Thursday, February 15, 2018

Systemic fructose is important

TLDR: Be cautious of anyone who tells you fructose metabolism is limited to the liver.

Fructose uptake by the liver is saturable. Drinking two cans of soda sweetened with high fructose corn syrup produces a peak plasma concentration 17mmol/l. Yes, 17mmol/l. On average.

Direct spectrophotometric determination of serum fructose in pancreatic cancer patients

Unfortunately the methods section makes no sense at all, so we have no idea how much fructose was actually consumed:

"In 3 of these subjects, intravenous access was obtained in an antecubital vein, and additional blood samples were taken at baseline and 15, 30, 45, 60, 90, and 120 minutes after ingestion (93 minutes) of two 75-mL cans of a proprietary soda, for determination of serum glucose and fructose concentration. Each 40-oz can of soda contained 75 g of high-fructose corn syrup, which consisted of 55% fructose and 45% glucose as constituent monosaccharides, equating to 41.25 g fructose and 33.75 g glucose, respectively".

Go figure. Two 40oz cans of soda? Some big cans there, even by USA standards!

Anyway, this is the graph they produced:

This next group seems to have managed to write an interpretable methods section but missed peak fructose levels by only sampling at 60 and 120 minutes.

Consumption of rapeseed honey leads to higher serum fructose levels compared with analogue glucose/fructose solutions

Ingesting 75g of neat fructose, as a solution, gives a blood concentration of 130mg/dl, ie they measured just over 7.0mmol/l in real units, at one hour post ingestion.

So fructose gets past the liver and will be taken up by any cells with GLUT3s on their surface. Whole body.

Like adipocytes.

This is a nice paper covering a lot of bases about how adipocytes deal with the fructose they are flooded with every time you down a couple of cans of soda. Or apple juice or.......

Metabolic fate of fructose in human adipocytes: a targeted 13C tracer fate association study

What do adipocytes do with fructose?

They don't oxidise much of it.

They don't convert much to lactate.

They do convert most of it to palmitate and a little to oleate.

They store the oleate.

They release the palmitate as FFAs.

You can't tell from the study how much this palmitate raises systemic FFAs because the study was being performed on "adipocyte-like" cells in cell culture. But, assuming that in most cases fructose would be co-ingested with glucose, you have here the classical situation of elevated free fatty acids, in combination with elevated glucose, in combination with elevated insulin.

This is my definition of metabolic syndrome. The hyperinsulinaemia will, until you become diabetic, eventually control the hyperglycaemia. It may well suppress the elevated FFAs. The glucose and FFAs will be pushed* in to any cell which will respond to insulin.

*Nothing is actually "pushed". Insulin facilitates diffusion (GLUT4s) and maintains a diffusion gradient by removing glucose to glycogen and FFAs to triglycerides.

The liver will be right in the frontline for accepting these FFAs, which should be in adipocytes, and experiencing sustained high levels of insulin (to control glycaemia) will make the hepatocytes hang on to those fatty acids. This is in addition to any intrahepatic trigycerides from fructose-driven DNL. Overall we end up with massively calorically overloaded liver cells. This is the prerequisite to hepatic steatosis and all that is then needed for the generation of inflammatory changes is a source of omega six PUFA. There is a desperate need for liver to say "no" to any more calories. It does by resisting insulin. Which it does by generating ROS. If those ROS meet linoleic acid, it's welcome to 13-HODE, 4-NHE and any other peroxide you care to dig up. These PUFA derivatives do cause insulin resistance per se (as well as 13-HODE stimulating cancer growth), but to me they are just an amplification system derived from what is already happening at the "front end" of the mitochondria... ROS generation by RET, essential to limit grossly excessive caloric ingress.



Eric said...

Hmm, this is in direct contradiction to what I learned from Rob Lustig's fructose 1.0 talk, and he supposedly verified it with the leading expert in the field. I believe his words were that fructose gets metabolized in the liver only, unlike ethanol, 20% of which get metabolized in other cells (such as brain...). Well, science moves on!

Now why do I experience a craving for fruit juice only and just about only after a good workout? If a yummy fruit juice is not available, gummi bears or wine will do. Normally I can do without all three. Is there a fructose depot that needs to be replenished?

Peter said...

Eric, I dunno. But 17mmol/l is what was measured. That's a LOT of millimoles.


valerie said...

In the first study, my understanding is that the subjecs drank two 75 mL cans of soda. 75 mL is about 2.5 ounces. So they drank about 5 ounces. A small glass.

Then the authors describe what the content is for a 40 oz can of soda. Maybe that's the format they buy their soda, before portioning it out, and they are just too lazy to do the math for their readers.

Peter said...

valerie, perhaps. Though I wouldn't like to try and replicate the study based on the methods. I tried to see if the 40 was a typo or a decimal point misplaced, with no convincing success. Ultimately, the 60 minute mark values are comparable with the oral fructose tolerance test dose of 75g from the second study. I was worried that they really did make them drink some vast amount of fructose to get the 17mmol/l in peripheral blood and it might be irrelevant to real life. In the second study 75g of neat fructose does seems quite a lot all, in one go, but it seems a plausible occasional consumption for some of the subgroups of the general population mentioned elsewhere in the paper...


