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Thursday 9 June 2016

Atkins, ketones, methylglyoxal and cancer

What you lose on the swings you make up for on the roundabouts.

Recently this study enjoyed a bit a revival as it was used in a presentation at a DAA meet. I'm not sure of the exact context but the Dietitians Association of Australia has been outstandingly fossilised in its attitude to low carb diets.

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.

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.

Glycation is the major cause of neurological, optic, tissue and vascular damage in diabetes. Glucose, fructose, and methylglyoxal are precursors of advanced glycation endproducts (AGEs). Glycation of proteins creates free-radical generating hotspots. Amongst other things, almost all bad, this does at least serve the function of keeping further excess substrate out of cells.

"Glycation has the potential to alter the biological structure and function of the serum albumin protein. Once it is glycated, it is less efficient for carrying long chain fatty acid.

In experimental model of adipocyte cell lines, albumin-derived AGE has been shown to trigger the generation of intracellular reactive oxygen species leading to an inhibition of glucose uptake."
Chris Masterjohn has written at length about methylglyoxal pathways here. Suffice to say that there are pathways to clear methylglyoxal, and that the effects of glycation, shown by elevated HbA1c, neuropathy, and microvascular complications have never so far as I know been reported in persons on ketogenic diets. That is, HbA1c in type 2 diabetics drops sharply on a ketogenic diet, but can rise in non-diabetics, though only within the normal range.

One reason for thinking that ketogenic diets are healthy is the Warburg effect. Otto Warburg won the Nobel Prize in 1931 for "discovery of the nature and mode of action of the respiratory enzyme". In 1924 he postulated the Warburg theory of cancer, which (according to Wikipedia) "postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria. The term Warburg effect describes the observation that cancer cells, and many cells grown in-vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis was that the Warburg effect was the root cause of cancer. The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of carcinogenesis, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen."

The ketogenic diet is proposed, and used, as a cancer therapy because it limits exposure to glucose and fructose, which cancer cells can use via the Warburg (and reverse Warburg) effect, and replaces a large part (up to half) of the glucose requirement with ketone bodies, which most tumours cannot easily use.
But what about methylglyoxal? Can cancer cells use methylglyoxal?

No. Methylglyoxal is cytotoxic, without being much of an energy substrate.
A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells. Link
 Antognelli C, Mezzasomaa L, Fettucciari K, Talesa VN.
The International Journal of Biochemistry & Cell Biology

Volume 45, Issue 4, April 2013, Pages 836–844The results suggest that this physiological compound merits investigation as a potential chemo-preventive/-therapeutic agent, in differently aggressive prostate cancers.

Here's a summary of methylglyoxal cancer research, which includes a human trial. The trial report is linked here.

Do levels of methylglyoxal on a ketogenic diet equal those used in the trial? Probably not. But a ketogenic diet both removes much of the glycolytic fuel that cancers prefer, and replaces it with ketones which they (mostly) can't use, and which is liable to turn into methylglyoxal, which is deadly poison to them.

A useful way of looking at these things is to compare cancer risk in type 1 and type 2 diabetes. Both are exposed to similar levels of excess glucose, but people with type 1 diabetes are occasionally exposed to higher ketone, and thus methylglyoxal, levels (I'm talking about the usual loose management of these conditions, not people on low carb diets).
"It turns out that the types of cancer that are elevated among type 1 diabetes patients are pretty much the same as those that are elevated among type 2 diabetes patients, and the elevation among type 1 diabetes patients is somewhat smaller than the elevation found among type 2 diabetes patients." Link

A ketogenic diet is great for making people metabolically healthy. I don't see why this would result in greater longevity compared to other people who are metabolically healthy. It's a way of catching up, not necessarily of racing ahead.

Tuesday 7 June 2016

#Context - Butter, eggs, and the epidemiology of cardiovascular disease and diabetes

When Ancel Keys started work on his hypothesis, in 1955, he reported that butter only accounted for 4.8% of fats consumed in the USA.[1] Remember that.

It’s well-known that eggs are associated with type 2 diabetes in the USA, but there’s no such association in the rest of the world, and in Finland eggs have protective association with type 2 diabetes.

