Thursday, November 12, 2009

Methylglyoxal on Atkins... Uh oh!

OK, time for a post. Shawn forwarded this this report which is interesting on several fronts.

It includes a specific named weight loss diet in the title of the paper. They omitted the "TM" after "Atkins" but I'm sure that won't offend anyone too much. This is science after all. This is not about ketogenic diets in general, it's got a commercial title. Smells bad to me.

What did they find? Well, ketosis produces ketones and these include acetol and acetone. Acetol is a scary chemical that I know nothing about, except I probably make a bit more now than I did 10 years ago.

Acetone is just acetone and, as these clowns undoubtedly know, acetone is a prime suspect as the candidate molecule which deprives intractable epileptics of their refractory seizures. Obviously something to avoid at all costs. Buy the phenobarbitone instead, even if it doesn't work for you.

But methylglyoxal, now there's a scary chemical. Apparently:

"...beta-hydroxybutyrate, acetoacetate and its by-products acetone and acetol... are potential precursors of the glycotoxin methylglyoxal."

A glycotoxin (gasp) from ketones (extra gasp)! Skip your pasta and you will die, from a glycotoxin. Hmmmmm.

No one (with a few exceptions) doubts that methylglyoxal is Bad Stuff. It does make me wonder why our poor body manufactures it in the first place. Blood concentration certainly increases in pathological ketoacidosis, so it may not have come as a complete surprise to these seekers-after-truth that methylglyoxal is also modestly elevated in benign ketosis.

Methylglyoxal is elevated in ketosis, but the bulk is produced by glycolysis. Why should this be so?

I would just like to speculate that it might actually be related to glycerol metabolism. The glycerol produced by the breakdown of triglycerides in adipocytes is exported to be used for gluconeogenesis or burned for energy production. Glycerol is phosphorylated then dehydrogenated to give DHAP. DHAP can break down spontaneously to give methylglyoxal but, when this method of production is inadequate, metabolism simply uses the enzyme methylglyoxal synthetase to do a better job.

Apart form diet assisted suicide and any career ehancing denigration of the Atkins TM diet, is there any use for methylglyoxal in the body? Methylglyoxal is an inhibitor of glycolysis. Well, it might just be useful to inhibit glycolysis under conditions when glycerol is more freely available than usual. As in lipolysis. It looks very neat to me that a product of lipid breakdown should inhibit the process of glycolysis. I'll bet that the gene for methylglyoxal synthetase is not expressed in neurons, certainly not during ketosis.

An aside. Let's just imagine this group had found that glucose restriction in C elegans worms produced a marked increase in respiration due to the use of fat and a significant increase in the production of free radicals as a result of this. As it does. I can just see the headline:

"Increased fat metabolism might generate excess free radicals. The increase in free radicals implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program"

I guess they either would forget to mention the increased longevity in their worms or have been damned sure to have thrown out their worm colonies at two weeks of age!

Another aside. How toxic is methylglyoxal? Compared to what? How about carbon monoxide, nitric oxide or hydrogen sulphide, all essential mammalian signaling molecules that you don't want to inhale in bulk. Well you can drink methylglyoxal. What happens?

It looks like you don't die immediately. Lots of your cancer cells, many of which are glycolysis dependent, might not fare quite so well under inhibited glycolysis.

So I would concur with Beisswenger et al in their Atkins bashing paper. Choose your diet for weight loss with care. Great care.

Peter

23 comments:

Bryce said...

Don't forget that saturated fat causes insulin resistance! It must be evil.

It amazes me that these scientists can analyze complex data, and yet are incapable of looking at things in the context of the big picture.

Saturated fat causes insulin resistance - but that's a good thing as you have pointed out as it saves the glucose for the brain.

The idea of slightly increased production of a glycolisis inhibitor being produced when glycerol is anticipated to be found in greater than normal concentrations makes such perfect sense from an evolutionary stand point. God for bid the scientific community puts two and two together and makes the connections here.

Thanks for another fascinating post, Peter.

-Bryce

Don said...

Thanks for another excellent post.

"Apart form diet assisted suicide and any career ehancing denigration of the Atkins TM diet, is there any use for methylglyoxal in the body?"

