Melpomeni Peppa

Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy

Diet is a major environmental source of proinflammatory AGEs (heat-generated advanced glycation end products); its impact in humans remains unclear. We explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and the other with 5-fold lower AGE (L-AGE) content on inflammatory mediators of 24 diabetic subjects: 11 in a 2-week crossover and 13 in a 6-week study. After 2 weeks on H-AGE, serum AGEs increased by 64.5% (P = 0.02) and on L-AGE decreased by 30% (P = 0.02). The mononuclear cell tumor necrosis factor-α/β-actin mRNA ratio was 1.4 ± 0.5 on H-AGE and 0.9 ± 0.5 on L-AGE (P = 0.05), whereas serum vascular adhesion molecule-1 was 1,108 ± 429 and 698 ± 347 ng/ml (P = 0.01) on L- and H-AGE, respectively. After 6 weeks, peripheral blood mononuclear cell tumor necrosis factor-α rose by 86.3% (P = 0.006) and declined by 20% (P, not significant) on H- or L-AGE diet, respectively; C-reactive protein increased by 35% on H-AGE and decreased by 20% on L-AGE (P = 0.014), and vascular adhesion molecule-1 declined by 20% on L-AGE (P < 0.01) and increased by 4% on H-AGE. Serum AGEs were increased by 28.2% on H-AGE (P = 0.06) and reduced by 40% on L-AGE (P = 0.02), whereas AGE low density lipoprotein was increased by 32% on H-AGE and reduced by 33% on L-AGE diet (P < 0.05). Thus in diabetes, environmental (dietary) AGEs promote inflammatory mediators, leading to tissue injury. Restriction of dietary AGEs suppresses these effects.

Diet‐Derived Advanced Glycation End Products Are Major Contributors to the Body's AGE Pool and Induce Inflammation in Healthy Subjects

Abstract: Advanced glycation end products (AGEs) are a heterogeneous group of compounds that form continuously in the body. Their rate of endogenous formation is markedly increased in diabetes mellitus, a condition in which AGEs play a major pathological role. It is also known, however, that AGEs form during the cooking of foods, primarily as the result of the application of heat. This review focuses on the generation of AGEs during the cooking of food, the gastrointestinal absorption of these compounds, and their biological effects in vitro and in vivo. We also present preliminary evidence of a direct association between dietary AGE intake and markers of systemic inflammation such as C‐reactive protein in a large group of healthy subjects. Together with previous evidence from diabetics and renal failure patients, these data suggest that dietary AGEs may play an important role in the causation of chronic diseases associated with underlying inflammation.

Restriction of Dietary Glycotoxins Reduces Excessive Advanced Glycation End Products in Renal Failure Patients

Advanced glycation endproduct (AGE) levels are elevated in renal failure patients and may contribute to the excessive cardiovascular disease in this population. Diet-derived AGE are major contributors to the total body AGE pool. It was postulated that a reduction in dietary AGE intake might impact on the high circulating AGE levels in renal failure patients. Twenty-six nondiabetic renal failure patients on maintenance peritoneal dialysis were randomized to either a high or a low AGE diet for 4 wk. Three-day dietary records, fasting blood, 24-h urine, and dialysis fluid collections were obtained at baseline and end of study. AGE levels were determined by ELISA for N(epsilon)-carboxymethyl-lysine (CML) and methylglyoxal-derivatives (MG). Eighteen patients completed the study. Low dietary AGE intake decreased serum CML (34%; P < 0.002), serum MG (35%; P < 0.008), CML-LDL (28%; P < 0.011), CML-apoB (25%; P < 0.028), dialysate CML (39%; P < 0.03), and dialysate MG output (40%; P < 0.04). High dietary AGE intake increased serum CML (29%; P < 0.028), serum MG (26%; P < 0.09), CML-LDL (50%; P < 0.011), CML-apoB (67%; P < 0.028), and dialysate CML output (27%; P < 0.01). Serum AGE correlated with BUN (r = 0.6, P < 0.002 for CML; r = 0.4, P < 0.05 for MG), serum creatinine (r = 0.76, P < 0.05 for CML; r = 0.55, P < 0.004 for MG), total protein (r = 0.4, P < 0.05 for CML; r = 0.4, P < 0.05 for MG), albumin (r = 0.4, P < 0.02 for CML; r = 0.4, P < 0.05 for MG), and phosphorus (r = 0.5, P < 0.006 for CML; r = 0.5, P < 0.01 for MG). It is concluded that dietary glycotoxins contribute significantly to the elevated AGE levels in renal failure patients. Moreover, dietary restriction of AGE is an effective and feasible method to reduce excess toxic AGE and possibly cardiovascular associated mortality.

Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction.

BackgroundThe general increase in reactive oxygen species generated from glucose-derived advanced glycation endproducts (AGEs) is among the key mechanisms implicated in tissue injury due to diabetes. AGE-rich foods could exacerbate diabetic injury, at least by raising the endogenous AGE.Materials and MethodsHerein, we tested whether, prior to ingestion, diet-derived AGEs contain species with cell activating (TNFα), chemical (cross-linking) or cell oxidative properties, similar to native AGEs. Glutathione (GSH) and GSH peroxidase (GPx) were assessed after exposure of human umbilical vein endothelial cell (HUVECs) to affinity-purified food-AGE extracts, each exposed to 250°C, for 10 min, along with synthetic AGEs.ResultsAnimal product-derived AGE, like synthetic methylglyoxal-bovine serum albumin (MG-BSA), AGE-BSA, and AGE-low density lipoprotein (AGE-LDL), induced a dose- and time-dependent depletion of GSH (↓60–75%, p < 0.01) and an increase in GPx activity (↑500–600%, p < 0.01), consistent with marked TNFα and cross-link formation (p < 0.05); this contrasted with the low bioreactivity of starch/vegetable AGE-extracts, which was similar to that of control BSA and CML-BSA and BSA (p:NS). Anti-AGE-R1,2,3 and —RAGE IgG each inhibited cell-associated 125I-dAGE by ∼30–55%; GSH/GPx were effectively blocked by N-acetyl-cysteine (NAC, 800 uM, p < 0.01) and aminoguanidine-HCl (AG, 100uM, p < 0.01).ConclusionThus, food-derived AGE, prior to absorption, contain potent carbonyl species, that can induce oxidative stress and promote inflammatory signals.

Studies of insulin resistance in patients with clinical and subclinical hyperthyroidism

OBJECTIVE Although clinical hyperthyroidism (HR) is associated with insulin resistance, the information on insulin action in subclinical hyperthyroidism (SHR) is limited. DESIGN AND METHODS To investigate this, we assessed the sensitivity of glucose metabolism to insulin in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes) in 12 euthyroid subjects (EU), 16 patients with HR, and 10 patients with SHR. RESULTS HR and SHR patients displayed higher postprandial glucose levels (area under the curve, AUC(0)(-)(300) 32,190±1067 and 31,497±716,mg/dl min respectively) versus EU (27,119±1156 mg/dl min, P<0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC(0)(-)(300) 11,020±985 and 9565±904 mU/l min respectively) compared with EU subjects (AUC(0)(-)(300) 7588±743 mU/l min, P<0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81±0.3 and 2.43±0.38 respectively) compared with EU subjects (1.27±0.16, P<0.05), while Matsuda and Belfiore indices were decreased in HR (4.21±0.41 and 0.77±0.05 respectively, P<0.001) and SHR patients (4.47±0.33 and 0.85±0.05 respectively, P<0.05 versus EU (7.76±0.87 and 1 respectively). At 100 μU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8±7 mean fluorescence intensity (MFI)) and SHR patients (522.2±25 MFI) compared with EU subjects (407±18 MFI, P<0.01 and P<0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8±5%) versus EU subjects (61.26±10%, P<0.05). CONCLUSIONS Insulin-stimulated glucose transport in isolated monocytes of patients with HR was decreased compared with EU subjects. Insulin resistance was comparable in patients with both HR and SHR.

