Wednesday, May 09, 2012

On GLUT5

Presentation-on-video is one of the least accessible sources of information for me. For a stack of practical reasons I don't get a lot of listening time. I made the effort the other day and got depressed. Why?

We all know hereditary fructose intolerance tends to produce death when some joker sets up an intravenous fructose infusion in the intensive therapy setting.

But why should anyone want to use IV fructose in the ITU setting? Calories. Critically ill people need calories. Lots of them. Meeting this need has been managed in many different ways over the years. Nowadays we do it through an enteral feeding tube or, if you can't get anything in through the gut, using intravenous emulsified soyabean oil (pardon the aside vomit) or emulsified MCTs (ah, that's better, let's have a few ketones in the ITU). You can't use glucose. Unless you add exogenous insulin to a glucose infusion (plus some potassium please) it just makes you hyperglycaemic and you then pee glucose out through your kidneys, especially if you are already as insulin resistant as a lot of critically ill patients are.

Not so with fructose. Infuse fructose in to a peripheral vein and it immediately disappears in to liver tissue to replenish glycogen stores before any excess becomes intra hepatic fat. But it also disappears in to muscle cells, big time. And adipocytes too. In fact, in to any cell expressing the GLUT5 transporter* on its surface. Even bits of the brain do this. No insulin required. Fructose gets calories in to tissues without wasting too much through exceeding its renal excretion threshold. That's why it got chosen for ITU work back in the 1970s. It works. A pity it kills people with hereditary fructose intolerance.

* Did you note "testis" in there? Human sperm appear to run on fructose. There is a post on sperm, fructose and nitrous oxide injected Morris Minors brewing for some day.

I've been particularly interested in whether oral fructose might cause whole body insulin resistance directly, especially adipocyte insulin resistance, rather than just being limited to hepatic de novo lipogenesis and the systemic sequelae associated hepatic insulin resistance. You have to ask whether fructose really stops at the liver, especially in human beings. After all, those GLUT5 transporters are not sitting there on myocytes and adipocytes awaiting an intravenous fructose infusion... So what is the plasma fructose concentration after something a bit like a large McDonald's Coca-Cola Classic®, the 32oz serving? With or without breakfast, and compared to assorted ratios of glucose and fructose? Here are the (very old) data:



Fructose penetrates well past the liver in humans after a 32oz cola. There are GLUT5 receptors on multiple non hepatic cell types. Fructose effects do not appear to be limited to the liver. I was really interested in this some time ago but never got to post about it. It's quite speculative.

The question is: Why are some of the nurses I work with skinny despite subsisting on sucrose in various guises?

Apart from the possibility that skinny folks who eat a sucrose based diet are chronically hungry (some certainly are), why else might they not be fat?

Perhaps: If you can dump a decent dose of fructose on to adipocytes you might well limit their response to insulin. These folks would still get the classic fatty liver and hyperinsulinaemia but fail to store large amounts of fat in adipocytes because fructose exposed adipocytes would become insulin resistant and so release inappropriately large amounts of FFAs for a given level of insulin. They are, after all, resistant to insulin's fat storage effect. No one would suggest that this is a healthy situation and terms such as "skinny-fat", "metabolically obese but slim" and "slim type 2" all come to mind. Weight per se is unimportant, chronic hyperinsulinaemia comes with its own costs.

Where did all of this come from? Tom Naughton and Makro both provided the link to this video.

I agree with a great deal of what Lustig has to say. But I find it hard to swallow an argument when certain easily disprovable biochemical statements are made. Saying that fructose uptake and its transporter are limited to the liver is disappointing. We have enough problems with misinformation on carbohydrate restriction from folks with carbophilia. It's depressing when we simplify our message to the point where even a politician can understand it, ie to the point where it is no longer true.

Sigh.

Peter

Addendum on skinny fructose fed rats:

Here's a typical paper, there are probably loads more out there.

Fructose fed rats are lighter than CIAB fed rats. Here's the table we want:



Despite the lack of gross obesity, the epididymal fat pads are bigger, the actual adipocytes in these pads are bigger than those from controls and the adipocytes are, of course, insulin resistant. Just look at the FFA levels in the table.

