Ketosis, Methylglyoxal, and AGEs

[Jeremy Shepard]

Robb, you seem to have done a significant amount of reading on ketosis. What is your current opinion regarding increased levels of methylglyoxal during ketosis? While we're at it, what is your feeling toward AGEs in general with regard to aging?


Ann N Y Acad Sci. 2005 Jun;1043:201-10.
Ketosis leads to increased methylglyoxal production on the Atkins diet.
Beisswenger BG, Delucia EM, Lapoint N, Sanford RJ, Beisswenger PJ.

Dartmouth Medical School, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA. paul.j.beisswenger@dartmouth.edu

In the popular and widely used Atkins diet, the body burns fat as its main fuel. This process produces ketosis and hence increased levels of beta-hydroxybutyrate (BOB) acetoacetate (AcAc) and its by-products acetone and acetol. These products are potential precursors of the glycotoxin methylglyoxal. Since methylglyoxal and its byproducts are recognized as a significant cause of blood vessel and tissue damage, we measured methylglyoxal, acetone, and acetol in subjects on the Atkins diet. We found that by 14-28 days, methylghyoxal levels rose 1.67-fold (P = 0.039) and acetol and acetone levels increased 2.7- and 6.12-fold, respectively (P = 0.012 and 0.028). Samples from subjects with ketosis showed even greater increases in methylglyoxal (2.12-fold), as well as acetol and acetone, which increased 4.19- and 7.9-fold, respectively; while no changes were seen in samples from noncompliant, nonketotic subjects. The increase in methylglyoxal implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program.

PMID: 16037240 [PubMed - indexed for MEDLINE]

[Robb Wolf]

Jeremy-
I've wondered about that. In general ketones are more reactive then aldehydes and alcohols. This explains some of the increased AGE production from fructose, a ketone sugar, vs glucose, an aldehyde sugar.

I'm curious if there are repair mechanisms that ameliorate the effects...

Now here is a nice piece form wikipedia (http://en.wikipedia.org/wiki/Methylglyoxal). It appears the main source of methylglyoxal formation, according to that article at least, is GLYCOLYSIS gone wrong.

then this article:
http://diabetes.diabetesjournals.org/cgi/content/abstract/48/1/198
that describes decreased rates of methylglyoxal formation in diabetics who are placed on metformin. Metformin increases insulin sensitivity and tends to mitigate some of the metabolic derailing common in glycolysis, especially in the diabetic.

Then we look here (http://www.ingentaconnect.com/content/klu/bgen/2007/00000008/00000002/00009034?crawler=true) and find that fasting is recommended as a means of decreasing methylglyoxal production, mainly due to its action on glycolysis...but fasting is a a state of ketosis!

So it looks to me that glycolysis is the main culprit in MG formation. Regarding the paper you cited it would be interesting to know the insulin sensitivity of the folks on the atkins protocol...and it would be super interesting to know EXACTLY how they implemented the protocol. Did the researchers introduce any non-glycemic load items that inhibit normal insulin sensitivity (artificial sweeteners, whey protein).

If ketosis was REALLY the issue we should see sky-high MG levels in fasting, starvation and to some degree in caloric restriction...but instead we see the opposite. This might be a good topic to email the lead author of that study and ask that question.

[Jeremy Shepard]

So it looks to me that glycolysis is the main culprit in MG formation. Regarding the paper you cited it would be interesting to know the insulin sensitivity of the folks on the atkins protocol...and it would be super interesting to know EXACTLY how they implemented the protocol. Did the researchers introduce any non-glycemic load items that inhibit normal insulin sensitivity (artificial sweeteners, whey protein).

To quote the authors:

"The highly significant relationship that was observed between acetol
and MG suggests that MG is produced directly from acetol by oxidative mechanisms. Although ketone bodies are likely to be an important source of MG, it is also possible that some MG is derived from increased triose phosphates resulting from increased production of glycerol (from accelerated triglyceride breakdown) or from lipoxidation products (from the high fat intake) undergoing degradation to MG."

The study participants were limited to >25 BMI and a fasting blood glucose of <100 mg/dL. None had been previously diagnosed as diabetic. As far as whey or artificial sweeteners, the participants were just instructed to follow the advice in Dr. Atkin's New Diet Revolution. It has been too long since I've read it to remember any mention he makes regarding that type of thing. So, typical self-reporting crap, but atleast they were tested to exclude the ones not following close enough to remain in ketosis.

I can get you the full text if you want to check it out, fairly interesting stuff.

[Robb Wolf]

Jerermy-
If you can hook me up with the full deal that would be peachy. I've been digging around on this and it does appear ketosis up regulates enzymes that deal with this problem...not so MG from glycolysis...