Sunday, January 8, 2012

What Causes Insulin Resistance? Part III

As discussed in previous posts, cellular energy excess and inflammation are two important and interlinked causes of insulin resistance.  Continuing our exploration of insulin resistance, let's turn our attention to the brain.

The brain influences every tissue in the body, in many instances managing tissue processes to react to changing environmental or internal conditions.  It is intimately involved in insulin signaling in various tissues, for example by:
  • regulating insulin secretion by the pancreas (1)
  • regulating glucose absorption by tissues in response to insulin (2)
  • regulating the suppression of glucose production by the liver in response to insulin (3)
  • regulating the trafficking of fatty acids in and out of fat cells in response to insulin (4, 5)
Because of its important role in insulin signaling, the brain is a candidate mechanism of insulin resistance.

Insulin Resistance in the Brain

When a person eats carbohydrate or protein, the pancreas responds by increasing insulin secretion into the blood, and this provides nourishment to tissues and prevents the massive spike in blood glucose that would otherwise occur following carbohydrate consumption.  It does this by two mechanisms, 1) by increasing the rate of glucose absorption by tissues, and 2) by suppressing the liver's secretion of glucose into the bloodstream.  This year, Dr. Claudia P. Coomans and colleagues published a paper on the contribution of the brain to these processes (6).

By blocking insulin signaling in the brain specifically, they were able to reduce insulin-stimulated glucose uptake into muscle tissue by 59 percent in mice.  The same procedure attenuated the ability of insulin to suppress glucose production by the liver by 20 percent.  This implies that a significant part of insulin's ability to constrain blood glucose following a meal is mediated via the brain.

Then they performed the same experiment on mice that had been rendered obese by diet.  Inhibiting insulin signaling in the brain had no effect in obese mice, indicating that the brain loses its ability to stimulate glucose uptake in obesity.  If this finding can be generalized to humans, it suggests that one source of insulin resistance is the brain failing to stimulate other tissues to respond to it appropriately.

As it turns out, insulin resistance in the brain is a well described feature of diet-induced obesity in animal models (7, 8, 9).  It occurs in parallel with leptin resistance, and is thought to also contribute to fat gain (10, 11).  Obese humans appear to be leptin resistant in a manner that is very similar to obese animal models, and although it has not been demonstrated that brain insulin resistance occurs in parallel, it seems likely since this is consistently observed in animal models.  Putting the pieces together, it is likely that insulin resistance in the brain occurs in humans and that it contributes to insulin resistance throughout the body.

How does insulin resistance develop in the brain?  Probably in a manner that is fairly similar to how it develops in other tissues.  Just as cellular energy excess and inflammation are implicated in insulin resistance in muscle tissue, the same mechanisms are implicated in leptin and insulin resistance in the brain, although there may well be other unidentified mechanisms that are unique to the brain (12, 13, 14).  The treatment strategy, to the extent of my knowledge, should therefore be the same for both sources of insulin resistance.


DM said...

And that treatment strategy would be?

Sanjeev said...

off topic: low reward diet question.

For a short term experiment, are there any fairly commonly available low reward foods high in fructose?

this question's motivated by considering a couple of ideas:

sucrose/fructose appear better at replenishing liver glycogen than starchy foods

liver glycogen level is one signal the brain/body uses to set hunger level

low liver glycogen encourages more overall body protein catabolism

Agave (one variant has a fruit that looks like pineapple) is high in fructose apparently - as part of a whole food I would think the fructose would be lower reward than high-fat, low-fiber candy bars, but one cannot find the fruit anywhere, or even seeds.

I'm just wondering if it's possible (probably not) to do Stephan's "highest" level, 3 food choices, with one choice being a high fructose, low-taste/low-reward fruit - say replacing the fibrous vegetable with a high fiber fruit.

Even if such fruit exists, who would sell it, since really, few would buy it ...

I have occasionally had peaches that were not sweet at all, so maybe there's a chance ...

bentleyj74 said...


allison said...

I wonder whether the presence of excess fat metabolites in muscle and organ tissue can explain why people on a VLC diet tend to have elevated fasting glucose levels? It would appear to be related to slightly diminished insulin sensitivity. I know that in my case, it would quickly reverse as soon as I added carbohydrates back into my diet.

