Methylglyoxal Revisited

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Methylglyoxal Revisited


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Old 05-28-2012, 10:10   #1
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Default Methylglyoxal Revisited

I am including a post of mine from another forum. I hope I don't get caught by some spam filter for "cross-posting" but this issue is so important that I feel it needs to be posted.

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History

A while back (a year or two, I believe) a study in Canada observed a direct role for methylglyoxal in causing both insulin resistance and beta cell dysfunction - i.e., DIABETES. This was a DIRECT measurement/observation, not an "observational" study or a statistical analysis. MG has a few sources in the body but overwhelmingly its source is the processing of glucose in the cells for energy where it is converted to ATP. MG exists both within cells (intracellular) and in circulation. Amazingly, they got the "sensational" headline right for a change and it was something like "High carbohydrate consumption causal of diabetes".

Needless to say, this created a bit of a stir. Shortly thereafter an article appeared EVERYWHERE about how the Atkins Diet (they actually mentioned it by name) causes increased methylglyoxal. What they obfuscated is that LC/HF causes an increase in SERUM MG (a good thing, overall) where the original findings of causing diabetes onset, its progression and its complications were about INTRACELLULAR MG. Peter tore that a new one here.

Next, lots of posters on diabetic forums - those not terribly enamoured of high-fat diets - began pooh-poohing the whole thing saying that MG is not bad or not "toxic" just look! It's being researched as a cancer cure (to which they posted lots of links)! Once again confusing serum MG with intracellular MG which completely invalidated their point.

I have seen many people speculating that T1 and T2 may really be just variants of the same underlying disorder. I never believed that and clung to the belief that T1 was strictly auto-immune causing the total destruction of beta cels where T2 was a slower degradation process aggravated by a glucose-heavy diet. The new findings regarding MG could also explain why more and more T1s seem to be developing insulin resistance after years of using exogenous insulin to push glucose into their cells.

Findings

The findings are getting more and more amazing. Unfortunately, all the good stuff requires paid subscriptions so I'm stuck with abstracts, but even these tell a lot.

MG is an extremely dangerous agent of oxidation which direclty results from glucose metabolism. I speculated long ago (after the Canadian research was published) that the difference between a diabetic and non-diabetic could be:

1) we produce too much of it
2) we are more susceptible to its harmful effects, or
3) we are less able to dispose of it

When this condition prevails, the elements of diabetes follow: diminished beta cell function (to zero for T1) and the various kinds of IR. This can be later followed by the well-known complications to retina, kidneys, various neves, etc. MG has a direct role in all of this, apparently.


Quote:
Abstract

Transient or chronic hyperglycaemia increases the formation of intracellular reactive oxygen species and aldehydes. The accumulation of reactive aldehydes is implicated in the development of diabetic complications. Methylglyoxal, a glucose dependent α-dicarbonyl might be the most important reactive aldehyde in diabetes and its complications. Diabetes was the first disease in which evidence emerged for the increased formation of methylglyoxal in the cells and in the serum. Methylglyoxal has a toxic effect on insulin secretion from pancreatic beta-cells, and on modifications of proteins and nucleic acids. Moreover, methylglyoxal is one of the major precursors of advanced glycation end-products. The glyoxalase enzyme system that exists in all mammalian cells is catalyzing the detoxification of methylglyoxal. This review summarizes the methylglyoxal metabolism in normoglycaemic and hyperglycamic conditions and the role of methylglyoxal in the development of late diabetic microvascular complications.
(Link)

The above talks about hyperglycemia, but MG can do its dirt without hyperglycemia. So, as long as one who is pre-disposed is metabolizing glucose, harmful MG is being produced in the cells. This is how metabolic syndrome can progress for years to diabetes before there is ever any hyperglycemia. This is also how diabetics (T1 OR T2) who have completely "controlled" blood sugar can still get complications.

Most amazing of all, this is IN COMMON between T1s and T2s. It seems highly plausible that T1s just have a much higher and more quickly "lethal" dose of MG which completley obliterates insulin production while T2s have a slower steady MG problem which causes the more gradual onset of T2. (And, it turns out they DO - see below!) Here it it:


Quote:
Abstract

AIMS/HYPOTHESIS:

We hypothesised that diabetic patients would differ from those without diabetes in regard to the handling of glucose-derived reactive metabolites, evidenced by triosephosphate intermediates (TP(INT)) and methylglyoxal (MG), irrespective of the type of diabetes, plasma glucose level or HbA(1c) value.
METHODS:

To test this hypothesis, erythrocytes were isolated from patients with type 1 (n = 12) and type 2 (n = 12) diabetes with varying blood glucose and HbA(1c) levels. These were then compared with erythrocytes isolated from individuals without diabetes (n = 10), with respect to MG, as determined by HPLC, and TP(INT), as determined by endpoint enzymatic assays.
RESULTS:

The concentrations of intracellular TP(INT) and MG were significantly elevated in erythrocytes from diabetic patients. Normalisation of either TP(INT) or MG to intracellular glucose concentration (nmol glucose/mgHb) confirmed that erythrocytes from diabetic patients accumulated more reactive metabolites than did those from healthy controls.
CONCLUSIONS/INTERPRETATION:

Diabetic patients can be characterised by an increased formation of TP(INT) and MG. The 25-fold increase of MG in type 1 and the 15-fold increase in type 2 diabetes, together with a several-fold increase in TP(INT) and decreased glyceraldehyde-3-phosphate dehydrogenase activity even under normal glucose conditions, imply that normalising glucose level cannot completely prevent late diabetic complications until this acquired error of metabolism has been restored.
(Emphasis added. Link)

Translation: dibetics have hugely increased amounts of MG and decreases in the enzymatic process which de-toxifies it (within cells). This condition is much more severe in T1s than in T2s.

