Methylglyoxal in insulin resistance

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When you’re insulin resistant, that is, you’ve got  metabolic syndrome, pretty much every chemical in the body is NOT QUITE RIGHT.  Some are up.  Some are down.  Few are actually at physiologically NORMAL levels.

Traditionally the focus is on the big guns.

  • Sugar
  • Insulin
  • And cholesterol

In this series, we  take a look at some of the other players.

Who they are, what they’re up to and how they’re part of the state of insulin resistance.

In this post, we feature methylglyoxal

In someone who is insulin resistant,  methylglyoxal is higher than it should be and this creates SERIOUS COMPLICATIONS.

So who/what is methylglyoxal ?

Important metabolite

It’s a metabolite and a metabolic signalling molecule.

A couple of biochemical pathways make it.

metabolic pathways making methylglyoxal

The biggest producer of methylglyoxal is glycolysis. This is , the process that splits  6 carbon sugars, such as glucose  compound, into two, three carbon compounds, referred to as trioses.

Trioses are small and nimble….

With a sticky nature

They sometimes, spontaneously do a little chemistry. It is this, chemistry, that creates methylglyoxal.  It’s estimated that around 0.05 -0.1 % of molecules going through the glycolytic process, fall apart like this, the problem with these methylglyoxals…

They’re  sticky !

the formation of methylglyoxal

They  “stick” onto lysine and arginine residues, of proteins, AGEing the proteins.  And it is quite a gadoenta, to get them off.


Cells deploy the GLOPACK

Cells have a couple of enzymes that can take care of the methylglyoxal problem, the most important is a pair of  enzymes,  GLO1 (glyoxylase I) and GLO2 (glyoxylase II). These enzymes  work sequentially,  to neutralize the methylglyoxal threat.

To give you some idea of how SERIOUS cells take this, glyoxalases make up 13 % of the protein inside of a cell.  How well yours work, depends on genetics and circumstances.

Cleaning up the stickiness

glyoxyalase chemical pathway

The methylglyoxal clean up, is a two step process.  GLO1  can grab onto the methylglyoxal, when it “reacts” with glutathione, the cell’s primary ANTI-OXIDANT.  GLO1 is able BLIND, hemithioacetal, creating S-D-lacoyGSH.  GLO2, then comes in for the “kill” and pulls the glutathione off, leaving a D-lactate behind.

The D-lactate is HARMLESS.

And in the long run, quite valuable – it can be recycled for energy.

A sticky escape

The system is set up, that when more glucose comes in, more GLO1 is made, to clean up, the methylglyoxal.

NOTE : This happens  because GLO1 expression, is triggered by insulin.

So a little extra sugar is NOT a problem…………..UP TO A POINT !

Unfortunately, EXCESS sugar, can leave cells, short of glyoxylase.  This happens,  when glycolysis speeds up a notch or two….

And this leaving methylglyoxal running amok….

Stick ups

different kinds of damage caused by methylglyoxal

Damage happens primarily INSIDE cells.

But, the damage is not always confined to inside cells, because methylglyoxal is small, it can zoot outside the cell and get up to mischief there too.

Higher plasma methylglyoxal levels are associated with heart disease and mortality.

So when does glycolysis SPEED UP ?

The sticking point

Stick ups happen…

when oxygen is in short supply and/or there is LOTS of sugar.

Unfortunately, these scenarios are very  common,  when you’re insulin resistant !

A couple of cells types are especially vulnerable, because they can’t shut the door on glucose. These include, the cells lining the blood vessels, as well as cells in the kidney, eye and nerves.

list of opathies of type 2 diabetes

These are the organs, more often than not, that break under the strain of metabolic troubles

Sugar wars

Now, you’ve heard of the war against SUGAR. Odds are, you’re in the trenches, RIGHT NOW !

Sugar spikes can be fought with lifestyle and meds.

There are quite a few different kinds of  glucose lowering meds.  They work in different ways, but most of them,  lower sugar levels IN THE BLOOD, by putting MORE SUGAR in the cells. Eish !

They’re effectively creating MORE METHYLGLYOXAL.

And the REAL ENEMY, is methylglyoxal, it’s 50 000 times, more reactive than glucose.

NOTE : What many diabetics don’t realize, is that good glycemic control, does not guarantee good health, this is probably the reason..

So, the war SHOULD BE, a war on methylglyoxal.

A new war

So, how do you go to war, against methylglyoxal ?

There are TWO options.