Now, let's look at the OGTT results:



The fructose fed rats clearly produce a ton of insulin in response to an oral glucose load, far more than the CIAB fed controls. If they can produce this much insulin, surely they must be able to overcome adipocyte insulin resistance and make themselves FAT? You can certainly store a whole load of extra fat in the adipocytes of an insulin resistant human by adding exogenous insulin in to their diabetes meds...

The group doesn't specify the diet exactly (they must be in obesity research) but it's made by Teklad Laboratories and is probably TD.89247. About 67% of calories from fructose, no other source of carbohydrate.

If so, the bottom line is that these fructose fed rats are on a mix of casein, lard and fructose. Only fructose. They NEVER eat starch. They NEVER eat glucose. They NEVER eat sucrose. Fructose per se is only mildly insulinotropic. An OGTT tells you NOTHING about the insulin response to a meal of TD.89247.

Which these rats live on.

Now what happens if you add fructose AND glucose to a rat's lard/casein diet? It's called sucrose. It is, err, obesogenic. Especially in the presence of easily storable fat.

Because here you spike insulin while simultaneously causing insulin resistance, which will cause a MUCH bigger insulin spike than even the rats on CIAB produce after each meal. Adipocytes can be forced to enlarge under these circumstances. It's called obesity.

Of course it might just be that sucrose is more rewarding than that significantly sweeter molecule, fructose. Perhaps fructose is sooooooo sweet it becomes unrewarding? Or boring. Or perhaps the idea of reward from sweetness is complete bollocks and we are dealing with a simple biochemistry process. I rather like biochemistry.




If we go back to my skinny workmates you can now start to ask questions about a person's ability to absorb fructose from the gut, the ability of their liver to mimimise passage of fructose to the systemic circulation and the level of expression of GLUT5 on adipocytes etc. You can even think about whether these people may, by going to Weight Watchers, limit their intake of starch which is a significant drive to insulin production when added on top of the insulin resistance from their sucrose fix.

But ultimately we're still thinking about biochemistry.

44 comments:

Beth said...

"I rather like biochemistry."

Yep, worth looking at. Also, I agree with you on the trouble with getting info from video or audio. It's ok in some situations, but too slow in many others.

Beth

Dave Bridges said...

is anything not highly expressed in testes?

George Henderson said...

I love this Peter.
and this line:
"It's depressing when we simplify our message to the point where even a politician can understand it, ie to the point where it is no longer true."

If there was a Yudkin prize for advancing knowledge about the effects of sugar, this post would top the nominees list.
The Yudkin Prize hasn't been awarded for some years now...

I think Lustig IS a politician, like Ancel Keyes before him.
It's a huge pity, but would they listen to anything else?
As with Ancel Keyes, the first experiment will be with the whole population.
At least we'll have some data then.
And probably some unintended consequences...
More aspartame, more polyols, God knows what new "sugar free" food abominations...

Unknown said...

Since Lustig wants to tax sodas, he most certainly is a politician. Science doesn't need to have a political component.

Stipetic said...

This speculating is lining up a lot of loose ends. Great stuff.

Chuck Currie said...

Seth Roberts went on a diet of sugar water and lost weight. As he did with his olive oil diet.

Lustig my be an imperfect advocate, and leaving out some details, but going beyond his simple, but at the same time complex, explanation, he would lose more listeners than he already does. And, someone has to turn the USDA food pyramid on its head - without adding another tax.

Growing up in the 50s - 60s we were told that sugar rots your teeth and makes you fat. It's still true, regardless of what the USDA says.

john said...

I have probably consumed more sucrose/fructose than most people in a lifetime (in my first 21 years or so). While I have always been very lean, I did have other indicators of poor health: cavities in my baby teeth, gum inflammation, acne as a young teen, appendicitis.

Interestingly perhaps, I never ate starches, besides bread with a sandwich, but even then I usually removed the top slice. I disliked pasta, potatoes, rice, etc. My diet was pretty much meat, dairy, and fruit/candy.

Chuck Currie,

I think Seth's overall sugar/carb intake was quite low though, because his sugar water (and refined olive oil) was just used in small amounts as an appetite suppressant.