Eric said...

Valerie, in my science and engineering experience, Americans sometimes just lack the gut feeling about SI units, so they don't always catch stupid mistakes, even if they have a solid science background. They also have annoying habits such as using an uppercase L for liter (ooops, I see you are doing it, too) or using mc for the prefix µ, and then I catch myself thinking, what the hell is micro-centi-grams until I realize its an American writing this.

Yes, 75 ml is roughly 2 1/2 fl. ounces, whereas 40 fl. ounces is nearly 1.2 l. I have seens paper or plastic cups that size at fast food outlets and parties in the US, but never cans.

Maybe someone should really ask the authors to clarify.

Eric said...

unrelated but interesting:

Apparently, they are having a real diabetes epidemic in India but without the obesity. Indians also tend to have a lot more visceral fat even if they look skinny and have a BMI well below 25. But according to the video (which by the way features a John Yudkin who happens to be the the nephew), what really drives type 2 diabetis is low birth weight due to malnourishment of the mother and low vitamin B12 levels, and kids with the lowest birth weight who made good later had the highest risk of developing T2D later on.

Eric said...

Also unrelated but interesting:

Look at the last couple of comments.

In the US, they use Intralipid for TPN which is based on soy oil and destroys people's liver within months or years. The FDA seems to be fighting tooth and nail not to approve Omegavan which is based on fish oils and does not destroy the liver.

Quite pertinent to the discussion of Omega 6 PUFA.

Peter said...

Eric, they do some really weird stuff in the states, at least it seems that way to us europeans. Omegaven is essentially free from mitochondrially targeted PUFA. Its lipid is mostly EPA and DHA, which will be shortened to fully saturated C8 in peroxisomes before the oxidation of this residual caprylic acid in mitochondria, with a decent FADH2 input to the CoQ couple. Obviously not as good as beef dripping but not as lethal as soybean oil.

It would be VERY interesting to see TPN based on linseed oil. I'm sure it would make excellent vanish.


Eric said...

Yes, linseed would save Prof. von Hagens plastifying corpses.

I can understand why they would want to supply essential fatty acids in TPN but why to they shy away from supplying other free fatty acids which do in fact occur physiologically. They are not packaged so 60% of calories maybe isn't a good idea, but does it have to be nearly 100% sugar?

Interestingly, intralipids is also used outside of TPN for its immunosuppressive properties.

Peter said...

I had a hunt around at alpha linoleic acid based TPN but there's not much published and people are being very careful not to look at the liver content of lipid under this fat emulsion. The omega 3s still have a holy reputation to be preserved......


Oh, just read the Roarofwolverine links. Sigh...... Not pretty.

Eric said...

Yes, not pretty. Wolverine's web page is a rabbithole to get lost in for a day easily. It contains plenty of rants but also incredible insights about medical thruths vs. medical reality.

Poor guy is battling multiple myeloma now which he credits to two tours of Campath that his doctors prescribed "preemtively" because one could not wait for 48 h for the pathology results to come back to confirm rejection. Unbelievably, he later learned it was possible to get results in 3-4 h in the same hospital if the doctor deigned to put an urgent sticker on the job.

Monica said...

Is Wolverine still alive though? His last article was written in spring 2014, and his last reply to a comment in the fall 2016. Another comment written in 2017 is left unanswered.

Eric said...

Monica, there are replies from April of 2017 in the second link. I believe he was also posting in summer.

Unknown said...

Mitochondrially targeted PUFA... Peter, would you be so kind as to expand that a bit?

Tangentially, I've been thinking about MitoQ, having seen it in some clinical trials. Does anyone else find the idea of replacing a key component of the ETC with a new,improved alternative sort of weird?

Peter said...

HI Robert,

Dr Speijer is a researcher who thinks about LECA, Last Eukaryote Common Ancestor. I integrated his ideas about FADH2:NADH ratio and peroxisomes vs mitochondria in to the Protons thread at This essay by Dr S was my introduction and I see from Pubmed that he is still actively promoting follow on ideas which I really need to read!


Yes, MitoQ will be amazing if it is as good as it sounds..... Needless to say there are a lot of questions about what it would do OUTSIDE of a lab rat cage!

Passthecream said...

MitoqQ sounds a bit like ---> there's an Ikea table kit in a flatpack, just squirt some superglue in there and it'll all come together properly.

Could varnish it with linoleic acid afterwards I suppose. There actually is a wood polishing method that uses linseed oil and superglue!

E-S said...


This is off-topic with regards to PUFA, but might interest you for its Protons implications.

