Article about glycosylation

I happened upon this article, and I thought I’d share it. It’s an older article, and it’s hardly a research study, but I think it presents the A1c and glycosylation in a way I hadn’t seen before.

"The glycosylation of hemoglobin is benign. It does nothing to hemoglobin’s ability to carry oxygen. However, that cannot be said for other proteins. Indeed, glycosylation has been directly implicated in the development of several diabetic complications. Glycosylation in and of itself is not the problem. Many proteins are glycosylated by enzymatic reactions and the various sugar chains placed on the surface of a protein plays an essential role in that protein’s function. Rather, it is the specific properties of this non-enzymatic attachment of glucose that appears to be pathological. Each of these proteins can undergo cyclization and rearrangement or crosslinking to create something called an advanced glycosylation end product (AGE).

AGEs can directly affect tissue flexibility by accumulating in extracellular matrix. The stiffening of tissues leads to decreased kidney function as well as an increased work load for the heart. The crosslinked sugars trap plasma proteins and low-density lipoproteins (LDL) leading to atherosclerosis."

There’s a whole bunch more that is super interesting. I highly recommend reading it. He mentions some clinical trials at the end that I’ll try to find.


Thanks @Katers87

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Really interesting article. Thanks for posting that!

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Despite his assertion, there don’t appear to have been many studies/trials that actually studied the effects of blocking AGE-RAGE interactions. I’m still looking, but the research article below appears to summarize the progress made so far. It’s fairly recent, published in 2017.

It describes some developments of RAGE inhibitors, but I didn’t really understand most of that portion of the write-up. I could follow most of the background, but the description of the inhibitors kind of looks like gibberish to me. I think the conclusion is that while there have been human clinical trials, they have not yet established any effective RAGE inhibitor treatments for humans. There is one study underway for people with mild alzheimers at a low inhibitor dose that appears to be promising, but it’s not yet complete. High doses were either ineffective or harmful.

It’d be nice to see more research on this.


This article is a bit easier to follow:

“In addition, tomato paste strongly suppressed AGE formation chiefly due to one of its antioxidant components, rutin.”

Good thing I eat lots of tomatoes :smile:

Conclusion: “However, synthetic AGE inhibitors might not be suitable to be further developed as drugs since they may induce adverse effects during clinical trials. Moreover, the complicated process for their synthesis is time-consuming and expensive. For this consideration, more and more attention has been paid to plant-derived polyphenolic compounds with a hope to identify potent antiglycative agents. The antiglycative activities of natural inhibitors were proven to be concentration-dependent and have a positive relationship with their respective antioxidant activities in most cases. For certain natural AGE inhibitors, abilities to scavenge reactive intermediate carbonyls during glycation also contribute to their suppression of AGE formation. To sum up, AGE inhibitors from natural products with relatively low toxicity are more promising candidates for the development of functional additives, nutraceuticals and even drugs for the treatment of diabetic complications and other AGE-asscociated diseases.”

I might take a more in-depth look at some of the promising natural AGE inhibitors. I wonder if Food & Function is a reputable journal. It’s produced by the Royal Society of Chemistry which seems reputable enough. Seems strange that doctors haven’t ever mentioned this AGE-RAGE stuff before though.

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This article suggests, “It is reasonable to consider that good glycemic control, incombination with a careful diet in terms of reduced AGE consumption and increased inhibitors of glycation from food sources should be among the new goals for optimal management of diabetic patients.”

It’s fascinating to me that I’ve never even heard of this. Maybe everyone else has, and I just missed it somehow.

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Apparently this was studied thoroughly in the Joslin medalist study. I’ve seen that data before, but I didn’t really understand what an AGE was then (not that I understand it that well now). I’m mostly just pasting this here for my own benefit because I don’t think anyone is reading this thread anymore. This seems pretty important to me though.