IcedCoffee said...

Very interesting stuff. Makes me wonder about distributions of Glut5 on skinny vs. obese t2d patients (pre-onset), and to what extent the liver's ability to metabolize the fructose affects the equation.

I'd also be interested to see if the distribution varies between subcutaneous and visceral adipocytes in a meaningful way.

Also makes me wonder about the affects of that serum fructose on things like CVD. Isn't fructose suppose to be like 10x more effective at glycation? Seems bad for those lipoproteins.

Peter said...

John,

I too had multiple baby tooth fillings and now have a mouthful of amalgam, all from pre reading Yudkin days. I probably did OK as an adult due to relatively low sugar intake. As a teenager my sucrose intake was huge, but so was my exercise output. At my highest level of competition my then-girlfriend's-mother commented that she would rather feed me for a week tha a fortnight! Understandable...

Icedcoffee, the main regulator I've seen is hyperglycaemia, which down regulates GLUT5. Oh, and of course fructose exposure increases it! There will be a complex set of interactions there.

Peter

Galina L. said...

I have to be honest and admit that I am bias toward LC diets (probably because it works for me), however, when I listen to Lustig, I feel like he is trying to sell me some snake oil.

Bill said...

Actually, I’m surprised ANYTHING can survive on a diet where 67% of calories come from fructose… rats, mice, whatever. That's impressive.

Great post Peter.

-Bill

js290 said...

Richard Feinman had a lot to say about that as well in the comments of that video on the UCTV website.

http://www.uctv.tv/skinny-on-obesity-sickeningly-sweet/

karl said...

Athletes tend to have trygly around 40-60mg/dL -- and a big dose of fructose spikes that to over 100 - so while trygly is spiking GLUT5 receptors are turned on.. And if "hyperglycaemia, down regulates GLUT5 while fructose increases it!" we have even more string to untangle.

I've wondered if there is something like fructose resistance. Fructose is much more likely to produce AGEs - I suppose there is also an inflammatory response. High blood fructose is really good at creating oxLDL.

So could it be that GLUT5 is triggering insulin resistance directly? Perhaps in an attempt to get the blood level down to safe levels?

I've seen where rice (turns to all glucose) is still associated with Type2 in Asian populations - but they didn't start getting fat until the fructose containing drinks came around.

Way more questions than answers..

Makro said...

Interesting, but would like to see larger / longer studies (as usual; if some billionaire is reading this, please donate lots of cash to metabolic research!):

http://www.metabolismjournal.com/article/S0026-0495%2811%2900315-5/abstract


Good call on Lustig´s mistake (unless I have misunderstood his point) on fructose metabolism; how about dropping him an email and pointing it out and see if he responds? (Also a good acid test for character that would interest me...)

George Henderson said...

Still, I'm backing Lustig in his little war.
The opposition to Keyes came from people who thought he was flat-out wrong;
Lustig's critics seem to be pedants like us, and libertarians.
The antismoking message can be criticised for some wildly inaccurate science statements and an attack on personal liberties, but that doesn't mean the tobacco company agenda should carry the day.

Makro said...

"Lustig's critics seem to be pedants like us, and libertarians."

A good principle is not caring too much about the identities of parties to debates. It easily leads to Tribalism.


"The antismoking message can be criticised for some wildly inaccurate science statements and an attack on personal liberties, but that doesn't mean the tobacco company agenda should carry the day."

Also, separating the empirical part of the debate from the normative part as much as possible is also a good idea, in my view.

Hence, I believe that Lustig´s quick jump from discussing the role of fructose in metabolic syndrome to demanding punitive taxation, etc. is a mistake that will make reaching solid conclusions more difficult.

pablo DLS said...

Sucrose is super good, really, im telling you, there, so trust me.
i eat it. with fat. All the time.
The real problem? Forks, knives, spoons... they ALL need to be taxed! Maybe Lusting needs to be taxed,look at all that fat.

karl said...

I've been thinking about this some more - circulating fructose is really bad stuff - if the body responds with insulin resistance -- how would that help lower fructose levels?

No answer - just a thought..

George Henderson said...