If your main goal is career-enhancing denigration of the Atkins TM diet, why would you ask that?

This type of article appears to illustrate how "science" consists largely of grovelling at the feet of the dispersers of funds, shoring up their prejudices, not any attempt to figure out how things really work.

Kurt G. Harris MD said...

Hey Peter

Thanks for another great post. I'd love to see more of your thoughts on the "dangers" of ketosis, since I am in that state most of the time. Can't find much so far that scares me. Do yo think JK's concerns are valid? (no quoting the bible allowed)

Candice said...

My take-out from this ...

"Lots of your cancer cells, many of which are glycolysis dependent, might not fare quite so well under inhibited glycolysis."

A primary goal for me is to remain disease-free and then to maintain a healthy body weight so it seems once again - being in a state of ketosis is the way to achieve this.

Thanks for another enlightening post.

willismorse said...

Jimmy Moore recently did a podcast with Dr. Thomas Seyfried on the subject of calorie restricted ketogenic diets vs brain cancer and epilepsy. Dr Seyfried is of the opinion that the supposed benefits of ketogenic diets really derive from transient drops in glucose, not necessarily from the ketones themselves. For this reason, extended ad-lib ketogenic eating is just as bad as high-carb eating because gluconeogenesis will result in high glucose levels. "As I have clearly written in my articles, 'more is not better' when it comes to eating the ketogenic diet for either epilepsy or brain cancer."

He says a range of 65-75 mg/dl glucose is required to see the benefits, at least in the case of epilepsy.

Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: role of glucose and ketone bodies seems to indicate that mice fed an unrestricted ketogenic diet had more susceptibility to epileptic seizures than those fed a calorie-restricted standard diet.

Role of glucose and ketone bodies in the metabolic control of experimental brain cancer seems to say similar things in the context of brain cancer.

This chart, for instance, shows the unrestricted ketogenic diet producing a higher glucose level after 10 weeks than the unrestricted standard diet. Huh?

All sorts of question come to mind, such as how long it takes a mouse to keto-adapt, what's really in that commercial ketochow, and does this in really apply to people at all?

Also, Don, your recent entry on Dr Sandler's research on lowcarb diets and polio seems relevant. We have to stay at 100 mg/dL to get protection from infectious diseases, but we have to get below 75 mg/dL to be protected from cancer? Seems kind of hard to reconcile.

ET said...

During the last six months, I donated blood twice, and as an enticement for donating blood, my non-fasting blood glucose was measured prior to the donation. One one occassion it was 84 and the other time 91. Hard for me to believe that frequent feedings of fat raises my blood glucose much at all.

The phrase "extended ad-lib ketogenic eating is just as bad as high-carb eating because gluconeogenesis will result in high glucose levels" doesn't seem to jive with my experience.

Diana said...

I would have to agree with ET.
I am a type 2 diabetic, dx'd Jan 2009 with a fasting BG of 178, A1C of 7.2. I follow a very low carb (20 g/day average) diet, and my fasting BG is now around 100. My last A1c was 5.1 (Aug 2009). The ketogenic diet does wonders for my blood sugars!

Diana said...

Oh yeah- I eat 60-70% fat, 30% saturated.

donny said...

-----------------------------------
Methylglyoxal (MG) is a metabolite of glucose. Our previous study demonstrated an elevated MG level with an increased oxidative stress in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. Whether MG causes the generation of nitric oxide (NO) and superoxide anion (O2*-), leading to peroxynitrite (ONOO-) formation in VSMCs, was investigated in the present study. Cultured rat thoracic aortic SMCs (A-10) were treated with MG or other different agents. Oxidized DCF, reflecting H2O2 and ONOO- production, was significantly increased in a concentration- and time-dependent manner after the treatment of SMCs with MG (3-300 microM) for 45 min-18 h (n = 12). MG-increased oxidized DCF was effectively blocked by reduced glutathione or N-acetyl-l-cysteine, as well as L-NAME (p < 0.05, n = 12). Both O2*- scavenger SOD and NAD(P)H oxidase inhibitor DPI significantly decreased MG-induced oxidized DCF formation. MG significantly and concentration-dependently increased NO and O2*- generation in A-10 cells, which was significantly inhibited by L-NAME and SOD or DPI, respectively. In conclusion, MG induces significant generation of NO and O2*- in rat VSMCs, which in turn causes ONOO- formation. An elevated MG level and the consequential ROS/RNS generation would alter cellular signaling pathways, contributing to the development of different insulin resistance states such as diabetes or hypertension
------------------------------

Oh look. Methylglyoxal increases ROS generation in epithelial cells.
N-acetyl Cysteine blocks it, though. Why does this all sound so familiar?;) (No shock if it blocks glycolysis.)