"Complication associations with AGEs
Given the lack of correlation between current HbA1c and complications, we assessed markers of long-term glycemic control in the Medalists by evaluating the early glycation product fructose-lysine/fructosamine and AGE concentrations including CEL, an AGE derived from methylglyoxal; pentosidine, a glycoxidation product; and CML, a glycoxidation and advanced lipoxidation product. CEL and fructose-lysine CML were significantly elevated in the Medalists as compared with nondiabetic, age-matched control subjects (n = 23, mean age 67.7 years) (Supplementary Table 3).

A combined biomarker of CEL and pentosidine was highly associated with complication status. Subjects with both CEL and pentosidine ≥median levels (“high CEL and pentosidine”: CEL ≥5.3 μmol/mol lysine and pentosidine ≥1.0 pmol/mg protein) were the most likely to have any complication (P = 0.001) or suffer from nephropathy (P = 0.007), neuropathy (P = 0.005), or cardiovascular disease (P = 0.002). Subjects with either CEL or pentosidine (but not both) at or above the median had an intermediate risk of severe complications, and subjects with both CEL and pentosidine below the median had the lowest complication risk. The odds of complications in Medalists with high CEL and pentosidine as compared with those with low CEL and pentosidine were 7.2-fold for any complication, 1.3-fold for retinopathy, 3.1-fold for nephropathy, 2.5-fold for neuropathy, and 2.3-fold for cardiovascular disease (Fig. 3A).

The relationship between current AGE concentrations and risk of progression to PDR was examined in Medalists with longitudinal follow-up. Increased risk of PDR was seen in subjects with high CEL and pentosidine as compared with the rest of the cohort (P = 0.05) (Fig. 3B). A combination biomarker that also included CML and fructose-lysine segmented by median (“low CML and fructose-lysine”: CML <59.8 and fructose-lysine <1,004 μmol/mol lysine) was even more strongly associated with PDR outcome (P = 0.02) (Fig. 3C). None of the four subjects with low CEL and pentosidine (CEL and pentosidine levels below the median) and high CML and fructose-lysine (CML and fructose-lysine levels above the median) progressed to PDR over the course of follow-up. Conversely, five of seven subjects with high CEL and pentosidine and low CML and fructose-lysine progressed to PDR."

Looks like the key is to lower the CEL and pentosidine.

Despite my certainty that no one else is reading this thread I’m going to now connect the “Naturally occurring inhibitors against the formation of advanced glycation end-products” article with the Joslin Study. The article says this about pentosidine and methylglyoxal/MGO (in the medalist study, CEL was defined as: “an AGE derived from methylglyoxal”):

"AGEs can be formed both in vivo through normal metabolism and in vitro by heating sugars together with fats or proteins.7 So far, more than a dozen of AGEs have been determined in different tissues.6 For examples, pyrraline was reported to be detected in brain tissue from patients with Alzheimer disease.33 Levels of both CML and pentosidine have been shown to increase in the skin collagen of diabetic patients.34,35 GOLD and MOLD were identified as major Maillard reaction cross-links in lens proteins and their concentrations were elevated with age.36 Meanwhile, AGEs were also reported to be determined in food matrixes. Dietary AGEs such as CML, pentosidine and pyralline, were commonly observed in bakery products and milk.37–39 As a common AGE marker, the highest levels of CML were found in foods with a high content of fats including roasted almonds, butters, olive oil and meats,40 but were also present in cola where pentosindine, GOLD and MOLD were determined as well.38 Whatever condition it is, the formation of AGEs is influenced by several factors, like sugar concentration, chemical structure, turnover rate of targeted protein and the degree of oxidative stress in the environment.41–44

