaluate nutritional status but, similar to other measurements, is not predictive of surgical complications.