The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction

In the paper

“making free-AGEs a good marker for dietary AGE intake while plasma protein-bound AGEs better represent endogenously produced AGEs.[31]”

What the sources say

• Not checked yetcites [31]

In the paper

“Thus, the absorption of AGEs as single amino acids or dipeptides occurs more efficiently than protein-bound AGEs, evidenced by higher levels of CML in the faeces when protein-bound CML is ingested.[36]”

What the sources say

• Not checked yetcites [36]

In the paper

“Dietary AGEs are absorbed by the gastrointestinal tract to exert their effects on health with dietary and circulating free-AGEs concentrations highly correlated, [28][29][30]”

What the sources say

• Not checked yetcites [28]
• Not checked yetcites [29]
• Not checked yetcites [30]

In the paper

“AGEs are produced both naturally in the body, as part of normal metabolism, and during the cooking and processing of food with a significant proportion being absorbed in the gastrointestinal tract.”

What the sources say

• Not checked yetcites [1] source

In the paper

“Free CML is absorbed by simple diffusion, [33] with dipeptides requiring the peptide transporter 1, [34] which also transports pyrraline dipeptides.[35]”

What the sources say

• Not checked yetcites [33]
• Not checked yetcites [34]
• Not checked yetcites [35]

In the paper

“AGE modification inhibits proteolytic digestion [32,38] thus, low molecular weight AGEs are absorbed more efficiently than protein-bound AGEs.[39]”

What the sources say

• Not checked yetcites [32]
• Not checked yetcites [38]
• Not checked yetcites [39] source

In the paper

“Also, the increased presence of AGEs in collagen across eight mammalian species has been shown to be associated with reduced lifespan, indicating that AGE levels determine lifespan and rate of ageing.[14]”

What the sources say

• Not checked yetcites [14]

In the paper

“Furthermore, the Western diet not only contains large amounts of AGEs, due to high levels of food processing, but is also high in fat and sugar, particularly fructose, which increases AGE production in the body, in part, by increasing circulating glucose levels via enhanced hepatic glucose production and insulin resistance.[4]”

What the sources say

• Not checked yetcites [4] source

In the paper

“Some of the most commonly formed AGEs include the hydroimidazolones, the most prevalent of these in human tissues is formed from the interaction of methylglyoxal with arginine residues.[23]”

What the sources say

• Not checked yetcites [23]

In the paper

“Advanced glycation end products (AGEs) are a complex and heterogeneous group of protein, lipid, and DNA adducts implicated in the development of numerous chronic diseases including diabetes related complications, cardiovascular, renal, and neurodegenerative disease, and have recently also been implicated in hypothalamic inflammation and obesity.[1]”

What the sources say

• Not checked yetcites [1] source

In the paper

“Activity of the glyoxolase is upregulated in diabetes to prevent the build-up of reactive dicarbonyls thereby suppressing AGE formation.[69]”

What the sources say

• Not checked yetcites [69]

In the paper

“In contrast to CML or CEL, the hydroimidazolone MG-H1 does not require attachment to a peptide carrier to exert its effect [47] and as the MG-H1 content of foods is much higher than either CML or CEL, free MG-H1 absorbed from the diet is likely to be a significant activator of mRAGE. [27,48]”

What the sources say

• Not checked yetcites [47]
• Not checked yetcites [27]
• Not checked yetcites [48]

In the paper

“AGER1 can counteract AGE-induced oxidative stress [61,62] as well as inhibit the activation of NF-𝜅B by promoting a sirtuin1-dependent deacetylation and suppression of NF-𝜅B.[63,64]”

What the sources say

• Not checked yetcites [61]
• Not checked yetcites [62]
• Not checked yetcites [63] source
• Not checked yetcites [64]

In the paper

“AGER1 is present in almost all cells and tissues, is upregulated by AGEs and increases their uptake and removal.[18]”

What the sources say

• Not checked yetcites [18]

In the paper

“It has been estimated that around 99% of all methylglyoxal is broken down via the glyoxalase pathway [67] detailed below.”

What the sources say

• Not checked yetcites [67]

In the paper

“Nonetheless, this protective mechanism begins to fail as the concentration of AGEs increases, with high levels of AGEs leading to a downregulation of both AGER1 and sirtuin1.[64]”

What the sources say

• Not checked yetcites [64]

In the paper

“However, the mass spectrometry techniques used now give absolute concentrations for AGEs such as CML meaning that values can be compared between studies carried out using this methodology.[27,48,110]”

What the sources say

• Not checked yetcites [27]
• Not checked yetcites [48]
• Not checked yetcites [110]

In the paper

“Moreover, ROS potentiate the inflammatory response by activating NF-𝜅B, which, once activated, migrates to the nucleus and induces not only the expression of inflammatory mediators, but also upregulates RAGE, thus establishing a positive feedback loop.[55,56]”

What the sources say

• Not checked yetcites [55]
• Not checked yetcites [56]

In the paper

“Nonetheless the restriction of dietary AGEs has been associated with reductions in inflammation and an increase in vascular function in humans, [96,97]”

What the sources say

• Not checked yetcites [96] source
• Not checked yetcites [97]

In the paper

“mRAGE interacts with AGEs, such as CML, CEL, which bind to the V domain of mRAGE to trigger an immunoinflammatory response.CML and CEL can only bind to mRAGE if they are incorporated into larger peptide structures.[45,46]”

What the sources say

• Not checked yetcites [45]
• Not checked yetcites [46]