@ carl, maybe the body is just saying "can't help you, Glucose. Insulin, you just keep fat out of my way, I'm all tied up with this fructose right now"

A "good news" (for some) Fructose story:
http://www.ncbi.nlm.nih.gov/pubmed/15203196

Makro, it's important to realise that much of the sniping at Lustig is coming from people who also have no love for sugar.
Given a choice, do we sabotage his mission because of his flaws, or do we help him to overcome them?

George Henderson said...

P.S.

there is absolutely no shame in being a pedant.
Or a libertarian.

George Henderson said...

The only objection to the fructose theory of MS comes from anthropology.
There are African hunter-gather tribes that still flourish on a diet of wild game and honey. Honey is their main carb (but any excess is fermented to beer). Similarly, classical Aethiopian civilisation (as discovered by Bruce in the 18th C.) subsisted on raw meat and honey with no harm; in fact, modern Ethiopians are a very lean people.


How we explain this ought to add something to the debate.
My favourite; what Yudkin called "dirt". Bring in the hygiene hypothesis and the bee as an "old friend".
And the diets being otherwise low in carbs; low in starch.

Honey is the elephant in paleo's room, isn't it?

Peter said...

George, I have been wondering whether fructose metabolism to intracellular lipid is of any consequence if you are alread physiologically insulin resistant: If you have a ton of intra cellular fat from ketosis/elevated FFAs, does more intracellular lipid from (some) honey matter?

And whether consuming a "physiologically tolerable" dose of fructose (where ever that lies, it's certainly not zero) matter if it is a method of increasing fat storage? Some fat is undoubtedly good for us.

The paper from the Pauling Institute is one I like. An idea I would like to explore in future is whether the uric acid is acting as an intracellular damping agent wiping out the signal from mitochondria to the nucleus as regards the mitochondrial redox state. Is excess fructose bad because it combines massive pyruvate delivery, no insulin mediated modification of the ETC, free radical generation from over substrate supplied mitochondria (especially succinate dehydrogenase when NADH levels are high and supporting a large inner mit memb potential) plus wipes out the signal for requesting more mitochondria, all at the same time? In moderation this is probably fine, but once you crack >33% of your calories from HFCS you may be outside physiological limits.... Just wondering.

Peter

Amir Timur said...

I was wondering whether the fructose content of Mangos is responsible for them having the reputation of being fertility enhancers, here in India. Anyway, I also want to congratulate you on your blog which is the ultimate authority I refer to in case of doubts on any subject. I also want to ask the following questions:

I found that India is great for a few things:
1) COCONUT OIL! at $3 per kg.
2) Ghee at $5 /KG.
3) Beef at $3 /kg.
4) Tallow for free!
5) Buffalo milk with 6% FAT!
6) Fine quality partially grass fed mutton at $9 /kg.
Spices and vegetables are also cheap.

However there are a couple nagging doubts that I have.
1) No beef is grown commercially in India.
The beef available is mostly older water/buffaloes cows or younger bulls/bullocks.
I tried looking at the diet of these animals and it seems that the male animals/older animals are mostly pastured but especially so during the 4 month long monsoon when green grass is free. Bearing this in mind, should I be buying ghee during the first month of the monsoon when animals feed on growing grass, or after they have had a 4 month diet of green grass, that is, in September at the end of the monsoon.
Also as far as tallow goes, would the older animal tallow be more nutrient rich? Would there be a greater accumulation of toxins? should I buy calf tallow or Old animal tallow? (The older animals seem to have a yellower tinge.)
Also, I looked at pollution levels in the Arabian sea and they seem to be reasonably low. Would it then be wiser to get more of my protein calories from ocean sourced Indian salmon/King mackerel/Tuna/Shrimp which are each about $2 per pound or beef which is closer to $2 per kilo but has an unknown diet?

I eagerly await your response.

George Henderson said...

