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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.

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Objective: Although clinical hypothyroidism (HO) is associated with insulin resistance, there is no information on insulin action in subclinical hypothyroidism (SHO). Design and methods: To investigate this, we assessed the sensitivity of glucose metabolism to insulin both in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes with flow cytometry) in 21 euthyroid subjects (EU), 12 patients with HO, and 13 patients with SHO. Results: All three groups had comparable plasma glucose levels, with the HO and SHO having higher plasma insulin than the EU (P!0.05). Homeostasis model assessment index was increased in HO (1.97G0.22) and SHO (1.99G0.13) versus EU (1.27G0.16, P!0.05), while Matsuda index was decreased in HO (3.89G0.36) and SHO (4.26G0.48) versus EU (7.76G0.87, P!0.001), suggesting insulin resistance in both fasting and post-glucose state. At 100 mU/ml insulin: i) GLUT4 levels on the monocyte plasma membrane were decreased in both HO (215G19 mean fluorescence intensity, MFI) and SHO (218G24 MFI) versus EU (270G25 MFI, PZ0.03 and 0.04 respectively), and ii) glucose transport rates in monocytes from HO (481G30 MFI) and SHO (462G19 MFI) were decreased versus EU (571G15 MFI, PZ0.04 and 0.004 respectively). Conclusions: In patients with HO and SHO: i) insulin resistance was comparable; ii) insulin-stimulated rates of glucose transport in isolated monocytes were decreased due to impaired translocation of GLUT4 glucose transporters on the plasma membrane; iii) these findings could justify the increased risk for insulin resistance-associated disorders, such as cardiovascular disease, observed in patients with HO or SHO.

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.

Abstract. 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 ⑀ -carboxymethyl-lysine (CML) and methylglyoxal-derivatives (MG). Eighteen patients completed the study. Low dietary AGE intake decreased serum CML (34%; P Ͻ 0.002), serum MG (35%; P Ͻ 0.008), CML-LDL (28%; P Ͻ 0.011), CML-apoB (25%; P Ͻ 0.028), dialysate CML (39%; P Ͻ 0.03), and dialysate MG output (40%; P Ͻ 0.04). High dietary AGE intake increased serum CML (29%; P Ͻ 0.028), serum MG (26%; P Ͻ 0.09), CML-LDL (50%; P Ͻ 0.011), CML-apoB (67%; P Ͻ 0.028), and dialysate CML output (27%; P Ͻ 0.01). Serum AGE correlated with BUN (r ϭ 0.6, P Ͻ 0.002 for CML; r ϭ 0.4, P Ͻ 0.05 for MG), serum creatinine (r ϭ 0.76, P Ͻ 0.05 for CML; r ϭ 0.55, P Ͻ 0.004 for MG), total protein (r ϭ 0.4, P Ͻ 0.05 for CML; r ϭ 0.4, P Ͻ 0.05 for MG), albumin (r ϭ 0.4, P Ͻ 0.02 for CML; r ϭ 0.4, P Ͻ 0.05 for MG), and phosphorus (r ϭ 0.5, P Ͻ 0.006 for CML; r ϭ 0.5, P Ͻ 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.

Background: The 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 Methods: Herein, we tested whether, prior to ingestion, diet-derived AGEs contain species with cell activating (TNF␣), 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 250ЊC, for 10 min, along with synthetic AGEs. Results: Animal product-derived AGE, like synthetic methylglyoxal-bovine serum albumin (MG-BSA

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 (