Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy

Abstract

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.

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

“…However, this is the first time that an increase in all three AGE subtypes has been demonstrated in ZDF rats, an increase that was suppressed simultaneously by drug intervention. In patients with diabetic nephropathy, urinary excretion of CML is reduced, and insufficient clearance may result in increased serum AGE concentrations as well as tissue accumulation of AGEs [26][27][28][29]. This is further supported by the fact that the AGE inhibitor aminoguanidine improved renal function in diabetic nephropathy, reduced tissue AGE deposits [30][31][32] and increased urinary excretion of dietary AGEs [33].…”

Simple non-invasive assessment of advanced glycation endproduct accumulation

“…Furthermore, the metabolic consequences of diabetes may have a higher impact on AGE accumulation than oxidative stress induced by smoking. Tissue AGE accumulation may be further influenced by nutrition [34].…”

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

“…Advanced glycation end products AGEs are long known to form in foods during heating (Lee et al ., 1981; O'Brien & Morrissey, 1989; Koschinsky et al ., 1997). There are two well‐characterized compounds, N ‐carboxy methyl‐lysine (CML) and methyl‐glyoxal (MG), derivatives of glucose–protein or glucose–lipid interactions, which serve as markers for AGEs (Dyer et al ., 1992; Vlassara & Palace, 2002).…”

“…There are two well‐characterized compounds, N ‐carboxy methyl‐lysine (CML) and methyl‐glyoxal (MG), derivatives of glucose–protein or glucose–lipid interactions, which serve as markers for AGEs (Dyer et al ., 1992; Vlassara & Palace, 2002). A positive correlation is shown between the amount of AGEs consumed and that found in the circulation (Koschinsky et al ., 1997; He et al ., 1999). Consistent with our findings of high serum MG association with faster cognitive decline, we have shown that in the elderly, consumption of high dietary AGEs is associated with a faster rate of cognitive decline (Cai et al ., 2014).…”