Or perhaps fructose and lipid, from honey or any other food, doesn't matter if your lifestyle is such that you intermittently fast.
The HG honey consumption is binge-and-bust. It runs out, they look for more.
For example, high-fat diets are supposed to be bad for rodents (especially junk fats in lab settings) but this study shows that high-fat mice who are intermittently fasted (8 hour daily windows) outperform "healthy eating" mice who eat ad libitum:
http://www.cell.com/cell-metabolism/abstract/S1550-4131(12)00189-1
There is further explanation here:
http://www.salk.edu/news/pressrelease_details.php?press_id=560

"After 100 days, the mice who ate fatty food frequently throughout the day gained weight and developed high cholesterol, high blood glucose, liver damage and diminished motor control, while the mice in the time-restricted feeding group weighed 28 percent less and showed no adverse health effects despite consuming the same amount of calories from the same fatty food. Further, the time-restricted mice outperformed the ad lib eaters and those on a normal diet when given an exercise test."

Asim said...

Amir, I'd actually worry more about whether your ghee is authentic or not... No matter the country, vegetable oil is cheaper....

http://articles.timesofindia.indiatimes.com/2011-12-21/ahmedabad/30542062_1_fake-ghee-vegetable-ghee-pure-ghee

George Henderson said...

I found a reference for ascorbate as diuretic (from 1937-1938): http://www.inchem.org/documents/jecfa/jecmono/v05je20.htm

Does fructose promote reductive stress? Would metabolism of fructose tend to skew NADH/NAD+ ratio so as to impair fatty acid beta-oxidation (which requires NAD+ and is supressed by high NADH ratio)? This would account for NAFLD.


Reductive stress may export superoxide radical; uric acid and intracellular SOD correlate:
http://atvb.ahajournals.org/content/22/9/1402.abstract
"These studies show that SOD1 and SOD3 are partially inactivated in atherosclerotic vessels of ApoE−/− mice and that levels of uric acid commonly encountered in vivo may regulate vascular redox state by preserving the activity of these enzymes."

George Henderson said...

http://ajpendo.physiology.org/content/295/2/E227.full

(Shortcut to the full text of the GLUT5 paper)

Do high fructose loads have the potential to disrupt metabolism in organs expressing GLUT5, apart from liver and fat?
Do adrenals, for instance, express GLUT5? Can fructose overload poison the prostate, or pancreas?
I await with interest further GLUT5 findings.

majkinetor said...

George: I found a reference for ascorbate as diuretic (from 1937-1938)

Its called Vitamin C Flush:
http://goo.gl/rEC30

Amir Timur said...

Asim I have a sources of ghee that are adulteration proof- its made under your oversight. It seems that the local buffalo are mostly put on a 1-1-1 diet of Grass/hay/Concentrated feed.

Jonty said...

Hi Peter - I think this is amazing:

http://hyper.ahajournals.org/content/23/6/1036.long
Balon found extra magnesium prevented insulin resistance in fructose fed rats
http://www.ncbi.nlm.nih.gov/pubmed/14675555?dopt=Abstract
Vasdev found additional vitamin C, vitamin E, vitamin B6, or lipoic acid prevented HTN (surrogate for IR) in fructose fed rats
http://www.ncbi.nlm.nih.gov/pubmed/15680273
Song found adding cysteine to the diet of fructose fed rats prevented IR and HTN in fructose fed rats
http://www.ncbi.nlm.nih.gov/pubmed/9361681
Huang used fish oil
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2478633/?tool=pubmed
Thirunavukkarasu used lipoic acid

So fructose at 67% of cals raises requirements of many nutrients well above ratty RDAs

Americans are nothing if not fructose fed and undernourished in for e.g. Mg and vit C - I wonder if minor vitamin deficiencies exacerbate fructose harmful effects

George Henderson said...

Here's a file on Hadza honey eating.
www.fas.harvard.edu/~hbe-lab/acrobatfiles/critical.pdf

Honey at 30% of calories for men.

Makro said...

"Makro, it's important to realise that much of the sniping at Lustig is coming from people who also have no love for sugar.

Given a choice, do we sabotage his mission because of his flaws, or do we help him to overcome them?"

I´m pretty solidly in the "overcome" camp, I hope I didn´t give any other impression.

Overall though, it´s just inherent in the nature of things that cocksure, political, high-profile stands lead to a kind of self-lobotomization that makes changing ones mind extremely difficult. It´s perhaps the number one danger of "campaign science" - hence, I prefer to keep science and campaigning/crusading separate.

Galina L. said...

