Friday, January 4, 2013

Your Brain on Fructose

Right on the heels of the little case study I wrote about last time came a paper in JAMA that made a bit of a splash in the news: Effects of Fructose vs Glucose on Regional Cerebral Blood Flow in Brain Regions Involved With Appetite and Reward Pathways.

I know. Sounds like a nail-biter.

Stone Temple Pilots: Pretty Penny (from 1994! Ancient history. I like the fresh time signature used in the song.)

The paper is a Tale of Two Sugars, glucose and fructose. Fructose is somewhat sweeter than glucose, and it is metabolized differently (as those in the paleosphere are no doubt agonizingly aware). Fructose, for example, only causes slight bumps in insulin, which is known to work in the central nervous system to increase the satiety and decrease the reward value of food. Compared to glucose, fructose also doesn't increase a satiety hormone glucagon-like polypeptide 1, and fructose doesn't decrease levels of ghrelin, an appetite stimulating hormone.

Let's translate into something simple rather than paperspeak:

Glucose: Increases insulin, increases GLP-1, decreases ghrelin: all of which increase satiety and decrease reward seeking behavior.

Fructose: Barely increases insulin, doesn't increase GLP-1, and doesn't decrease ghrelin, so after ingestion you will presumably still be hungry and looking for the next bag of skittles.

In rats, if you inject fructose into the brain, it stimulates food-seeking behavior. If you inject glucose into the brain, rats decrease their food intake. Please do not inject fructose or glucose into your brain. And while that rat factoid is certainly interesting, I'm hoping that when you drink a vat of agave nectar*, much of the fructose doesn't get past the liver anyway, as it is pretty oxidizing and toxic in the bloodstream.

In human and rat brains, appetite is controlled in the hypothalamus. Sleep kinda lives there too. It's also part of the HPA axis that makes up our stress response. And the researchers hypothesized that if fructose stimulates appetite more than glucose, it will increase blood flow in the hypothalamus and other reward areas of the brain. They rustled up some humans and stuck them in a functional MRI to measure brain blood flow, and out came some data.

Here's another good STP song that you may not have heard, Atlanta (from No. 4)

20 normal weight, non-diabetic "healthy" volunteers were used, 10 men and 10 women, average age 31.The women were all scanned during the follicular phase of their menstrual cycle. Each volunteer was scanned and blood samples were taken after an overnight fast. Then they drank a glucose and (on a separate day) a fructose sweetened drink and were scanned again after 60 minutes. The order of drinks was blinded and randomized. The drinks are described as 75g** of sweetener, plus cherry flavored water. Participants were asked to rate fullness, and serum levels of glucose, appetite hormones, insulin, etc. were measured at 10 minute intervals after injestion through the scanning. Serum levels of fructose were also examined, to see how much got past the liver.

In a complimentary rodent experiment, they gave rats fructose IV and then measured the amounts of fructose that were in the brain to see if some made it through the blood brain barrier. Interesting.

The results! Well, hypothalamic blood flow tended to decrease after ingestion of glucose (within 15 minutes) ingestion wheras it did not with fructose. At all time points, blood flow in the hypothalamus was decreased after glucose compared to fructose drinks (presumably meaning that appetite was decreased after the glucose ingestion but not decreased with fructose ingestion). Glucose also decreased activity in the brain's striatum, which fructose did not. Predictably, both plasma glucose and insulin increased with glucose ingestion, whereas there was very little increase with fructose ingestion.

Plasma fructose in humans did increase after fructose ingestion compared to glucose (scary, and, duh), but levels of ghrelin and leptin were not different in the two groups. Another hormone, PYY, and then lactate was higher in the fructose drinkers. The glucose drinkers felt less hungry and more sated after drinking, whereas fructose drinkers still felt somewhat hungry and not quite as satisfied after the drink.

In the rodent study, fructose in the plasma did translate to an increase in fructose in the brain (compared to a saline IV), and they found that the RNA for fructose transporters (GLUT5) were expressed in the hypothalamus, liver, and kidney.

So, for a small study, rather interesting. Big difference in straight up fructose vs. glucose in how the brain and appetite centers react, and one would tend to think from the results that glucose decreases appetite and reduces food-seeking behaviors, whereas fructose doesn't really fill you up. Of course, no one drinks straight fructose unless you are glopping agave nectar into your tea, and it would have been interesting to see what the soda version of HFCS (from memory, I think it is 55% fructose, 42% glucose) did compared to straight-up glucose. And fizzy (hard to blind that one)! And cherry-flavored! Someone get me some healthy volunteers and an enormously expensive functional MRI machine!

*don't drink a vat of agave nectar
** the typical oral glucose tolerance test is 50g of dextrose in an orange-flavored concoction.


  1. Great post, Emily - why I'm fascinated by this stuff I have no idea (actually, I do - I want to lose weight and figure scientifically is the best way).

    Two points: 1) I feel sorry for the volunteers who had to drink 75g of that crap, and 2) who asked the rats how satiated they were?

    Elliott Weir

    1. Elliott! Talk about a blast from the past! Re: 2) When a rat burps and rubs its belly, you know it is satiated. I think successful people who lose weight are the ones who make permanent lifestyle change, restricting either kinds of food or calories (or both). The tracking happy people now can track everything in a smartphone app… for me I prefer to eat nutrient rich whole foods and not track every last molecule of it, so I tend to restrict what I eat (meaning very limited junk food or processed food of any kind.) Right now I'm doing a "Whole30" just for the month of January.

  2. Thank you for the post!

    What I am still wondering is what happens when we consume "sugar" in its natural, unrefined form, from plants, with the glucose and fructose bound whatever way they are before the mad food scientists get hold of it. (Or is it not permitted to use real food in scientific experiments?)