So we already know cancer is very much a disease of cellular respiration:

And Laurent Schwartz recently hinted that osmotic pressure from glucose onto the mitochondrial membrane can be shown (or made ?) to cause the full Warburg effect and turn a healthy cell into a cancerous one. He says inflamation and chloride dioxyde play a major role in this, but he's keeping the details and publications under wrap until their 11th of March presentation in France:

Sorry if you already know about all this, feel free to delete...

Gyan said...

Defatted soy chunks are popular among vegetarians in India. They actually have a very favorable protein to carb ratio.

I don't quite understand why it should be necessary to supply a great deal of essential fatty acids to adults. What happens if this "essential nutrient" is not supplied?

Peter said...

Defatted soy chunks. Mmmmmmmm, yumee!


Eric said...

At least takes out the nasty soy oil to harm people elsewhere.

My wife picked up some pretty good tasting und not too sweet burger sauce in France, but after reading the label, I don't want to touch it: main ingredient is soy oil. Also, some pretty decent mayonaise. Main fatty ingredient is not egg, but canola oil :(

Eric said...

Have non-alcoholic beer three weeks prior to and two weeks after a marathon? Aren't we past carb loading? Beer does one thing right, it has to fructose but still too much starch for my taste.

Eric said...

meant to type no fructose

cavenewt said...

@Eric re

I read, with total fascination, this entire website years ago. It made a lasting impression on me. If I ever need TPN, gawd forbid, I'm going to Europe. Another tip: avoid any medical treatment in Florida. A friend of mine who edits medical textbooks (Pathophysiology) confirmed this bit of advice.

I especially remember the comment that the high level of sugar will destroy your veins within six months. This could be important for other people, such as those who get regular infusions of immunoglobulin; some brands are stabilized in glucose. Yikes.
@Gyan "I don't quite understand why it should be necessary to supply a great deal of essential fatty acids to adults."

Because...they're essential? Essential means we can't make them ourselves.

"What happens if this "essential nutrient" is not supplied?" You get sick!

Perhaps your question was ironic, in which case, my bad.

Unknown said...

There are several brands available on Amazon and in stores in the US. Probably not flying off shelves, patented and $$, but there it is.

Gyan said...

You get sick but with what sickness?
What does essential fatty acid deficiency look like?
I know DHA is essential to infants for eyes and brain but why are omega-6 fats essential in adults?

raphi said...

i just saw this post of your now, glad I didn't miss it entirely.

My podcast co-host Gabor Erdosi and I have been talking about how fructose can wreck metabolic.

1) Fructose can mess with adipocyte differentiation. From there it's easy to speculate about how this can then result in hyperplasia and hypertrophy, with more insulin sensitive fat cells sending a 'call' for more food to fill 'em up.
2) Fructose seems to mess with the adipocyte's cytoskeletal network. GLUT4 requires proper F-actin guidance which, maybe, fructose interferes with. If this is the case, maybe this is what stops proper glucose uptake but excessive lipolytic release of FFAs towards ectopic invasion

just some thoughts

raphi said...

regarding the fructose-cytoskeleton-GLUT4 thingy, here's part of the rationale "aldolase functions as a scaffolding protein for GLUT4 and that glucose metabolism may provide a negative feedback signal for the regulation of glucose transport by insulin"

raphi said...

oooppss forgot to link to a podcast i did with Gabor on study where monkeys were fed lots of fructose (show notes available for those who don't have the time to listen)

study <> Bremer et al. 2011

“the animals showed a progressive decrease in fat oxidation throughout the study period" and didn't do so by increasing their calories (gasp! shock! awe!)

PS: don't mind the comments regarding fructose being seen as hepatocentric

Peter said...

Interesting stuff raphi.

cavenewt said...

@Gyan said

"You get sick but with what sickness?
What does essential fatty acid deficiency look like?
I know DHA is essential to infants for eyes and brain but why are omega-6 fats essential in adults?"

I can't answer that. I only know that some fatty acids are considered essential because we can't make them ourselves, like there are some essential amino acids. Perhaps google will help.

Unknown said...

Another reason to be cautious of anyone who tells you fructose metabolism is limited to the liver: fructose is first cleared by the small intestine, so fructose only really reaches the liver after the small intestine has been saturated.

Also fructose malabsorption appears pretty common:

Peter said...

Yes, I think that when at a public health message, which may be correct, becomes unconcerned about the truth it then becomes a political slogan rather than a scientific statement. As always, be careful when you see a politician's lips move....


karl said...

What has always amazed me it that it was well established a long time ago that fructose spiked Trygly - yet the cholesterol=bad folks didn't pick up on it ( Trygly is associated with CAD ) instead focusing on LDL.

see - there are a set of links to work on chemically defined diets.. such work seems missing in action today.

Peter said...

Karl, I do wonder how much of this blindness goes back to Keys and his biases, bullying and general unconcern with the truth. You just have to PubMed his publications through the 60s and 70s to see what a driving force he was. Right over the metabolic cliff from the 70s onwards. It's hard to be understanding with Keys. Or the more you understand, the less you like his legacy...


cfmorais said...

Moderate doses of fructose and small intestine?