Sanjeev said...

watermelon's pretty sweet, thanks for considering the question though ...

I realized a clearer way of asking: how to get a little fructose the same way that potato delivers glucose - with near zero sweetness and low reward.

I thought there may be some form of digestible fructan but no, none of the common fructans is documented to deliver actual fructose through human digestion.

Carl M. said...

@Sanjeev: try eating raw fruits that are a close to natural as possible. Seeded vs. unseed. Heirloom vs. hybrid. Eat one type at a time. No mixing. You will get a taste change response that makes it hard to eat too much.

Weight loss is very likely. Whether this is healthy long term is another matter.

antispirit said...

Get crystalline fructose and dissolve it in water. Without any flavors, "sweet" is not very rewarding. Or you could use orange juice and drink it through a straw. Try to bypass the sweet receptors in your tongue. I wish I could get my hands on the orange juice before they add in the "flavor packs". That would be the perfect low palatability food.

bentleyj74 said...

@ Sanjeev,

What about sweet potatos? Those are low reward with a decent amount of fructose.

yolio said...

So it sounds like although the brain is important in insulin regulation, the specific mechanisms are still pretty dimly understood.

What I don't understand is how IR leads to weight gain. And is this link inevitable and universal? The studies you link to indicate that IR in the brain increased food intake. But how, exactly? Does the IR impact appetite regulation hormones? Maybe I am missing something, but I get the impression that no one really knows the answer to this question yet.

Sanjeev said...

thanks for the suggestions, will try them. Sweet potato looks like it meets the most criteria.

There is the pure fructose flavour-free route but being purely industrial and way non-physiological that's not preferred in anything but small amounts.

Definitely looks like there's no sweetness-free, real-food way to do it.

don't want to hijack the post with this though, so that's good for now - I've clarified the original thought a bit and I'll look for a way to discuss this type of thing on another forum (sans hi-jacking).

gunther gatherer said...

Hi Stephan,

I'm confused about cellular excess. Are you saying there can be cellular excess at one meal when eating too much, or is this over a day or week or month of caloric surplus?

And can you explain the cascade of metabolic derangement now as 1) food reward too high, 2) cellular excess, 3) insulin resistance? Where is obesity in this scope?

Alex said...

You're all basically guessing about food reward. Sweet potatoes could be very rewarding for all you know. According to Stephan, if it's not proven to reduce body fatness it's not proven to be low reward.

Rip & Clip said...


Any food can reduce body fat(twinkie diet)

Sarah Barracuda said...

@Sanjeev, bentley - Wait err, how are sweet potatoes high fructose? They are mostly starch, with most of the sugar being sucrose and maltose (and no free fructose), at least according to . (No, really, I am confused now!) Is there such a thing as a high-fructose food that is not sweet? I'm rather botanically ignorant, but I'm curious whether those heirloom fruits that Carl M. mentions really have any appreciable amount of fructose.

@Alex - I am honestly not getting where people are reading that the effect of reducing body fatness is a necessary condition for a food to be low in reward. Rewarding-ness of a food reinforces the behavior of eating the food: more rewarding means you come back for more. That does not mean it is a proximate cause of obesity. If celery were addictive by itself (without ranch dressing/other caloric seasonings), that would mean that it is rewarding. Does that mean it is fattening? Considering the urban legends about celery being a 'negative calorie food', I would emphatically venture a NO. Sorry if I'm coming across as short-tempered, but I think this bizarre contortion of what Stephan has been reiterating is at the heart of (much LC) hostility to the ideas.

Sanjeev said...

Thanks Sarah, you are correct - I just looked it up and they are high starch. I may use them just because they're the "best" match for what I'm looking for in my experiment.

I ate sweet potato long ago and from memory they were not rewarding at all.

I might leave some sweet potatoes on the plate while still being moderately hungry

@Alex, I'm pretty certain that successfully losing fat using food "X" as a staple does not indicate X's reward value. It's a clue, not a definitive measurement.

Sanjeev said...

Sweet potato's fructose would have to come out of the sucrose component.

Many fruits provide significant fructose but since I find most of the commercially available fruits pretty rewarding, I'm tapering down on these as part of my low reward experiment.