“On the other hand, MGO-induced chemical modification of proteins76 may have a significant impact on the functions of proteins. More and more evidence showed that the majority of the methylglyoxal present in vivo was bound to biological ligands84 and some research studies have pointed out that glycation caused by MGO could inactivate key cellular enzymes including glyceraldehyde-3-phophate dehydrogenase, glutathione reductase and lactate dehydrogenase,85 impair the activity of ribonuclease A,86 and lead to the loss of albumin antioxidant capacity.87 As proteins play important biological roles in both intracellular and extracellular activities, MGO-associated modification of proteins could also interfere with relevant cellular pathways and affect cellular functionality.88,89 Thus, effects of MGO on cellular functions have been widely investigated in different cell lines. Results showed that MGO is cytotoxic and could cause apoptosis in cultured human leukemia 60 (HL60) cells and decrease the viability of Chinese hamster ovary cells.90,91 Considering the detrimental effects of MGO, several MGO scavengers, such as aminoguanidine (AG) and tenilsetam, have been used as protectors to reduce negative impacts of MGO on proteins and cellular activities in cells. It was found that both AG and tenilsetam could decrease the toxic effects of MGO on human neuroblastoma cells.92 In rat L6 myoblasts, AG could hamper MGO-associated impairment of insulin signaling pathways to some extent.93 Another recognized MGO scavenger, N-acetyl cysteine, has also been demonstrated its ability to reserve both increased MGO level and insulin resistance state in 3T3-L1 adipocytes.94 These findings may offer favorable candidates for future drug development aiming at alleviating negative effects from MGO-associated disorders. Cell line models provide a relatively rapid, simple and direct platform for evaluating effects of extraneous stimulations (compounds) on cellular functions, facilitating the downstream animal studies or clinical trials, and become a useful tool in the fields of biochemistry and medicine.”

Of course, to support my theory that tomatoes can save the world :wink::wink::

“G-rutin, a water soluble rutin glucose derivative, was tested for its in vitro antioxidant activity and tissue anti-glycative property in three body protein sources susceptible to initial and advanced glycation reactions. The findings indicated that G-rutin is a potent glycation inhibitor, especially for kidney proteins.202 Moreover, rutin and its five circulating metabolites could inhibit both fluorescent and nonfluorescent AGEs during the glycation of collagen induced by glucose in vitro. Among its metabolites, those containing vicinyl dihydroxyl groups had stronger inhibitory effects on the formation of some AGEs including pentosidine and fluorescent adducts than metabolites without vicinyl dihydroxyl groups. All the five metabolites of rutin were effective to prevent the formation of Nε-carboxymethyllysine (CML) adducts.203”

Anyway, I’ll stop rambling now… unless I find an article/study that describes any other natural inhibitors of pentosidine and CEL/MGO we could be ingesting. I do recognize that a lot of this isn’t solidly proven, and I don’t understand a lot of it. I think I’d like to though, so maybe I’ll start learning.


I don’t know any of the specifics of this article. and I am not saying there is no truth to the ideas.

But I am always super skeptical, overly skeptical I guess, of anything that seems to be a miracle food.

Yes, tomatoes are good for you. Loaded with healthy vitamins and antioxidants. I don’t question that!

But sometimes you read this stuff, and then you dig into it and you might see something like this:

(purely a contrived example, for the sake of illustration :slight_smile:)

Contributing to this study was Dr. Amari Agarwal, Associate Professor Research Institute For Endocrine Sciences at Colgate University

Dr. Agarwal was elected chairman of the Tomato Growers Farm Association board of directors in January 2014. He also served as the vice chairman from January 2009 through December 2011. Dr. Agarwal grows tomatoes in his hometown of Dalton, Texas. He is vice chairman of the Tenth District Farm Council. He is a founding member of Tomato Leaders, and serves on the boards of the Texas Agricultural Cooperative Council.

No conflict of interest was found in those contributing to the study.


Fair, but Dr. Agarwal wasn’t a part of the original research team. He helped with the summary article. The tomato study is referenced in the footnotes/references (191) as done by Kiho T1, Usui S, Hirano K, Aizawa K, Inakuma T. I don’t know anything about those people of course. If you click on them though in the link below, they appear to have done a decent number of studies that are not directly related to tomatoes :wink:

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Oh, I know, I was just making up the tomato stuff.

