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Glucose Metabolism: Glycation and Methylation

Methylation has been getting a lot of attention but it’s also important to understand how it ties in with the rest of our biochemistry.  In this post I hope to illustrate a small connection between methylation and blood sugar control, as well as the damaging effects a high sugar diet can have on the body.  When you eat sugar it gets absorbed into the bloodstream, enters the cells, and then enters the mitochondria inside the cell which acts as a furnace to burn the sugar molecule and turn it into energy.  But what happens if you eat more sugar than the cells can handle?


GLUCOSE METABOLISM:  Insulin and Fatty Liver


Glucotoxicity and Carbohydrates

Cells can only take up so much glucose.  When they get full and reach their saturation point the excess unused glucose in the blood vessels will bind to proteins locally on the blood vessel walls and in other parts of the body causing damage.  This binding of glucose to proteins is a process called GLYCATION.  Glycation of LDL cholesterol and haemoglobin are two main factors in the development of heart disease.  In fact, glycated LDL cholesterol independently stimulates the uptake of more cholesterol into the atherosclerotic plaque already attached to the blood vessel wall.  This is one way how sugar contributes to blocking blood vessels and cause heart disease.


HbA1c and Fructosamine 3-Kinase (F3K)

Having high HbA1c levels in itself however is not a risk factor for AGEs.  HbA1c is an adduct for AGEs formation but other things have to go wrong as well to make this a risk factor.  Chris Masterjohn has done a nice podcast on this.  Simply put it’s the breakdown (or deglycation) of HbA1c (or glycated Red Blood Cells) by Fructosamine 3-Kinase into glycation byproducts that becomes toxic to the cell when endogenous detoxification is not on board.  According to Chris these small aldehydes that are formed can be >20,000x more reactive than glucose and should be the focus when looking at diabetes and cardiovascular disease, rather than glucose and fructose (and thus HbA1c) directly.  One of these endogenous toxins or aldehydes is called methylglyoxal.



Methylglyoxal is not all bad and has a function in the body, so the sole purpose should not be to eliminate all methylglyoxal.  In cancer for instance the aim would be to shunt energy metabolism away from glycolysis, and glyoxal and methylglyoxal both seem to put the breaks on uncontrolled cellular replication.  However, that is beyond the scope of this article.

Methylglyoxal in excess is very cytotoxic and seems to be the major contributor in most cells to AGEs.  In fact, constant production and exposure to methylglyoxal may lead to the development of diabetes and its complications, even to the point in becoming insulin-dependent (when the pancreas has become exhausted), according to some rodent studies.  It can be produced via 3 mechanisms:

  • Glycolysis – being the main one
  • Lipid peroxidation
  • 3-aminoacetone – an intermediate of threonine metabolism

To keep it all in balance methylglyoxal is broken down in the Glyoxalase Pathway via two enzymes – Glyoxalase I and II – using Glutathione and producing D-lactate in the process.  


Glyoxylase Pathway

Glyoxylation is part of our Endogenous Detoxification which is separate from the usual Phase 1 (liver), Phase 2 (liver), Phase 3 (intestines) pathways we are more familiar with.  Endogenous Detoxification removes compounds produced inside the cells as part of the body’s normal biochemistry and metabolism.  In this case it is methylglyoxal, but also includes other aldehydes.  To do so these endogenously produced toxins need to be able to cross the cell membranes to be moved out of the cells.  Healthy cell membranes need omega 3’s and phospholipids for stability and integrity.  If cell membranes are not healthy, nutrients cannot move in and toxins cannot move out.  

The TPI (Triosephosphate isomerase) enzyme is a very efficient enzyme that works hard at keeping the balance between DHAP (Dihydroxyacetone phosphate) and GAP (D-Glyceraldehyde 3-phosphate).  When this balance is disturbed in favour of DHAP we end up with an accumulation of methylglyoxal and an increased demand for glutathione to break it down.

Modified from PNAS at www.pnas.org

Modified from PNAS at www.pnas.org


So how does glutathione and phospholipids get produced?  That’s right.  Methylation.  But before we get to methylation let’s just quickly mention another endogenous toxin responsible for AGE’s formation.  Along with methylglyoxal, 3-deoxyglucosone is another aldehyde formed during HbA1c deglycation by F3K that can contribute to AGEs formation.



Methylglyoxal is the major overall contributor to AGEs inside cells, but in the blood 3-deoxyglucosone plays a larger role.  3-deoxyglucosone is formed during the deglycation process where F3K removes HbA1c.  A diet high in fruits, vegetables and polyphenols will stimulate the detoxification of 3-deoxyglucosone and convert it into the more stable 3-deoxyfructose to be excreted out of the body.



