Endogenous advanced glycation endproducts (AGEs) include chemically crosslinking species (glycotoxins) that contribute to the vascular and renal complications of diabetes mellitus (DM). Renal excretion of the catabolic products of endogenous AGEs is impaired in patients with diabetic or nondiabetic kidney disease (KD). The aim of this study was to examine the oral absorption and renal clearance kinetics of food AGEs in DM with KD and whether circulating diet-derived AGEs contain active glycotoxins. Thirty-eight diabetics (DM) with or without KD and five healthy subjects (NL) received a single meal of egg white (56 g protein), cooked with (AGE-diet) or without fructose (100 g) (CL-diet). Serum and urine samples, collected for 48 hr, were monitored for AGE immunoreactivity by ELISA and for AGE-specific crosslinking reactivity, based on complex formation with 125 I-labeled fibronectin. The AGE-diet, but not the CL-diet, produced distinct elevations in serum AGE levels in direct proportion to amount ingested (r ‫؍‬ 0.8, P < 0.05): the area under the curve for serum (Ϸ10% of ingested AGE) correlated directly with severity of KD; renal excretion of dietary AGE, although normally incomplete (only Ϸ30% of amount absorbed), in DM it correlated inversely with degree of albuminuria, and directly with creatinine clearance (r ‫؍‬ 0.8, P < 0.05), reduced to <5% in DM with renal failure. Post-AGE-meal serum exhibited increased AGE-crosslinking activity (two times above baseline serum AGE, three times above negative control), which was inhibited by aminoguanidine. In conclusion, (i) the renal excretion of orally absorbed AGEs is markedly suppressed in diabetic nephropathy patients, (ii) daily inf lux of dietary AGEs includes glycotoxins that may constitute an added chronic risk for renal-vascular injury in DM, and (iii) dietary restriction of AGE food intake may greatly reduce the burden of AGEs in diabetic patients and possibly improve prognosis.

OBJECTIVE -The current study was designed to test the acute effects of dietary advanced glycation end products (AGEs) on endothelial function of diabetic and nondiabetic subjects.RESEARCH DESIGN AND METHODS -Flow-mediated dilation (FMD) of the brachial artery and serum levels of AGEs, plasminogen activator inhibitor 1 (PAI-1), vascular cell adhesion molecule 1 (VCAM-1), and glucose were assessed before and after a single oral AGE challenge (ϳ1.8 ϫ 10 6 AGE units) in 44 diabetic and 10 nondiabetic subjects.RESULTS -The diabetic patients had higher baseline levels of serum AGEs (P ϭ 0.020), PAI-1 (NS), and VCAM-1 (P ϭ 0.033) and lower baseline values of FMD compared with nondiabetic subjects (P ϭ 0.032). Ninety minutes after a single oral AGE challenge, serum AGEs and PAI-1 levels increased and FMD decreased significantly in both healthy subjects (AGEs: 7.2 Ϯ 0.5 to 9.3 Ϯ 1 units/ml, P ϭ 0.014; PAI-1: 5.4 Ϯ 0.4 to 6.8 Ϯ 0.4 ng/ml, P ϭ 0.007; and FMD: 9.9 Ϯ 0.7 to 7.4 Ϯ 0.9%, P ϭ 0.019) and diabetic subjects (AGEs: 10.5 Ϯ 0.7 to 14.2 Ϯ 1 units/ml, P ϭ 0.020; PAI-1: 6.5 Ϯ 1 to 10 Ϯ 2 ng/ml, P ϭ 0.030; and FMD: 5.4 Ϯ 0.4 to 4.0 Ϯ 0.3%, P ϭ 0.032). Serum glucose and VCAM-1 levels remained unchanged.CONCLUSIONS -Significant increases in serum AGEs can occur together with altered clinical measures of endothelial function in diabetic and nondiabetic subjects after a single modest AGE-rich beverage. Thus, repeated or chronic exposure to high AGE diets could over time lead to and/or accelerate vascular disease. Diabetes Care 30:2579-2582, 2007C ardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes (1,2). Elevated levels of oxidants such as advanced glycation end products (AGEs) are known promoters of high oxidative stress, playing a significant role in the pathogenesis of diabetic CVD (3-5).Whereas AGEs are better known as products of hyperglycemia, they are also abundant in the standard Westernized diet (6 -9). AGEs are especially elevated in dietary mixtures of proteins, lipids, and sugars processed under elevated temperatures, as in broiling, roasting, or grilling (6,7). Specific immunoassays provide practical and reliable means for the detection of representative types of AGEs that are present in human serum, urine, and tissues, as well as in dietary products (8,10,11). Among the more frequently used assays are immunoreactive probes for N ε -(carboxymethyl)lysine (CML) or methyl-glyoxal derivatives, serving as examples of dietary oxidants, shown to share the proinflammatory and prooxidant properties of the endogenous AGEs, based on in vitro studies (8) and animal models of CVD (12-14). The reduction of certain dietary AGEs has been associated with the prevention of CVD in mice (12-14), whereas in diabetic patients, their restriction has produced significant decreases in serum AGE levels, in parallel with a reduction in circulating vascular cell adhesion molecule 1 (VCAM-1), tumor necrosis factor-␣, and C-reactive protein, despite sustained hyperglycemia (15), strengthe...

Background: Receptors for advanced glycation endproducts (AGE-R) mediate AGE turnover, but can also trigger inflammatory genes that promote diabetic tissue injury and diabetic complications (DC). High AGE levels and reduced AGE-R sites in kidneys of NOD mice prone to type 1 diabetes (T1D) and to renal disease (RD) suggested that impaired AGE-R function may contribute to RD in these mice. Materials and Methods: In this study, after confirming reduced AGE-R1 expression in NOD mouse peritoneal macrophages, we tested for differences in AGE-R1,-R2, and-R3 gene expression in 54 human subjects by RT-PCR and Western analysis. Fresh peripheral blood mononuclear cells (PBMN) were isolated from 36 persons: 18 T1D patients with severe RD (DC); 11 age-and DM-duration matched patients without DC (n-DC); and 7 normal volunteers (NL). EBV-transformed lymphoblasts were obtained from an additional 18 subjects (12 T1D patients, 6 with and 6 without DC, and 6 nondiabetics). Results: AGE-R1 mRNA and protein of PBMN from n-DC patients were enhanced (p Ͻ .05 versus NL

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