Even with significant fruit though I have had zero cravings for things I ate several times a month for most of my life, and craved when I was restricting them ...

indian sweets like gulab jamum, jalebi
regular western pastries (baklava, cake, eclairs)
chocolate bars
ice cream

Basically I've had zero junk food and very low to zero cravings since starting one meat, one vegetable, one starchy tuber, some fruit (maybe soon zero fruit)

Kurt G. Harris MD said...


The highest free or excess fructose in a whole food that TO ME is not very high reward is in Stephan's logo -apples. That's why IBS sufferers avoid them.

Apples are about 70-80% fructose with half of the sugar content free fructose.

Sweet onions also have a fructose predominant profile and nearly as much sugar as an apple

Watermelon is going to be easier to eat a lot of and for most people is high reward.

My wife can't stop eating it, but I hate the flavor of all melon like fruits.

She also likes apples and I am indifferent to them.

Yves said...

Food reward is a red herring imo, it's susceptibility that matters. Eating in general is a low-reward activity for me.. so many more interesting things to do. Foods I like don't seem to make me fat (meat,butter,eggs,ice cream, sugar, fruit, etc.). Some people like me are on the opposite side of the spectrum. If I eat a bland diet my energy levels crash with the lower calorie intake "eating to appetite". I think the reward model works for some people, and for others falls flat. For what it's worth I've been on extremely low reward diets in the past like raw paleo, so that may have reset some reward threshold; I just don't expect food/eating to be pleasurable.


Stephan, do you plan on following up on the role of digestive health on insulin sensitivity? From my own experience digestive health is hugely important.. do you feel endotoxins are the main culprits, or a general state of intestinal inflammation? The significance of common pathogens (blastocystis infects nearly 1/4 Americans) Practical solutions?

Rip & Clip said...

@kurt harris-

You must be joking about watermelon. Have you ever tried to get enough calories from watermelon? I have and its one of the hardest foods to eat enough of. You have to eat 15lbs of pure flesh to get 2000 cals. I personally became the skinniest I've ever been when I attempted to eat mostly melons.

An all plain fruit diet, no matter what the fruit is, will always be low food reward. Just look at 30bad where they tell you you have to force feed to get enough calories.

Alex said...


If you don't think it's necessary, please provide another method for objectively determining food reward.

@Rip & Clip

As a part of a varied, healthy, non-calorie restricted diet? I doubt it.


So how do you objectively determine a food's reward value then?

You are all saying "oh I might do this" "oh this isn't as appealing or as tasty". None of this is objective.

allison said...

If you want to experiment with appetite control, try a truly low reward, high nutrient diet, by eating liver and other organ meats. Liver triggers a strong gag reflex in some people. I bought some grass fed braunschweiger (which I find mildly revolting) and as an experiment would eat a portion when I was hungry between meals. My appetite dropped right off the scale.

I think we confuse eating to survive with eating for pleasure. Throughout most of human evolution, we ate to survive and procreate. Think about the dietary habits of humans prior to the discovery of fire. How much would some semi-putrified carrion stimulate your appetite?

Todd said...

Getting back to the main thesis of Stephan's post: I think that Stephan is right in his conclusions, but doesn't go far enough. There is evidence that the type of insulin resistance relevant to obesity not only CAN start in the brain, but most likely ALWAYS starts in the brain -- specifically the hypothalamus.

This is borne out by the fact that diet-induced insulin resistance typically shows up in the brain much earlier than in the liver or muscle. See, e.g. Ono et al ( The genetic knockout LIRKO mouse, which lacks insulin receptors in the liver, fails to become obese probably because it retains hypothalamic insulin sensitivity, even while its liver is artificially "insulin resistant".

Obici et al ( showed that impaired insulin signaling can impair normal insulin sensitivity in the liver. And it is well known that pancreatic secretion of insulin is neurally regulated by multiple mechanisms (

I've summarized this in a recent blog post, including evidence that ties hypothalamic insulin resistance specifically to intra-abodominal obesity:

Sarah Barracuda said...

@Alex - It's not that hard to observe how much of a food an organism eats. Touch once and won't even go back? Low reward--maybe even 'negative' reward. Eat and eat and eat and go back for more of it? High reward.