Dietary glycotoxins correlate with circulating advanced glycation end product levels in renal failure patients

BACKGROUND Levels of advanced glycation end products (AGEs), well-known proinflammatory compounds, are markedly elevated in patients with renal failure, raising the speculation that they have a role as cardiovascular risk factors in this population. Although elevated AGE levels in patients with renal failure have been attributed to impaired renal clearance and increased endogenous AGE formation, recent data suggest an important role for diet as a source of AGEs. METHODS To determine the relationship between dietary AGE content and serum AGE levels, a cross-sectional study was performed in our long-term dialysis patients. Dietary AGE intake was estimated by means of dietary records and questionnaires, and sera were obtained for measurement of 2 well-characterized AGEs, carboxymethyl-lysine (CML) and methylglyoxal (MG) derivatives. RESULTS The study population included 189 patients; 139 hemodialysis and 50 peritoneal dialysis patients. Serum CML level correlated significantly with dietary AGE intake, based on either 3-day food records (r = 0.5; P = 0.003) or dietary questionnaires (r = 0.22; P = 0.03). Although no correlation was observed with nutrient intake (protein, fat, saturated fat, or carbohydrate), both serum CML and MG levels correlated with blood urea nitrogen (r = 0.2; P = 0.03 and r = 0.2; P = 0.02, respectively) and serum albumin levels (r = 0.16; P = 0.04 and r = 0.18; P = 0.02, respectively). CONCLUSION Data indicate that dietary AGE content, independently of other diet constituents, is an important contributor to excess serum AGE levels in patients with renal failure. Moreover, the lack of correlation between serum AGE levels and dietary protein, fat, and carbohydrate intake indicates that a reduction in dietary AGE content can be obtained safely without compromising the content of obligatory nutrients.

High Levels of Dietary Advanced Glycation End Products Transform Low-Dersity Lipoprotein Into a Potent Redox-Sensitive Mitogen-Activated Protein Kinase Stimulant in Diabetic Patients

Background—LDL modification by endogenous advanced glycation end products (AGEs) is thought to contribute to cardiovascular disease of diabetes. It remains unclear, however, whether exogenous (diet-derived) AGEs influence glycoxidation and endothelial cell toxicity of diabetic LDL. Methods and Results—Twenty-four diabetic subjects were randomized to either a standard diet (here called high-AGE, HAGE) or a diet 5-fold lower in AGE (LAGE diet) for 6 weeks. LDL pooled from patients on HAGE diet (Db-HAGE-LDL) was more glycated than LDL from the LAGE diet group (Db-LAGE-LDL) (192 versus 92 AGE U/mg apolipoprotein B) and more oxidized (5.7 versus 1.5 nmol malondialdehyde/mg lipoprotein). When added to human endothelial cells (ECV 304 or human umbilical vein endothelial cells), Db-HAGE-LDL promoted marked ERK1/2 phosphorylation (pERK1/2) (5.5- to 10-fold of control) in a time- and dose-dependent manner compared with Db-LAGE-LDL or native LDL. In addition, Db-HAGE-LDL stimulated NF-κB activity significantly in ECV 304 and human umbilical vein endothelial cells (2.3-fold above baseline) in a manner inhibitable by a MEK inhibitor PD98059 (10 μmol/L), the antioxidant N-acetyl-l-cysteine, NAC (30 mmol/L), and the NADPH oxidase inhibitor DPI (20 μmol/L). In contrast to Db-LAGE-LD and native LDL, Db-HAGE-LDL induced significant soluble vascular cell adhesion molecule-1 production (2.3-fold), which was blocked by PD98059, NAC, and DPI. Conclusions—Exposure to daily dietary glycoxidants enhances LDL-induced vascular toxicity via redox-sensitive mitogen-activated protein kinase activation. This can be prevented by dietary AGE restriction.