Make less  methylglyoxal and beef up, methylglyoxal defences.

Make less methylglyoxal

First prize…………send in less sugar, by cutting carbs,  is A NO BRAINER.

Now, the glucose that enters a cell, has a couple of options. It can be stored as glycogen, used in the pentose phosphate pathway or split, to generate energy i.e. undergo glycolysis.

a cells glucose options

Storing it, stops glycolytic flux.


Now, the amount of glucose, stored by any given cell, is finite i.e. when the cupboard is FULL, it’s FULL, so you can’t necessarily, pack MORE IN.

But, you can empty the cupboard, on a regular basis…

Empty the cupboard

This is what, a bout of vigorous exercise does. The other benefit of a little sweat, is it improves blood flow and thus oxygen delivery.


NB. The glycolysis pathway, is favoured, under circumstances, where there is less oxygen.

Unstick it

What about beefing up defences ?

GLO1 can only BLIND, methylglyoxal that has hooked up with glutathione, so adequate supplies of glutathione are an absolute necessity.

Unfortunately,  the high levels of oxidative stress, that go hand in hand, with insulin resistance, makes keeping glutathione levels,  satisfactory,  inherently challenging. I’ll cover glutathione, in an upcoming episode of the Ups and Downs of insulin resistance.

In the mean time, here are the cliff notes –  EAT MORE PROTEIN !   Glutathione is made of three amino acids, joined together.

GLO more

Fortunately, it is  relatively easy to boost GLO1 production.

As I have already mentioned, the gene has an insulin response element, so insulin turns up production.  If you’re producing truck loads of insulin, which you are, when you’re insulin resistant, you’ve got this one covered.

The other way, to boost GLO1 production,  is to take a soupçon of poison, with most meals  – this will activate the antioxidant response element, turning on the gene expression of multiple defence enzymes, including GLO1 and glutathione.

Watch this video to discover why the anti-oxidants in vegetables, are a perfect source of “good” poisons.

So eating  vegetables, is a two for one deal, too.

Cut back on those AGEs

Finally,  GLO1 should be considered a finite resource,  so give your little guys some time off.

Officially, the glyoxylase system is  designed to clean up methylglyoxal, but, it can and it does, do duty, disabling other dicarbonyls, which often arrive via dinner.

You can minimize the level of these compounds, you’re consuming, by cooking like an Italian mamma.  Use a low moist heat, with lots of tomato and lemon juice.

Methylglyoxal,  is just one of hundreds of chemicals in the body that are amiss, if you’re suffering from metabolic syndrome.  Click here, to visit the “Ups and Downs of insulin resistance” page, to learn more about some of the other players.

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Elevated Levels of the Reactive Metabolite Methylglyoxal Recapitulate Progression of Type 2 Diabetes.  Cell Metabolism (2018)  27:926–934.  Alexandra Moraru, Janica Wiederstein, Daniel Pfaff, Thomas Fleming, Aubry K. Miller, Peter Nawroth, and Aurelio A. Teleman.

Methylglyoxal, a highly reactive dicarbonyl  compound, in  diabetes, its vascular complications and other age-related diseases.  J Physiology (2020) 100(1):407-461. C.G. Schalkwijk and C.D.A. Stehouwer.

Methylglyoxal Metabolism and Aging-Related Disease: Moving from Correlation toward Causation. Trends in Endocrinology & Metabolism (2020) 31(2):81-92. Kold-Christensen and Johannsen.

Methylglyoxal-Glyoxalase 1 Balance: The Root of  Vascular Damage. Int. J. Mol. Sci. (2017) 18: 188. Cecilia Nigro, Alessia Leone, Gregory Alexander Raciti, Michele Longo, Paola Mirra, Pietro Formisano, Francesco Beguinot and Claudia Miele. 

Further reading

sugar gremlin making a women look old

Sugar addicts WILL LOOK OLD before their time

Any time you eat or drink a high carb snack, your sugar level will rise, temporarily – if this happens often enough, you’ll look old before your time

cholesterol turning sticky because of sugar

Meet the real villain in the high cholesterol saga

If you want to avoid a cardiac event you need to do more than lower LDL, you need to keep sugar levels in check as sugar turns ordinary LDL into a sticky glob

sugar spikes are personal

Getting personal about sugar spikes

The sugar spike caused by the food you eat, has very little to do with the food per se, it’s got more to do with you and who you’re living with.


Want to discover more ways to create BETTER BODY CHEMISTRY ?