Don't we need to look at glycated protein turnover, as well as formation?

Ross said...

Even if methylglyoxal is a potent anti-cancer agent, it's not harmless. It is a highly reactive compound and is the most agressive glycation reaction producer of any chemical yet known.

Glycation => AGE's => accelerated aging.

I suspect that the tiny absolute quantity of endogenous methylglyoxal whether in ketosis or not means that it's glycation effects are not very significant. But I wouldn't count on the same sort of insignificant effect if you're downing pharmacologically significant doses orally.

Theo Tiefwald said...

Just passing along a news story:

"High-carb diets may put dieters in better moods" - Both groups lost a significant amount of weight -- about 30 pounds. In the early weeks of the study both groups showed an improvement in mood. However, over time that changed. Mood improvements remained in the high-carb group but went back to original levels for the low-carb group. - http://latimesblogs.latimes.com/booster_shots/2009/11/highcarb-diets-may-put-dieters-in-better-moods.html

Bryce said...

Weird,

You mean the people who kept getting their opiate fix from all of those carbs remained in an elevated mood?

Give it time. That mood will become chronic depression for a good portion of them.

westie said...

Hello Peter, very convenient timing for this post! :)

Methylglyoxal forms harmful AGEs but it also seems to have more complex role in the cells. In hyperglycemia it seems to kill normal healthy cells but in "normoglycemia hyperglycolytic states" it kills forming cancer cells. That happens only when glycolysis leads to increased MG concentration and if it doesn't we have a tumour.

In carcinogenesis too little MG is bad news and atleast some plant derived polyphenols may act as a anticarcinogenic substances through inhibiting MG clearance and thus letting MG concentration to increase. Increasing MG effects intracellular ATP levels which may activate respiration. After that abnormal cell will be thrown in the waste basket. Very interesting stuff.

blogblog said...

It is no coincidence that severe lack of appetite is one of the most common cancer symptoms. This is natures way of killing cancers - starvation-induced ketosis.

Dr William Colley combined starvation and immunogenic fevers with a great deal of success as a cancer treatment in the early 20th century.

Peter said...

Hi Kurt,

Yes, should lump all the info together. The problem is a large chunk is anecdote, ignoring religion. I'll see what I can do!

Willismorse,

Yes, I listened to the interview. It was very hard to tell where data blends in to opinion. All of us do this. But a 7 day fast would be a bit serious for me with a BMI just over 20. I got the impression that he was suggesting the SAD with an annual housekeeping fast might do it. But some of us are not on the SAD and would loose a serious amount of weight on a ketogenic fast. As with so many aspects there is just no database for humans on a weight stable near ketogenic diet...

I've posted my opinion as to why a ketogenic diet elevates FBG in some people under the physiological insulin resistance posts. I have trouble tying that in to elevated gluconeogenesis, though it's always possible. Actually the next post does need fitting in with this, as does what factors determine the body's preferred set point for glucose, which will undoubtedly be a CNS decision.

ET and Diana, yes 185mg/dl to 100mg/dl is (relatively!) easy. 100 to 86 (Berstein's target) is altogether another matter and you have to ask how necessary this is...

Ross, methylglyoxal holds no fears for those who have enjoyed tripping on IV doxrubicin and/or cysplatin. I agree it may be bad in industrial doses, and we would need other groups to look at it as a therapy, but there is some logic to its use. Most traditional chemo seems to work by inducing apoptosis in cells which cannot protect themselves from free radicals generated by the agent in use... Methylglyoxal may be different.

Glycation => AGE's => accelerated aging (expect in Naked mole-rats).