    I like to have a little not-too-sweet fruit sometimes, especially berries, and I am curious about what happens. Judging from my experiences with it so far, the answer might be "nothing much."

    1. As I recall from "Food and Western Disease" you literally have to eat more than 3 pineapples to exceed 60 grams of fructose, and pineapple is pretty much the highest density fructose fruit. Even a cup of pineapple chunks is only 16 grams of "sugars." It's pretty easy to exceed the fructose threshold with apple sauce, fruit juices, and cola. For whole fruits, unless you are diabetic or someone who can eat a dozen apples a day, I honestly wouldn't sweat it at all.

    2. I think dates may be the highest in fructose (info from this database, search for dates). No wonder Larabars are so unsatisfying!

    3. That's funny. I do sometimes carry larabars for plane rides and such, and ultimately I do find them unsatisfying, whereas trail mix of various kinds can be very filling.

  3. I just had to do the 75g of glucose to test me for gestational diabetes. I noticed that I was surprisingly NOT hungry at all for several hours after the drink (I strenuously objected to the orange on the grounds I'd barf it up again and somebody found me some lemon-lime stuff which was WAY better). It actually wasn't unpleasant at all. Boring, sitting around a lab for 2 hours after chugging, but that just made me look forward to the blood-sucking part. If the volunteers were paid even a few dollars it was probably worth it. Very interesting study. Why do people still think agave nectar is healthy, again?

    1. I hated those tests. At one hour my glucose was high 70s. At 2 hours I would have a massive sugar crash and be forced to eat, but I'm pretty sensitive to that sort of thing.

  4. Fascinating stuff, as always.

    So, glucose decreases your appetite, and decreases brain activity - is that why we feel sleepy after a meal with a lot of potatoes or rice (but not wheat)?

    Sounds like the ticket is get your fructose in the mornings/daytime, glucose in the evenings. Everyone who has an orchard knows that fruit is best picked before, and eaten at, breakfast.

    As for straight fructose, I do believe that honey meets that criteria, but then, it's hard to eat more than two teaspoons of honey at one sitting - *unless* it is on a wheat pancake, muffins etc with butter. I just can't do much honey on my buckwheat pancakes, but maple syrup no problem and "golden" syrup (sugar cane) or agave will have me going back for more and more. There is something about honey that is the same as angostura bitters in a soda - you just can't gulp the stuff down.

    1. Honey is not pure fructose. About 1/3 fructose, 1/3 glucose, and the other 1/3 is a combination of other carbohydrates.

  5. I never crave sweets during the day but at times do so in the evenings. A small spoon of honey before sleep is just the thing that makes me sleep well :-) I guess a piece of boiled potato would do the same thing. As long as there is no fat ingested with the glucose, it makes one sleep well and loose weight at the same time while asleep :-) Hint: for insulin production fat is needed and if it is not in the food, it will come off your adipose tissue.

  6. "Fructose, for example, only causes slight bumps in insulin, which is known to work in the central nervous system to increase the satiety and decrease the reward value of food. Compared to glucose, fructose also doesn't increase a satiety hormone glucagon-like polypeptide 1, and fructose doesn't decrease levels of ghrelin, an appetite stimulating hormone."

    Emily, did you decide to write about this because of what is going on over at Hyperlipid this week?

    1. No, I didn't. I haven't seen his most recent stuff, though of course I've seen some chatter about a little tussle with Stephan G. Actually it brings up an important point… that 75mg of glucose on a fast would probably satiate me briefly, but at the 90-120 mark I would probably crash and need to eat more. Not everyone is like me. It would have been interesting to see some of the time indexes moved out to see what happens later in the day for hunger, satiety, and total food intake.

  7. "Please do not inject fructose or glucose into your brain."

    I LOL'd.

    Anyway, I'd been toying with the idea, but hadn't decided. You've convinced me to add a magnesium supplement.

    I don't use that many different ones: I'm a bit reluctant to take most individual nutrients, since how one could possibly "balance" them with all the other nutrients, I don't know. I'm inclined to whole food supplements like the "greens" powders from a whole array of sources. I figure that most of the ingredients should be good, if one isn't oh well it's just in a tiny amount, and suspect that nutrition (and many other things, like stress-management practices) generally works synergistically, increasing their effects.

    For example, I've found yoga nidra, mindful meditation, and hypnosis, among other techniques, extremely helpful. Which is the best? Does it matter?

    They work together nicely: the first one reduces stress and cortisol dramatically, the second one reduces stress and cortisol somewhat while making every day tasks just seem more peaceful and like "mini meditations", and the last one helps one adopt positive ideas ... in a much easier way since one's cortisol (--> anxiety, fear) is lower, there's less resistance!

    That's nought to do with nutrition, but it has a lot to offer therapy and psychiatry, I suspect.

    Since beginning these practices, my serenity, happiness, etc., have raised immeasurably (and extremely quickly, once I combined them).

    And now magnesium. What the heck. I'll give it a try. Should also help insulin sensitivity, and that's a bonus.

    For what it's worth, low-dose metformin helped mentally as well as physically. I suspect for some people, insulin resistance and the resulting energy and concentration issues exacerbate a lot of people's issues, including in the emotional realm.

    Thanks for the post.

  8. I have reactive hypoglycemia. I took an OGTT and after one hour my blood sugar dropped. I've had 35 in the glucometer and scary episodes like blood sugar crashes after eating an apple. In this scenario what can you suggest to overcome this? If it is enterely possible? I'm 20 years old, female. I already given up wheat and gluten, and it's been really hard fighting my family and friend's beliefs. I seek help from a well known doctor in my country and she recommended eating carbs every 2 hours. It almost killed me. Since then I've been reading many blogs and papers, and I have to say yours is one of my favourites. Thank you for everything.