"Given a choice, do we sabotage his mission because of his flaws, or do we help him to overcome them?"

Flows damage credibility , Lustig's proposal to treat soda as an alcohol will face a big resistance by several influential groups. It is better for him and his message to have as little flaws in his scientific explanations as possible.

James said...

Hi all,

Sorry ahead of time for changing the subject. I have a few queries that are related to a LC diet that some of you may be able to help me understand.

Is exercise as important on a LC diet as it is on the SAD? Part of the benefit of high intensity aerobic exercise, for example, is due to improved insulin resistance and better glucose control. Does this mean that LC'ers mustn't worry about this type of exercise because insulin resistance and hyperinsulinaemia are almost non-existent in these people? Or are the other benefits that come from exercise, such as increased BDNF and mitochondrial genesis, important enough that one must attempt to get their heart rate up and do some resistance training even while in full ketosis?

Another query is related to Peter's posts on how plant anthocyanins downregulate the body's natural antioxidant defences. Does this mean that calorieless plant derived "nutraceuticals" -- such as green tea -- are overall going to do you more harm than good in the long run? Couldn't the case be made that other effects of these types of substances, such as their ability to down regulate inflammation and upregulate genes involved in cell survival, outweigh their ability to downregulate the body's natural antioxidant defences?

Any opinions or knowledge would be very useful :)

Nigel Kinbrum said...

Hi Peter,

According to somebody called Thom, you think I'm a nonsense-spouting idiot.

Please confirm/deny the above allegation, with supporting evidence if confirming.

Cheers, Nigel

Peter said...

Nigel, I'm a great believer in people forming their own opinions so am loathe to comment.

Peter

Nigel Kinbrum said...

Peter,

Observing the completely different opinions that people form given exactly the same information makes it extremely easy to spot their cognitive biases.

Nigel

WELLNESS PROFESSOR said...

I do not know much about fructose and your article has got me curious. I need to have basic understanding of this in order to understand your article clearly. You have shared your views so intelligently and i am glad you are sharing your nursing knowledge via this blog. I need to be here often. Thanks for sharing.

marco said...

Hi Peter.

JK says (page 71 - Optimal Nutrition):
"The most common mistake committed by people losing weight is eating too little or no carbohydrates. Some people believe that if they don't consume carbohydrates at all, they will lose weight faster. That is wrong!".

Do you know the rationale behind this assertion?

I've been thinking at ketogenic diet as the faster way to lose fat...

Is thyroid and reverse T3 involved in all this?

Does a ketogenic diet, even with high calories from fat, suppress thyroid function and increase reverse T3?

Thank you.

Catherine said...

It is one of harmful effects you can get if you continue taking foods with fructose. I suggest you read this article to know more about fructose and insulin resistance.

marco said...
This comment has been removed by the author.
marco said...

Catherine,
No fructose is involved here.

As I've said before, J.K. says that, for weight loss, it'd be better to consume a little portion of starch (50 grams?) in a meal.

Since I've been thinking keto diets to be the best/fastest method for weight loss, I couldn't imagine the rationale behind that.

Peter, could you clarify?

Does a keto diet, slows your thyroid (via reverse T3), even with very high calories from fat?

Peter said...

marco, not really. There is a phenomenon of reactive or paradoxical hyperinsulinaemia in ketogenic dieting mentioned in comments some time ago but it's not a subject I've chased up or downloaded citations on... Whether 50g/d of carbs would stop this... KJ is never one to mention his sources!

Peter

George Henderson said...

Marco,

I don't think this 50g carb increases weightloss, but I do think it may help to prevent rebound once you stop dieting. The only evidence is the epigentic research into hungry parents having fatter kids.

I know we all hate video, but this presentation by Lustig
http://www.youtube.com/watch?v=zpxm4kmcDww&feature=g-vrec
from AHS is very long and detailed, with no politics, and might be a better example to critique;
I wonder if there's a transcript out there.
I liked it, FWIW. He certainly doesn't come across as a clown when his audience doesn't require it. Remember, he's a pediatrician, so maybe it's his bedside manner that gets in the way; perhaps to him the media, the general public, and politicians are like children.
Funny that....