In the paper

“Indeed, apart from playing a pivotal role in diabetic complications, including cardiovascular, kidney and neurodegenerative diseases such as Alzheimer's and Parkinson's disease, AGEs have also been implicated in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM) as well as obesity.[1,18,[114][115][116][117][118]”

What the sources say

• Not checked yetcites [1,18,[114]

In the paper

“while high loads of dietary AGEs have been associated with premature cognitive decline in humans [98] and in animal models fed a high MG diet equivalent to 19 𝜇mol per day.[99]”

What the sources say

• Not checked yetcites [98]
• Not checked yetcites [99]

In the paper

“The impact of AGEs on insulin resistance in humans has also been confirmed using hyperinsulinemic-euglycemic clamps, the gold standard for the assessment of insulin sensitivity [48] with a low AGE diet inducing an improvement in insulin sensitivity compared to a diet high in AGEs, which decreases insulin sensitivity.[48]”

What the sources say

• Not checked yetcites [48]

In the paper

“PGC 1𝛼 regulates mitochondrial energy metabolism and biogenesis, thus playing a pivotal role in modulating mitochondria bioenergetics, which has been reported to be impaired in individuals affected by T2DM.[128,129]”

What the sources say

• Not checked yetcites [128] source
• Not checked yetcites [129] source

In the paper

“In these studies mice fed a high-AGE diet containing synthetic MG-BSA at 1 mg per g of diet showed a decrease in insulin receptor and IRS phosphorylation, and defective downstream activation of AKT in skeletal muscle, adipose tissue, and liver.[64]”

What the sources say

• Not checked yetcites [64]

In the paper

“In skeletal muscle, a tissue pivotal for the control of glucose homeostasis, AGEs downregulate GLUT4 and promote the activation of inflammatory pathways as well as endoplasmic reticulum stress as indicated by the upregulation of nuclear factor NF-kappa-B p50 subunit and 78 kDa glucose-regulated protein.[124]”

What the sources say

• Not checked yetcites [124]

In the paper

“Importantly, PGC 1𝛼 appears to be instrumental in this process as genes under its control are downregulated in individuals suffering from T2DM and its upregulation has also been shown to have insulin sensitizing effects in vitro as well as in animal models.[129,132,133,134]”

What the sources say

• Not checked yetcites [129] source
• Not checked yetcites [132] source
• Not checked yetcites [133]
• Not checked yetcites [134]

In the paper

“with an AGE-restricted diet improving insulin sensitivity in T2DM with a normalization of the expression of AGER1 and sir-tuin1 as well as a decrease in NF-𝜅B acetylation circulating TNF𝛼, serum AGEs, and leptin.[63]”

What the sources say

• Not checked yetcites [63] source

In the paper

“Importantly, AGEs activate both JNK as well as the IKK/NF-𝜅B signaling pathway supporting the relationship between AGEs and insulin resistance.”

In the paper

“Cell culture studies also showed that the molecular mechanism responsible for AGE-induced oxidative stress relies on increased mitochondrial ROS production as well as the activation of JNK which, in turn, activates NADPH oxidase further fueling oxidative stress.[136]”

What the sources say

• Not checked yetcites [136] source

In the paper

“Energy balance is controlled by an intricate, finely-tuned neuroendocrine system.[141,142]”

What the sources say

• Not checked yetcites [141]
• Not checked yetcites [142]

In the paper

“AGEs exert cytotoxic effect on 𝛽-cells and induce apoptosis, which may be dependent on ROS production.”

What the sources say

• Not checked yetcites [135] source

In the paper

“In addition to inflammation, the AGE-RAGE axis also triggers oxidative stress, which is associated with the development of insulin resistance.[122,123]”

What the sources say

• Not checked yetcites [122] source
• Not checked yetcites [123] source

In the paper

“AGEs, by inhibiting mitochondrial cytochrome oxidase, [137] compromise 𝛽-cell ATP synthesis capacity causing an impairment in ATP-induced shutdown of K + channels, 𝛽-cell depolarization and consequently the influx of Ca 2+ thereby preventing the exocytosis of insulin-containing granules.[138]”

What the sources say

• Not checked yetcites [137]
• Not checked yetcites [138]

In the paper

“AGEs can also activate pro-inflammatory pathways; JNK and IKK/NF-𝜅B both of which have been implicated in mediating high-fat diet induced hypothalamic insulin and leptin resistance leading to hypothalamic dysfunction.[145][146][147][148][149]”

What the sources say

• Not checked yetcites [145]
• Not checked yetcites [146]
• Not checked yetcites [147] source

In the paper

“The Western diet contains elevated levels of highly processed foods and as such represents a source of AGEs, which contributes to promoting obesity, insulin resistance, and deterioration in metabolic health.”

In the paper

“Insulin and leptin are the main anorexigenic hormones and inform the hypothalamus, particularly the arcuate nucleus of the hypothalamus (ARC), the master regulator of energy balance, about longand short-term energy status.[143,144]”

What the sources say

• Not checked yetcites [143] source
• Not checked yetcites [144]

In the paper

“The role of AGEs in promoting hypothalamic inflammation was confirmed in animals lacking RAGE and ALCAM which have an improved metabolic phenotype and decreased microglial reactivity on a high-fat diet.[1]”

What the sources say

• Not checked yetcites [1] source

In the paper

“The hypothalamus receives and integrates central and peripheral information related to the nutritional status of the individual and responds to these neural, nutritional, and hormonal cues by triggering orexigenic and anorexigenic responses in order to preserve energy homeostasis and maintain body weight within a tight range.[142]”

What the sources say

• Not checked yetcites [142]