But my point is that with human-nature, there is always some vested interest in a study going a certain way. Just like they never let low A1C’s in a research study, because they want to show big improvements.

So you just never know what conflicts of interest exist.

That’s why I like what we are doing here. It is unbiased digging into facts.

If you turn up healthy news about tomatoes, I would eat more of them, because you have no profit motive.

(but of course, I already eat a ton of them, because I am Italian :tomato: :grinning: )
(heck, maybe that’s part of the reason my A1C’s have always been on the low side. I have no idea.)


Haha. Should’ve read that a bit closer.

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I bet @Eric secretly dislikes tomatoes and just has an agenda he’s pushing. He claims to be Italian and love tomatoes but what do we really know about @Eric? Fake news is everywhere these days. You keep posting these articles, @Katers87. I read it all. I only surface when I think I have something to contribute, something to ask, or someone to heckle if their name is @Eric. (It should be noted that I’m procrastinating helping my sons clean their room after I’ve been helping build a Lego set w 230 pages of instructions so I might be a bit punchy here.) :hugs:


It should be noted that I’m procrastinating helping my sons clean their room after I’ve been helped build a Lego set w 230 pages of instructions so I might be a bit punchy here.

Totally understand!


I am so old :older_man: :older_woman: , I am from the era when Legos did not have instructions! :grinning:


We’ve been suckered by movie marketing. My oldest is OBSESSED with Jurassic World. He’s building the huge Lego set for that movie which comes with tailored instructions.

He’s fantastic at improving upon the designs of each Lego set. He builds it “correctly” the first time to see what they were going for, then he makes it way cooler. You’d probably see eye-to-eye with him on a lot of things. :slight_smile:

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me too. I am sort of philosophically opposed to these “one and done” Lego sets. If you lose even one piece it’s basically useless, unlike original Lego, where you have endless possibilities.


The new incredibly informative study I found warns that:

"results of in vitro experiments may be misleading due to several
reasons. Most AGEs products are formed by glycooxidative mechanisms that require oxygen and are
catalyzed by traces of redox active transition metal ions [59,60]. In vitro assays for AGE formation and
inhibition cannot adequately mimic the metal ion distribution or antioxidant and detoxification
mechanisms in tissues and their various compartments. Especially, the sugar concentration and oxygen
pressure are usually much higher in the in vitro experiments than in vivo. Autooxidation of glucose
(Wolff pathway) or Schiff bases (Namiki pathway) may dominate at high glucose in vitro but not at low
glucose and high oxygen level in vivo [60].
Prevention of Protein Glycation by Natural Compounds (aka The new informative study :smiley:)
Izabela Sadowska-Bartosz 1,* and Grzegorz Bartosz 1,2

Unfortunately, I think the rutin/tomato conclusions were based on an in vitro experiment. It appears there are actually many similar rutin studies (, so maybe I’ll find one that is in vivo.

The new informative study states that, “In vitro glycation assays showed that a number of polyphenols exerted inhibitory effects on the glycation reaction. Polyphenols are the most abundant antioxidants in our diets.” Note: tomato is a polyphenol (specifically a flavonoid). Also note: I repeatedly read that there’s a correlation between a food being an antioxidant and that food being an AGE inhibitor (measured in vitro). Eating/Drinking more antioxidants may be a fairly straightforward, easy step toward inhibiting AGEs (assuming that results observed in vitro directly translate to in vivo).

“Phenolic acids are the main polyphenols made by plants…Recent investigations suggested that cinnamic acid derivatives such as ferulic acid (3-methoxy-4-hydroxycinnamic acid) and isoferulic acid (3-hydroxy-4-methoxycinnamic acid), which are the main active components of the rhizoma of Cimicifuga heracleifolia, an anti-inflammatory drug used frequently in Japanese traditional medicine, are also AGEs inhibitors [69–71]. The results obtained by Srey et al. (2010) indicated that ferulic acid effectively inhibits CML and CEL formation inmodel food systems [72].” CEL was the AGE that is lower in Medalists without complications.