I refer you back to my celery example. If all the people munching celery sticks were doing so because "once you pop, you can't stop!" (and not because it's a diet food that's supposed to displace other more 'fattening' foods), then celery would be high reward.

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

I answered the "objective methods" question, and it's obvious I'm not using one of those
> You are all saying "oh I might do this" "oh this isn't as appealing or as tasty". None of this is objective.
Agree completely, not objective.

Once a set of foods is established as rewarding, you can see the pattern, that's what some people are doing.

I wasn't even asking about trying something, I was asking if it's even feasible (the exact thing I was thinking of probably is not feasible)

As long as I don't convince myself I've done something rigorously, stringently objective, and keep the "I've just applied a guideline, let me see what happens" I don't think I'll run into too many problems.

Sanjeev said...

So how do you objectively determine a food's reward value then?
fMRI studies (find if a food abnormally highly activates the same pathways as addictive substances)

opiate agonist / antagonist in combination with food studies

neurotransmitter blockade studies

neurotransmitter agonist / antagonist studies (like bromocriptine, which I think majorly fiddles with food reward, but not with the reward of any one food or even food class)

(This is my personal guess, not tested AFAIK) training studies: find which foods are best for reinforcing pavlovian-style conditioning

if you have the stomach for it you might even do Joseph LeDoux style "kill the neural pathway" studies.

Sanjeev said...

I somehow missed typing "attitude"

... and keep the ATTITUDE "I've just applied a guideline, let me see what happens" ...

original below:
As long as I don't convince myself I've done something rigorously, stringently objective, and keep the "I've just applied a guideline, let me see what happens" I don't think I'll run into too many problems.

Sanjeev said...

@ Alex, thanks for reminding me of this - I don't think Stephan's covered it here yet.

Lyle McDonald wrote a book about the LSD relative bromocriptine ... many on Lyle's forums have reported MASSIVE appetite suppression when using it

It's mechanism seems mostly due to its effects on reward circuits
click for bromicriptine reward

or copy and paste, (so you're sure it's work safe)

Sanjeev said...

It's mechanism seems mostly ...

ITS mechanism ...

... someone please shoot me with a grammar bullet (aim for Broca's area, please).

Sanjeev said...

@ Kurt G. Harris MD said...

Thanks for that ... Some of the local Macintosh apples are just barely sweet, and very sour.

They meet some the guidelines ... very desirable when hungry, marginaly desirable otherwise, low calorie density.

I share the concern about watermelon, I do find it tastes good anytime, whether I'm full or not.

And the concern is not about getting consuming excess watermelon, but that the flavour is not very distinct from the generic sweetness of many candies and pastries, so it's a step "up the reward ladder".

Your earlier point about your clients that sought to make the 7 steps taste as good as possible, and that being the prelude to going completely OFF the diet should be repeated often.

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john said...

You said, Then they performed the same experiment on mice that had been rendered obese by diet. Inhibiting insulin signaling in the brain had no effect in obese mice, indicating that the brain loses its ability to stimulate glucose uptake in obesity. If this finding can be generalized to humans,"

I say, "Using rodent studies to propose an interesting hypotheses can be an intriguing method to write a provocative blog and try to show "a tie in" to make a point. Too often that point pushes some folks to the concept from correlation to causation. We should not fall for that type of logical fallacy. In fact most nutritional research work is first done in rodent studies to see if there is biologic plausibility. However, using such studies one can’t extrapolate these findings directly to humans. This fact is often not stated and the reader is allowed to freely associate the possibilities of the correlation effect found in the said study. Moreover, this is a more critical distinction when one is discussing metabolic pathways used in nutrition and how they might effect the animal when different diets are introduced for study. For example, mice have a basal metabolic rate that is 6-8 times that of a human’s BMR, so only 50% calorie restricted diet in a mouse represents a situation that resembles only a therapeutic fast in humans. So when one compares a rodent study to a human study in nutrition one must be aware of these dubious relationships before conclusions are drawn. It is an apples to oranges comparison at best. "

Rip & Clip said...

This whole watermelon deal is classic, obviously you guys have never tried it. Your all making huge assumptions.