SAMe is produced from folate, B12 and methionine via the methylation cycle.  SAMe donates large amounts of methyl-groups to PEMT for phospholipid production, and after it donates its methyl-groups to other methyltransferases it becomes homocysteine that continues down the CBS cycle with the help of Vitamin B6 to form Glutathione via GSS.  So what happens when methylation is impaired either due to nutrient deficiencies, infections or other blocks on specific enzymes?  Well lots, but low carnitine is one of them.


Low Carnitine

Carnitine is really just methylated lysine.  Lysine and methionine are the essential amino acids obtained from food, then converted to carnitine through methylation.  Carnitine transports long-chain acyl groups from fatty acids into the mitochondria of cells where they are broken down to acetyl CoA for energy (ATP) using glucose, so it enhances the disposal of glucose from cells.  Acetyl-l-carnitine seems to inhibit glycation in high glucose and fructose diets, and thus the formation of AGE’s directly.  So it has both a preventative and protective role against the formation of AGE’s.  


Low Glutathione

When glutathione is insufficient either due to poor methylation, high demand or poor recycling, it is more likely that methylglyoxal will start to accumulate.  In the presence of free lysine, arginine and cysteine thiols, methylglyoxal will form AGEs (Adanced Glycation Endproducts) which can cause all kinds of problems as per diagram and can be linked to a whole variety of chronic diseases such as diabetes, arthritis and auto-immune disease.  So what needs to go wrong?


Glycolysis Dysfunction

If we look at the top end where glucose is the starting point, it is fairly obvious that high sugar and low protein/fat diets, poor blood sugar control and diabetes can already create a higher than optimal glucose load.  Mutations of TPI or any of the other genes may also contribute.  At the bottom of the pathway we have pyruvate which has to enter the Citric Acid Cycle.  Any blocks in the Citric Acid Cycle or mitochondrial dysfunction may prevent this from happening which will cause it to back up and possibly move towards DHAP.


Glycation & Gut Health

The nerve damage incurred from AGE’s (through uncontrolled blood sugar) can glycosylate nerves along the digestive tract and interfere with motility (small intestine) and peristalsis (large intestine).  This leads to constipation or irregular bowel motions, creating an ideal environment for bacteria and other unwanted organisms to grow.  Further problems of SIBO (Small Intestinal Bacterial Overgrowth), IBS, fibromyalgia, food intolerances, auto-immune disease, etc. may follow as a result.


Insulin Signalling

Last but not least, insulin signalling is also just as important.  We need our cells to be insulin sensitive so we only produce the amount of insulin we need and not exhaust the pancreatic beta-cells.  We need the cells to respond appropriately to this insulin signal.  So making sure the pancreas is healthy and contain all the nutrients to produce and secrete insulin, and making sure insulin receptors on cells are healthy and working, is pretty important.  This is done through all the general things that you would do to treat insulin resistance.


So a diabetic with poor blood sugar control may be predisposed to higher methylglyoxal levels.  In combination with low glutathione there may be increased formation of AGE’s leading to cellular/DNA damage, LDL cholesterol oxidation and increased risk for atherosclerosis.  Apart from AGE’s, methylglyoxal can also bind directly to nerve endings and increase chronic extremity soreness in diabetic neuropathy.

It’s a great illustration how diets high in sugar (glycolysis), low in leafy greens and quality protein (methylation) can contribute to heart disease, diabetes, nerve damage and DNA damage, just to name a few.

As always, the long-term way to fix to prevent this is through a healthy organic, low sugar and antioxidant-rich Anti-inflammatory diet, or a Ketogenic diet.

If you need guidance in the treatment of this or any other condition, please make an appointment with one of our practitioners.


This article is for information purposes only.  Please refer to our Medical Disclaimer policy for more information.  The opinions expressed here represents the author’s and not necessarily those of Realize Health.  In addition, thoughts and opinions change from time to time due to updates in research and as a necessary consequence of having an open mind.  Views expressed in out-of-date posts may not be the same to those we hold today.



The association of advanced glycation end-products with glutathione status.

Potential inhibitory effects of L-carnitine supplementation on tissue advanced glycation end products in patients with hemodialysis.

Acetyl-L-carnitine decreases glycation of lens proteins:  in vitro studies.

L-carnitine inhibits protein glycation in vitro and in vivo:  evidence for a role in diabetic management.

Critical evaluation of toxic versus beneficial effects of methylglyoxal.



Author Info

Elizma Lambert

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