Did you get that last part? Completely controlling blood sugar levels is not enough to prevent complications. "Eat to your meter" while much better than the "binge and medicate" approach does not address the matter in a comprehensive manner. BLOOD SUGAR CONTROL EVEN IF PERFECT IS NOT ENOUGH. Clearly, as we each look for what "works" we need a more comprehensive definition of what "works" means!

So, what does this mean for treatment? Well, as I see it there are two choices. 1) Find a way to repair the "acquired error of metabolism" mentioned in that last abstract, or 2) Metabolize a LOT less glucose and thereby produce less MG and hopefully diminish or eliminate the harm. This is where we should be thankful that ketosis exists. It IS actually possible to wean 95% of your cells basically OFF glucose and train them to derive their energy from FFAs and ketones instead. Neither of these alternative energy pathways produce methylglyoxal.

Number 1) would be nice, but I'm not holding my breath. Meanwhile, it seems clear that number 2) is the most and best we can do for now. Of course, the big money will ONLY focus on 1) and continue to oppose 2) as a threat to forecasted profits should they solve the puzzle. My hope is that those of us who pursue 2) won't even need 1) even if they eventually succeed and get their patent.

This issue is NOT elevated serum glucose. Which makes sense because a) this symptom only appears very late in the game and 2) even complete control of this symptom appears not to prevent EITHER progression or complications. Getting the glucose out of circulation and accepted by the cells via exercise, insulin, medications to reduce IR or any other means is hardly a solution - it only increases intracellular MG production, advancing the disease and its complcations (in spite of joyful meter readings). Insulin resistance as DEFENSE MECHANISM not disease attempting to protect your cells from further poisoning with MG. Fighting it is NOT a good idea.

Clearly, elevated BG is worse than normal BG, but the real issue here is the sum total of glucose being USED. Therefore, I have made this my focus: take all steps possible to reduce glucose utilization all around while maintaining good health via its alternatives at the cellular level. BG readings are secondary. Mine are actually slightly higher (at least moring reading) when I'm doing my best at minimizing glucose than they are when I "slip" a little.

Food for thought (pun intended).

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Old 05-28-2012, 12:01   #2
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Food for thought indeed. I'm going to re-read this in the morning, not having much brain function left after three phone calls to the Australian Tax Office call centre late this afternoon (thank God for the third operator I spoke to). And I'm ketogenic. I'd hate to have tried what I did today before my diabetic diagnosis.

 
Old 05-28-2012, 13:36   #3
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Promising stuff!

Thanks for posting. Give me a couple weeks to think about this -- especially in relation to IUGR and the prenatal environment .... hmmmmm ....

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Old 05-28-2012, 14:58   #4
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Well according the conclusion, we need to minimize glucose production or carb consumption, and I have found that I must virtually eliminate carbs to approach normal bg levels, staying in ketosis continually. This sounds like the best we can do?

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Old 05-28-2012, 15:44   #5
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Quote:
Originally Posted by frankly View Post
Well according the conclusion, we need to minimize glucose production or carb consumption, and I have found that I must virtually eliminate carbs to approach normal bg levels, staying in ketosis continually. This sounds like the best we can do?
That's the way it looks to me..... so far. I think until you replace glucose as the main energy source at the cellular level you haven't really touched the fundamental problem. Only ketosis can do that as far as I know.

It seems you can definitely reduce the harm and/or slow it down by just making enough changes to get BG down, but as long as cells are still getting all their energy from glucose and therefore making more MG than we can effectively de-toxify, the harm will continue.

It appears the two are the same in your case since reducing carbs to the point of acceptable BG takes you to the levels which produce ketosis.

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A1C 11/2010: 5.1 (DX + 14 months)
A1C 9/2011: 5.6 (DX + 2 years)
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Old 05-28-2012, 16:19   #6
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Is it possible to tell from the abstracts what was the range of blood glucose and A1c in the diabetic vs. non-diabetics?

While I am bought into the concept of total glucose metabolized being more important than total blood glucose, I am curious if they were comparing "well controlled" diabetics to non-diabetics or diabetics like many of us with non-diabetic blood sugars to non-diabetics.

So often they will call someone "well controlled" that to us really isn't. Though even if they used diabetics with non-diabetic numbers**, I would not be surprised that even they have elevated MG.

** I need a better, shorter term for this.

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Old 05-28-2012, 16:26   #7
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Would it be wrong to assume that even if in ketosis glucose coming from processing excess protein would be a contributor the same as glucose from carbs?

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Old 05-28-2012, 16:54   #8
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Mbuster, look for the ketogenic ratio posts! SMorgan gave us a formula, for keeping in ratio, and it includes some protein restriction. I cut my protein intake in half after reading it!

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Old 05-28-2012, 17:20   #9
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I'll need more time to get this read thoroughly - I started out reading it aloud to OWC - and it sure looks as though ketogenic is the best answer we can get right now. If people could just get through their heads that it isn't an unsustainable WOE. In fact, it may be easier that many. If I can do it, anybody can.




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Old 05-28-2012, 17:53   #10
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Quote:
Originally Posted by foxl
Mbuster, look for the ketogenic ratio posts! SMorgan gave us a formula, for keeping in ratio, and it includes some protein restriction. I cut my protein intake in half after reading it!
I have a hard time just eating 6-8 ounces of a 20 ounce rib-eye. Don't have the appetite to triple up on more food (fats) to keep the ratio right. Will be interesting to see if I can exercise portion control.

Curious if being in ketosis covers intracellular MG. gotta read more about this. When in ketosis, and there is an increase in BG, what directs which cells use it?

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