Maybe you guys forgot that watermelon is over 90% water and you usually get a stomach ache from eating so much water before you can even begin to get enough calories. I could see maybe if you were talking about dates but your talking about watermelon the most calorie poor fruit of them all.

Low food reward has a lot more factors than how something taste. Watermelon is tasty but it also also a very bulky extremely hard to eat food(calorie wise).

You guys keep forgetting there is a whole forum dedicated to force feeding your self fruit(way beyond satiation) in the hopes of getting enough calories. Go to and just take a look for yourself, it's pretty ridiculous. I find it pretty absurd that people think fruit is high reward, where are the people who became fat eating nothing but fruit? Where are the people who are fat from eat nothing but sugar?

Kurt G. Harris MD said...

@Rip and Amp

"You must be joking about watermelon. Have you ever tried to get enough calories from watermelon? I have and its one of the hardest foods to eat enough of."

No, I am not joking. I think you are misconstruing my comment.

Firstly, Sanjeev is asking for a whole food that is relatively LOW reward. I mentioned apples first, and was dismissive of watermelon , as for MOST people it is higher reward than apples.

You asked me if I could eat a lot of watermelon. But I already said I don't like it it in my comment so the answer is no.

My wife, OTOH, like most people I've observed at picnics over the years, will eat whatever watermelon is there until it is gone.

FR of any particular food is not uniformly the same for everyone, as its major factor of palatability is not the same for everyone, depending on conditioning and maybe genetics.

And Sanjeev seems to be constructing a LOW FR diet that has some components with excess fructose to replenish glycogen. He is not trying to get 100% of calories from a single food source.

Finally, eating any single food that is itself relatively high reward is a LOW REWARD diet. So a diet of nothing but watermelon would not be high in FR even if it had no water in it.


Because variety is a major component of of FR. That is why you can lose fat on the twinkie diet, but adding twinkles to your existing diet is not a low FR strategy.

Kurt G. Harris MD said...

"I find it pretty absurd that people think fruit is high reward, where are the people who became fat eating nothing but fruit? Where are the people who are fat from eat nothing but sugar?"

My previous comment addresses these questions.

No one thinks "fruit is high reward" in the sense you mean it. But Sanjeev was wondering if some whole foods like fruits might be LOWER in reward than others.

If we grant that some are lower in FR, then some fruits may well be more rewarding as COMPONENTS of your diet than others, even if fruits in general are not as rewarding as manufactured junk food.

This can be true without it being the case that people get fat eating nothing but fruit, just like fatty food could be rewarding without it being true that people get fat eating nothing but fatty foods The same thing for sugar.

FR depends on combinations of components and variety in the whole diet.

So to say that no one got fat eating nothing but "x" is besides the point entirely. It's not relevant to FR.

To be clear, I personally don't think watching fruit consumption is the key to a low reward diet.

Avoiding baked goods and bread, candies and cakes, and all liquid calories, even milk, is probably most bang for the buck.

Evelyn aka CarbSane said...

@john: "So when one compares a rodent study to a human study in nutrition one must be aware of these dubious relationships before conclusions are drawn. It is an apples to oranges comparison at best. "

Apparently you missed Stephan's use of the word "if".

I suppose we could be more informed by hibernating worm studies ;)

Evelyn aka CarbSane said...

@Stephan: Looks like a lot of new work from this group. I don't know exactly how they would do it, but it would be interesting to see what happened to the insulin response if the DIO mice were switched to their regular diet but ate enough calories so they wouldn't lose weight. It would also be interesting to follow some DIO animals through the stages to assess when this brain effect kicks in.

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justjuliebean said...

Kurt Harris says "To be clear, I personally don't think watching fruit consumption is the key to a low reward diet.

Avoiding baked goods and bread, candies and cakes, and all liquid calories, even milk, is probably most bang for the buck."

I would completely agree that this is how MY weight works, regardless of food reward. Not sure how much is food reward or palatability or blood sugar or what, but I can eat fruit all day, but eating lots of cake and cookies (like too many holiday parties) will put on the pounds like nothing else will.

Try bingeing on fruit, it's tasty, but a disappointment wrt reward, if I'm understanding the concept correctly.

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Mike said...