“When stratified by geographic area, there was a 39% higher risk of DM (95% CI: 21%, 60%) comparing highest with lowest egg consumption in US studies (I2 = 45.4%, P = 0.089) and no elevated risk of DM with egg intake in non-US studies (RR = 0.89; 95% CI: 0.79, 1.02 using the fixed-effect model, P < 0.001 comparing US with non-US studies). In a dose-response assessment using cubic splines, elevated risk of DM was observed in US studies among people consuming ≥3 eggs/wk but not in non-US studies.”[2]

In this chart you can see that Finland is an outlier.[3] In 2 studies, egg consumption has a protective association with type 2 diabetes.

You might well ask, does this have something to do with the way eggs are consumed? In The USA, as far as I can tell from watching TV shows, eggs are mainly consumed fried and scrambled in oil, or in cakes and pancakes. They are also consumed as egg whites. They lie around in warming drawers and skillets for most of the day being reheated, too. How are eggs consumed in Finland? The internet is pretty consistent about that. In Finland eggs are hard-boiled, then mashed up with a cup of butter. Cheese might be added.

We know from the Malmö Diet and Cancer study that butter has protective associations with regard to type 2 diabetes.[4]
So what about CVD? There is only a little evidence on butter and CVD. Malmö again (probably the best quality epidemiological study to date) has no correlation, even non-significant, for a high intake of butter vs none.[5] EPIC-Netherland has a protective association for butter, HR 0.94 (0.90, 0.99).[6]
There are only 2 studies where butter is positively associated with CVD. In another Netherlands study, butter has no association with IHD mortality in men (1.0 ns) but an association in women - 1.08 (1.01, 1.15).[7]

A curious finding arises from another study in women in the Swedish Mammography Cohort.[8] “Whereas total dairy and cheese reportedly had inverse relationships with CVD risk, butter (as a spread) was associated with disease but total butter consumption was not.” This is perhaps explicable by the role of canola-based spread in Scandinavia; plausibly, people who use butter, but don’t eat fatty fish (which can be contaminated in inland parts of these countries), are missing out on supplemental omega 3. Certainly, Scandinavia is not the place to look for epidemiological evidence that canola spread is harmful (cooking oil or "margarine" is another story).

Anyway, the conclusion is "clear" – if you want to eat eggs, eat them with butter (and don't overcook them - boiling limits temperature to 100oC) -, and if you’re a woman and you want to eat butter, don’t eat bread.

[1] Keys A. Atherosclerosis and the diet. SAMJ. 1955.

[2] Djoussé L, Khawaja OA, Gaziano JM. Egg consumption and risk of type 2 diabetes: a meta-analysis of prospective studies. Am J Clin Nutr. ajcn119933.

[3] Wallin A, Forouhi NG, Wolk A, Larsson SC. Egg consumption and risk of type 2 diabetes: a prospective study and dose–response meta-analysis. Diabetologia. June 2016, Volume 59, Issue 6, pp 1204–1213

[4] Ericson, U, Hellstrand, S, Brunkwall, L, Schulz, C-A, Sonestedt, E, Wallström, P, et al. Food sources of fat may clarify the inconsistent role of dietary fat intake for incidence of type 2 diabetes. AJCN 2015;114.103010v1

[5] Sonestedt E, Wirfält E, Wallström P, Gullberg B, Orho-Melander M, Hedblad B. Dairy products and its association with incidence of cardiovascular disease: the Malmö diet and cancer cohort. Eur J Epidemiol. 2011 Aug;26(8):609-18. doi: 10.1007/s10654-011-9589-y. Epub 2011 Jun 10.

[6] Praagman J, Beulens JWJ, Alssema M et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition–Netherlands cohort. Am J Clin Nutr. ajcn122671

[7] Goldbohm RA, Chorus AM, Galindo Garre F, Schouten LJ, van den Brandt PA. Dairy consumption and 10-y total and cardiovascular mortality: a prospective cohort study in the Netherlands. Am J Clin Nutr. 2011 Mar;93(3):615-27. doi: 10.3945/ajcn.110.000430. Epub 2011 Jan 26.

[8] Patterson E, Larsson SC, Wolk A, Akesson A. Association between dairy food consumption and risk of myocardial infarction in women differs by type of dairy food. J Nutr. 2013;143:74–79. doi: 10.3945/jn.112.166330.