Skeletal muscle insulin resistance in endocrine disease.

We summarize the existing literature data concerning the involvement of skeletal muscle (SM) in whole body glucose homeostasis and the contribution of SM insulin resistance (IR) to the metabolic derangements observed in several endocrine disorders, including polycystic ovary syndrome (PCOS), adrenal disorders and thyroid function abnormalities. IR in PCOS is associated with a unique postbinding defect in insulin receptor signaling in general and in SM in particular, due to a complex interaction between genetic and environmental factors. Adrenal hormone excess is also associated with disrupted insulin action in peripheral tissues, such as SM. Furthermore, both hyper- and hypothyroidism are thought to be insulin resistant states, due to insulin receptor and postreceptor defects. Further studies are definitely needed in order to unravel the underlying pathogenetic mechanisms. In summary, the principal mechanisms involved in muscle IR in the endocrine diseases reviewed herein include abnormal phosphorylation of insulin signaling proteins, altered muscle fiber composition, reduced transcapillary insulin delivery, decreased glycogen synthesis, and impaired mitochondrial oxidative metabolism.

Prevention and Reversal of Diabetic Nephropathy in db/db Mice Treated with Alagebrium (ALT-711)

Background: Alagebrium (ALT-711) has been shown to improve renal dysfunction in animal models of diabetes. Methods: To test its effects in diabetic nephropathy (DN), ALT-711 was administered (1 mg/kg daily i.p.) to 9-week-old female db/db mice (n = 15, group A1) for 3 weeks and to 3-month-old (n = 15, group A2), 7-month-old (n = 7, group A3), and 12-month-old (n = 5, group A4) female db/db mice for 12 weeks, while a similar number of diabetic and nondiabetic mice were used as controls. The ΕN-carboxymethyllysine (CML) levels in serum, urine, skin, and kidney tissue were measured by enzyme-linked immunosorbent assay. The renal morphometric parameters were assessed by electron and light microscopy. Results: By the 3rd week of treatment, the serum CML level decreased by 41%, and the urinary CML concentration increased by 138% from baseline, while the urinary albumin/creatinine ratio was lower (p < 0.05) in diabetic and nondiabetic group A1 mice. After 3 months of treatment, serum, skin, and kidney CML levels and urinary albumin/creatinine ratio were lower (p < 0.05) and the urinary CML levels higher (p < 0.05) in treated group A2, A3, and A4 animals compared with groups which received phosphate-buffered saline, with a similar pattern observed in nondiabetic mice. The renal morphological parameters characteristic of DN decreased in treated compared with untreated mice. Conclusion: Alagebrium may prevent, delay, and/or reverse established DN in db/db mice by reducing the systemic advanced glycation end product pools and facilitating the urinary excretion of advanced glycation end products.

Lipid Abnormalities and Cardiometabolic Risk in Patients with Overt and Subclinical Thyroid Disease

Dyslipidemia is a common finding in patients with thyroid disease, explained by the adverse effects of thyroid hormones in almost all steps of lipid metabolism. Not only overt but also subclinical hypo- and hyperthyroidism, through different mechanisms, are associated with lipid alterations, mainly concerning total and LDL cholesterol and less often HDL cholesterol, triglycerides, lipoprotein (a), apolipoprotein A1, and apolipoprotein B. In addition to quantitative, qualitative alterations of lipids have been also reported, including atherogenic and oxidized LDL and HDL particles. In thyroid disease, dyslipidemia coexists with various metabolic abnormalities and induce insulin resistance and oxidative stress via a vice-vicious cycle. The above associations in combination with the thyroid hormone induced hemodynamic alterations, might explain the increased risk of coronary artery disease, cerebral ischemia risk, and angina pectoris in older, and possibly ischemic stroke in younger patients with overt or subclinical hyperthyroidism.