Sat, Sep-16-17, 05:09
Acetoacetate vs. Methylglyoxal
The body's own fat-metabolism protects against the harmful effects of sugar
Researchers have discovered that the fat-metabolism in the cells takes place simultaneously with a detoxification of the harmful substances from the blood sugar, which can avert the damage that can in turn lead to age-related diseases such as diabetes, Alzheimer's and cancer. This indicates that we have a detoxification system which we were not previously aware of.
For several years, medical researchers, doctors and dieticians have known that a low carbohydrate diet and plentiful fat can prevent a range of lifestyle and age-related diseases and thus promote healthy aging. But researchers from around the world have not been able to explain why this is the case. They have just been reasonably certain that the energy metabolism and its chemical intermediates (metabolites) play a central role.
An interdisciplinary team of researchers from Aarhus University has now found more than just an important piece of the puzzle -- a piece that suggests that the puzzle that is our metabolism looks somewhat different than science has so far believed. This is also the reason why the research group's article has made the front cover of the journal Cell Chemical Biology.
On a general level, the researchers have discovered that the fat-metabolism in the cells takes place simultaneously with a detoxification of the harmful substances from the blood sugar, which can avert the damage that can in turn lead to age-related diseases such as diabetes, Alzheimer's and cancer. This indicates that we have a detoxification system which we were not previously aware of.
The detoxification takes place in an unexpected chemical process -- unexpected because it happens without the involvement of the enzymes that science has so far focused on in understanding the metabolism and the decomposition of sugar.
The newly discovered process involves one type of metabolite, the ketone acetoacetate, which originates from the body's fat-metabolism, capturing and inhibiting another type of metabolite, methylglyoxal, which originates from the body's sugar metabolism.
The process is important because methylglyoxal is a reactive metabolite, i.e. it is toxic for the cells. It plays a major role in the above-mentioned age-related diseases. This means that untreated diabetics have increased concentrations of sugars and methylglyoxal in their blood. They also have increased amounts of ketone substances (see the fact box below).
In chemical terms, what happens in the process between the two metabolites is that a third metabolite, 3-HHD, emerges, which does not have the harmful effects of methylglyoxal. The Danish research team are the first to find 3-HHD in blood from people who lacked insulin and/or had fasted the night before -- a condition known to give ketosis.
As suggested above, the study helps to uncover new aspects of the metabolic process in living organisms.
"Previous research partly based on animal experiments using mice and monkeys shows that a diet with less sugar and more fat protects against diseases such as diabetes, Alzheimer's and cancer. At the same time, it has also been known that methylglyoxal causes age-related diseases. We have found a new metabolite that demonstrates an alternative chemical detoxification of methylglyoxal when we burn fat. It is a surprising discovery, as ketones in themselves can lead to the harmful sugar metabolite methylglyoxal. The explanation may be a delicate balance between creation and detoxification. In any case, this illustrates that biological systems are enormously complex," said Mogens Johannsen, who is professor of chemical biology at the Department of Forensic Medicine at Aarhus University and one of the leading capacities in the research partnership.
He emphasises that the study could only be carried out due to the close collaboration between the individual research groups at the Department of Chemistry, the Department of Clinical Medicine and the Department of Forensic Medicine at Aarhus University.
"It is a unique situation to take a reaction from a chemistry laboratory and use it to finally prove that it takes place in living human beings and potentially can play a role in vital biological processes," he added.
From chemistry lab to living humans
Mogens Johannsen does not doubt the value of research into the role of ketones and reactive metabolites in biological aging.
"Now we have evidence for saying that ketones can minimise the amount of harmful methylglyoxal in living organisms, and that is a discovery that gets noticed, as it involves two of the most debated substances within biological aging and late diabetic complications. Moreover, these substances react with each other," said Mogens Johannsen.
The study is relevant for developing treatments of people suffering from complications after diabetes, in particular patients with late diabetic complications such as neuropathy, which can be very painful.
"One perspective could be to follow a diet with fewer carbohydrates and more fat. The fat helps to encapsulate and destroy the sugars that cause the pain," said Mogens Johannsen. Though he also emphasised that clinical trails will be needed to establish this aspect before he would recommend particular diets.
Dr Mike touched on methylglyoxal here;
Peter at Hyperlipid;
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.