Theo and Bryce, Jenny takes this report seriously. I noticed Peter Clifton was an author and immediately thought very uncharitable thoughts about it. Seriously, Jenny does have a point, assuming there is no falsification of the data. A moderately large research group makes this difficult but not impossible to do. I will now go and wash out my mouth with soap and water. Post was titled Shazia and Dr Clifton in the index down the right.

Westie, do you have some refs there? Sounds interesting.

Blogblog, that will be Coley's toxin? I didn't know he used ketones too. The concept is interesting and the politics of why it was never adopted/investigated are as depressing as any saga of wrong decisions in medicine! He's another chap who never claimed to have a panacea, 40-60% was about his claim if I remember correctly. Barry Groves has links to this.

Peter

willismorse said...

Peter -

I tracked down some of the numbers in his papers. If I'm converting the non-US glucose levels correctly, the unrestricted ketogenic mice were seeing fasting glucose levels in excess of 200 mg/dL. I can see why he might be concerned about that.

Alan said...

for your reading pleasure....

Biochemistry (Mosc). 2009 Oct;74(10):1059-69.

Critical evaluation of toxic versus beneficial effects of methylglyoxal.

Talukdar D, Chaudhuri BS, Ray M, Ray S.

Department of Biological Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, 700032, India.

In various organisms, an array of enzymes is involved in the synthesis and breakdown of methylglyoxal. Through these enzymes, it is intimately linked to several other physiologically important metabolites, suggesting that methylglyoxal has some important role to play in the host organism. Several in vitro and in vivo studies showed that methylglyoxal acts specifically against different types of malignant cells. These studies culminated in a recent investigation to evaluate a methylglyoxal-based formulation in treating a small group of cancer patients, and the results were promising. Methylglyoxal acts against a number of pathogenic microorganisms. However, recent literature abounds with the toxic effects of methylglyoxal, which are supposed to be mediated through methylglyoxal-derived advanced glycation end products (AGE). Many diseases such as diabetes, cataract formation, hypertension, and uremia are proposed to be intimately linked with methylglyoxal-derived AGE. However methylglyoxal-derived AGE formation and subsequent pathogenesis might be a very minor event because AGE are nonspecific reaction products that are derived through the reactions of carbonyl groups of reducing sugars with amino groups present in the side chains of lysine and arginine and in terminal amino groups of proteins. Moreover, the results of some in vitro experiments with methylglyoxal under non-physiological conditions were extrapolated to the in vivo situation. Some experiments even showed contradictory results and were differently interpreted. For this reason conclusions about the potential beneficial effects of methylglyoxal have often been neglected, thus hindering the advancement of medical science and causing some confusion in fundamental understanding. Overall, the potential beneficial effects of methylglyoxal far outweigh its possible toxic role in vivo, and it should be utilized for the benefit of suffering humanity.

PMID: 19916918

Alan said...

and...

Toxicol Appl Pharmacol. 2006 Apr 1;212(1):45-58. Epub 2005 Aug 19.

In vivo assessment of toxicity and pharmacokinetics of methylglyoxal. Augmentation of the curative effect of methylglyoxal on cancer-bearing mice by ascorbic acid and creatine.

Ghosh M, Talukdar D, Ghosh S, Bhattacharyya N, Ray M, Ray S.

Department of Biological Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700 032, India.

Previous in vivo studies from several laboratories had shown remarkable curative effect of methylglyoxal on cancer-bearing animals. In contrast, most of the recent in vitro studies have assigned a toxic role for methylglyoxal. The present study was initiated with the objective to resolve whether methylglyoxal is truly toxic in vivo and to reassess its therapeutic potential. Four species of animals, both rodent and non-rodent, were treated with different doses of methylglyoxal through oral, subcutaneous and intravenous routes. Acute (treatment for only 1 day) toxicity tests had been done with mouse and rat. These animals received 2, 1 and 0.3 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. Chronic (treatment for around a month) toxicity test had been done with mouse, rat, rabbit and dog. Mouse, rat and dog received 1, 0.3 and 0.1 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. Rabbit received 0.55, 0.3 and 0.1 g of methylglyoxal/kg of body weight in a day through oral, subcutaneous and intravenous routes respectively. It had been observed that methylglyoxal had no deleterious effect on the physical and behavioral pattern of the treated animals. Fertility and teratogenecity studies were done with rats that were subjected to chronic toxicity tests. It had been observed that these animals produced healthy litters indicating no damage of the reproductive systems as well as no deleterious effect on the offspring. Studies on several biochemical and hematological parameters of methylglyoxal-treated rats and dogs and histological studies of several organs of methylglyoxal-treated mouse were performed. These studies indicated that methylglyoxal had no apparent deleterious effect on some vital organs of these animals. A detailed pharmacokinetic study was done with mouse after oral administration of methylglyoxal. The effect of methylglyoxal alone and in combination with creatine and ascorbic acid on cancer-bearing animals had been investigated by measuring the increase in life span and tumor cell growth inhibition. The results indicated that anticancer effect of methylglyoxal was significantly augmented by ascorbic acid and further augmented by ascorbic acid and creatine. Nearly 80% of the animals treated with methylglyoxal plus ascorbic acid plus creatine were completely cured and devoid of any malignant cells within the peritoneal cavity.