This article lists some sources of Ferulic acid: (of course tomatoes are present :wink: )

"Ellagic acid is another phenolic acid that, per the new informative study, “seems to
involve, apart from inhibition of a few fluorescent AGEs, predominantly inhibition of CEL through
scavenging of the dicarbonyl compounds. Furthermore, MALDI–TOF-MS (matrix assisted laser-desorption
ionisation–time-of-flight MS) analysis confirms inhibition of the formation of CEL on lysozyme on
in vitro glycation by ellagic acid. Prevention of glycation-mediated β-sheet formation in hemoglobin
and lysozyme by ellagic acid confirm its antiglycating ability [74]. Ellagic acid is found in berries, pomegranate, apples, grapes, orange, guava and cumin.” More Tacos!!! :wink:

The new informative study states, “Carnitine was found to be an effective anti-glycating compound both in vitro and in vivo [84].” Beef is the best source of Carnitine per the NIH:

I sort of just pasted the entire next section from the new informative article below. I plan to go through and look at the sources eventually, but before looking at the sources, it’s pretty convincing that lowering intake of foods with AGEs could be a big help. Much of what is listed below is in vivo so supposedly it’s worth our time.

"Dietary AGEs constitute a significant source of AGEs in the body. AGEs formation can be rapidly
accelerated by increasing the time and degree of exposure to heat and can be introduced into the body
in heat-processed foods (E. g., pretzel sticks are a rich source of pentosidine and pyrraline)…

"It has been estimated that ca 10% of ingested immunoreactive AGEs are transported into circulation, two-thirds of which remain in the body. Exogenous AGEs are incorporated covalently in tissues, and only one third is excreted via the kidneys [88]. A significant correlation between the amount of ingested AGEs and the
plasma levels of these compounds was found in humans [89]…

"long-term consumption of AGEs in rats was found to increase the levels of fasting glucose, insulin and serum AGEs [91], and induced a dose-dependent increase in proteinuria that over time could induce renal damage [92]. In mice, reduced dietary AGEs have been found to attenuate insulin resistance, increase the prevention of diabetes and, in diabetic mice, reduce diabetic vascular and renal complications, and improve impaired wound healing [93]…

"Human studies demonstrated that intake of dietary AGEs by people with type 1 and 2 diabetes
promotes the formation of pro-inflammatory mediators, leading to tissue injury [95]…

“All these data suggest that reduction of dietary intake of AGEs and reduction or elimination of
smoking can contribute to lowering the level of AGEs in the body…”

“A study of the effect of 15 natural flavonoids :tomato::tomato::tomato: (best emoticon ever! courtesy of @Eric), stilbenes and caffeic acid oligomers pointed to significant inhibition by all the flavonoids tested, especially hesperidin, naringin, quercetin and kaempferol. Resveratrol, piceatannol, epirabdosin, lithospermic acid and lithospermic acid B had also anti-glycating activity similar to aminoguanidine [105]. However, polyphenols act also via interference with RAGE signaling; this effect may contribute to the antitumor activity of polyphenols [106] so the effects observed may be contributed by other mechanisms irrespective of inhibition of glycation.”

A few portions of this write-up contain in vivo studies, but most of the studies were in vitro. I’m going to do some more research in determining what has been tested in vivo. The new informative study lists some in vivo experiments, but it’s going to take a bit to see which are relevant. All of them are on mice, rats, or zebrafish (strangely).

I’m pretty convinced that eating lots of polyphenols could be helpful in limiting/reducing AGEs. Good news is that these are in a ton of “natural” foods, so simply eating a less processed diet could make a difference.


So you are saying that my magical pizza, Dorito, Diet coke, and Oreo diet isn’t going to work? Damn, I had such high hopes.


Pizza has tomatoes. You’re good. It cancels out everything else. At least that was my take away.


So if we had never invented farming and then food processing we would have no diseases and would live for ever just like in palaeolithic times :smile:

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