Hi Stephan,

Thanks for all the valuable info. I've been reading your posts for a couple of years now. The whole food reward thing you're doing is interesting, but in my opinion doesn't equate to "Whole Health"... Besides being unsustainable over the long term (who wants to eat bland food? eventually you are going to want to eat something delicious), it doesn't seem to have a high nutrient range. Though I appreciate your insight, I hope this new year you go back to your roots a bit more, and include the "Whole Health" spectrum, not just fat loss, using strange bland food torture techniques.

Sanjeev said...

Hi Stephan.

I appreciate your hard work, open mind and generosity in sharing your work.

Wish there were a lot more people like you out there.

Gys de Jongh said...

Congratulations :)

J Clin Invest. doi:10.1172/JCI59660.

Obesity is associated with hypothalamic injury in rodents and humans


Gordon Rouse said...

One of the curious missing pieces of science regarding obesity and diabetes is the lack of clinical evidence that calorie-restriction can improve mortality outcomes for obese people and/or diabetics. (Despite the general recommendation for calorie restriction).
It is clear that calorie restriction improves insulin sensitivity.

I regularly make comments on lifestyle articles about obesity challenging the 'diet-health' camp to find evidence that calorie restriction improves mortality outcomes. I generally offer a slab of beer reward if someone can find a randomised clinical study. (there is no greater motivator in this land!)

Apart from the problem of maintaining long-term weight loss in clinical studies, I am wondering if there is more to the calorie-control mortality issue that makes calorie restriction useless in improving mortality outcomes?

It seems to me that making a fat diabetic into a skinny 'diabetic' may make the indicators look good, but is not really treating the underlying problem - if so what is the underlying problem?

What are you and your peers thoughts on this - do you think I am going to have to give away a slab of beer in the future if I keep offering this challenge?

PS - I won't offer the challenge here because I have no idea how I would deliver a slab of beer to the US!

Glen said...

@Gordon Rouse... You said... "It seems to me that making a fat diabetic into a skinny 'diabetic' may make the indicators look good, but is not really treating the underlying problem - if so what is the underlying problem?"

I think the underlying problem varies amongst differing individuals.

I myself have Type II diabetes, which I personally contribute to BOTH dietary and genetic causation.

My entire family has a very high incidence of diabetes, and most are obese.

For me however, I ate a diet very high not only in carbohydrate, but refined carbohydrate. I'm what most would term "working poor" and the least-expensive grocery items are unfortunately overly-processed/refined carbohydrate. We tried eating lower-fat, but that didn't help.

I was officially diagnosed exactly one year ago with a fasting blood glucose of 14.8 mmol/L (267mg/dl) and an A1c of 12.1%

I was also about 300lbs ... my scale literally "scraped" as it went up, so I can't be sure of the weight then, but it was a lot.

My changes were twofold - DIET and EXERCISE. I added daily cycling to my regime, and I started by cutting all sugars and starches.

After doing more research I cut out all refined/processed carbohydrate. My only carbs now come from non-starchy veggies and small portions of fruit - mostly berries for glycemic consideration.

I typically eat under 100g of carbohydrate a day. All natural and un-refined.

Many wouldn't call this low-carb ... but I also eat more than 3,000 calories a day currently, and was consuming over 4,000 daily while cycling regularly. (Too cold outside now.) 400 calories of carbs from 4,000 calories of food is fairly low-carb, I'd say. (Today was about 60g of carbohydrate on 3,000 calories - about 8%)

Not exactly what you'd call "calorie restrictive" and most people wouldn't think I'd lose weight on this... but I did. LOTS.

I currently weigh about 220lbs. I'm 6'3" and large-framed (True Mesomorph). I now have a 35" waist, and am aiming for a 34". My A1c is now 5.7%, well-under the diagnostic criteria for diabetes. My fasting blood glucose is now usually under 5.5 mmol/L (<100mg/dl) which is not perfect, but much, much better.

One thing I've found out as a diabetic who's been researching obesity, diet, exercise and doing lots of n-1 tests, is that we are ALL physiologically different.

As such, I'm not sure there's any ONE underlying problem. Myself, I was genetically prone to it, and didn't eat in a way that prevented it.

James said...

I posted a summary of Dr. Guyenet's important new article on the hypothalamus and obesity here:

Good work, Stephan.

James Hill, MD

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