PMID: 16112157

Peter said...

Yes, Ray's group really think they are on to something. They won't be popular, especially if they are correct!

Peter

Nigel Kinbrum BSc(Hons)Eng said...

I was going to write a Blog post containing some random thoughts on MethylGlyoxal (MG) but a lot of those thoughts have been covered by the replies here, so I'll add them here.

My cousin works in the field of bowel cancer and as of yesterday, she hadn't heard of MG and was unaware of the Indian studies. She has now! After she did a search on PubMed, she told me that a colleague of hers (un-named) had published a study on MG & Diabetes that showed that MG was a bad thing for diabetics. A light bulb suddenly turned on in my brain.

Diabetes-UK (& ADA) dietary advice for diabetics is to eat starchy carbs at every meal, aiming to get ~50% of total Calories from carbohydrate.

As MG inhibits glycolysis in cells, uptake of Blood Glucose by cells decreases. Oh, look. Cells have become Insulin Resistant! As uptake of Blood Glucose decreases, Blood Glucose rises. Oh, look. Increased Advanced Glycation End-products! It's bleedin' obvious that, on a high-carb diet, MG is undesirable. It's a no-brainer that MG's undesirable effects diminish/vanish on a low-carb/keto diet, when you actually want cells to burn fatty acids/ketones rather than glucose.

Cheers, Nige.

Peter said...

Hi Nigel,

I would concur with this completely. If you are on a diet which requires insulin to make use of your caloric source, you need to be insulin sensitive. If you are on a diet which is not dependent on insulin you HAVE to become insulin resistant, methylgyoxal or palmitic acid do the job. I wonder if MG is a key switch in the same manner as palmitic acid?

Even on a carb based diet you need something to switch off glycolysis when you have done something stupid with bagels and your tissues can't or don't want to cope with the hyperglycaemia...

Peter

Debsk said...

I'm confused is methylglyoxal a good thing or not? I have stage one lymphocytic luekemia with a BMI of 35. I just started a ketosis diet and am considering supplementing methylglyoxal. Any input on the manuka honey? Thanks. Debbie

Peter said...

Hi Debsk,

Methylglyoxal is simply a part of normal metabolism which increases during fasting or LC eating. The fact it increases in ketosis was used to do a little Atkins bashing by some ethically challenged, grant seeking "scientists". This merely tells us something about those individuals.

There is a considerable interest in ketogenic diets per se for cancer management and most of the studies look encouraging but are far from conclusive. I don't think there is any way ketosis can be bad, but I would certainly suggest that any ketogenic diet is utterly Food based. I think it is one of the circumstances where I might think of green leave vegetables as the source of carbohydrate to absolutely limit glucose and insulin excursions. And I'd severely limit omega 6 fats at the same time.

Whether adding industrial doses of methylglyoxal is good or bad requires that you, and it will be you trying this, critically review the Indian papers and review articles. I've not looked for any other group corroborating their ideas, that needs doing too. From what I have read the results are encouraging. No one can ever have looked at the long term effects, so all bets are off there.

The manuka honey effect requires that trace plant compounds are effective chemotherapeutics in humans when carried in an assortment of sugars. I have much more time for methylglyoxal.

I realise that's not a lot of help but it's the current limit of my knowledge...

I hope you do well

Peter