Sunday, August 9, 2009

A GUT Feeling about Insulin

Ask ten people how to lose weight (fat), and you'll likely get ten different answers. In fact, if you ask ten "experts" the same question, you'll probably also get ten answers (usually attached to some product or service requiring you to part with some money). Why all of the confusion? After all, it seems a fairly simple question at its base: how do you burn more fat than you store?

I believe there's two key failures in critical thinking underlying the confusion. The first is that obesity itself is a "disease", which needs to be "cured". Many other diseases (heart disease, cancer, etc.) are associated with obesity, and the prevailing thought is that curing obesity reduces risk for these other diseases. However, this ignores the mountain of evidence that an organism's metabolism is self-regulating. In this view, obesity is a symptom of of some underlying disease process which causes systemic failure of metabolic regulation. It is this underlying disease which needs to be fixed; further, it is possible that you can have this disease and not be obese (there are plenty of skinny Type II diabetics). Modern medicine is very skilled at treating symptoms and ignoring the root cause; indeed, this effect is rampant for obesity treatments. How many people do you know that have lost large amounts of fat, only to have it come back worse?

The second failure comes from "black box" thinking. When hearing various prescriptions for curing obesity, I'm reminded of a famous Sidney Harris cartoon. For instance, a friend was recently telling me about a lemon juice diet. You drink lots of lemon juice, and the fat miraculously flows out of the fat cells. This supposedly had something to do with changing the acidity of your blood, but of course when prompted this person couldn't supply any actual physiological mechanism to explain this effect.

To understand the problems with black-box thinking, we can use the example of, uh, a black box. It has a hole where you can put stuff in, and lots of different colored lights that blink in response to whatever you provide as input. Your job is figure out the rules of how the input relates to the blinking lights. As we try different things we find many patterns of colored lights, with no obvious patterns. For instance, we supply two different cube-shaped objects, but each elicits a different light pattern. So "cubiness" is not apparently relevant to the lights.

The behavior of our black box may appear complex, but we don't really know if it's inherently complex, or if we just lack enough information to tease out the rules. We might crack the box open and examine how it actually works, and find that there really is a simple rule at the core, i.e. specific lights turn on depending on the molecular composition. The rule turns out to be simple, but it's the variety of different inputs that result in apparently complex behavior. Once you know how the box works inside, it becomes relatively easy to predict its response to a given input.

If you notice, most studies on diet and health take the black box approach: they diddle some inputs, and observe how those inputs are associated the outputs (e.g. fat loss). But if you don't have some understanding of what's going on inside the box, you just wind up with a mass of confusing observations and associations. So the lack of consensus and mercurial nature of dietary recommendations should come as no surprise.

Unification and Symmetry
Science often faces such situations. The core difficulty is a lack of symmetry. Symmetry means "sameness in the face of change". A perfectly smooth cue ball will look the same no matter how you turn it. Paint some dots on the ball, and you break the symmetry.

We often encounter cases where our observations seem to reflect a lack of symmetry, but if we look hard enough we find a deeper symmetry, one that unifies our observations under a common model. Such was the case in particle physics in the 20th century. Physicists had observed a vast zoo of different particles, first in cosmic rays (high-energy particles from space), then in "atom smashers". There were also four apparently disparate "forces" of nature: electromagnetic, weak nuclear, strong nuclear, and gravitation. The drive (which continues today) was to unify these different things by identifying the underlying symmetry. A "grand unified theory" (or GUT) would explain the all subatomic phenomena with a single model. Some progress has been made, e.g. many of the different particles were found to be composed from a much smaller family of more fundamental particles called quarks. The electromagnetic and weak nuclear forces (the latter causes radioactive decay) we discovered to actually be one in the same, the apparent difference occuring because the universe is relatively cold.

A Unified Theory of Fat Storage
Can we find a corresponding unifying principle for how fat loss and gain are related to diet? I think the answer is a qualified "yes". We likely need to restrict the domain of our model to one where the observed effect (obesity) has a common cause. Metabolic regulation is complex, and excess fat storage can have multiple root causes. We'll focus here on one possible cause, because it appears to be common and becoming more so: too much insulin, and/or not enough sensitivity to that insulin. Insulin is arguably the boss hormone for metabolic regulation: it effects many systems, and itself is affected by many factors. By examining the effect of insulin both on the behavior of individual cells and at the level of global metabolic regulation, we can in effect "open the box": see how inputs affect insulin and insulin response, then follow the effects of insulin in the body, particularly on fat storage.

I am going to make the bold claim that insulin is the unifying factor, tying together many different observations about fat gain/loss. I intentionally said "many" instead of all, because there are other metabolic pathways influencing fat storage (e.g. increased adrenaline promotes release of fatty acids from fat cells). I'll make the further claim that just about any successful reducing strategy (one that results in fat loss) can be explained by its effects on insulin, whether that strategy involves diet, physical activity, drugs/supplements, or a combination. We should also be able to explain both the relative efficacy of different strategies both in terms of rate of fat loss and final equilibrium fat mass (e.g. many diets result in fat loss, but all seem to "stall" at some point; we should be able to explain this stall via our model). Some examples are given below.

Our Grand Unified Theory theory then provides a more solid foundation for discussing the relative merits of different reducing strategies, and more importantly for making decisions about which lifestyle modifications are most appropriate. Instead of sifting through piles of observational evidence and "expert" testimony, you simply ask two questions:
  1. Is my obesity insulin related? (The answer is probably "Yes" for most, but not all. Those whose obesity has some other cause, like a genetic leptin disorder, will need to seek other avenues of treatment).
  2. How does X affect my insulin? From here you should be able to make a more informed decision about whether or not to pursue X for fat loss.
Perhaps more importantly, by moving the focus from a symptom (obesity) to an underlying cause, we can begin to recognize that controlling insulin should have wide-ranging implications for health (insulin does many things beyond controlling blood sugar and fat storage).

A Brief Primer on Insulin
The effect of insulin on fat storage has been covered elsewhere in detail, most notably in Gary Taubes' book Good Calories, Bad Calories. But it is probably worthwhile to hit the high points again. Insulin also does not act in isolation, but plays an intricate dance with other hormones and the nervous system. Some of these relationships are covered here.

Insulin is a protein (you can see a computer-generated representation here). Like all proteins, there is a gene that encodes the particular sequence of amino acids for manufacturing insulin. One of the interesting facts about insulin is that it's structure is remarkably consistent across time and species. Thus, species which appear genetically divergent, like humans and hagfish, do make different forms of insulin and the insulin receptor, but they're more simillar than different: human insulin has a large degree of cross-reactivity with hagfish insulin receptors, and vice-versa. So insulin has been around a long time, and the relative lack of cross-species mutation is an indication of it's key role in the survival of an organism.

The effects of insulin are initiated when an insulin molecule binds to an insulin receptor at the surface of a cell membrane. This binding triggers a series of chemical reactions, generally culminating at the cell nucleus, where genes are either up-regulated (meaning they make more of some protein) or down-regulated. Most people are familiar with the role of insulin in controlling blood sugar. One major effect of insulin binding is the manufacture of glucose transport (GLUT) proteins, which move glucose out of the blood, across the cell membrance, and into the cell. But insulin has many other effects. It is mitogenic, which means that it promotes cell division (i.e. insulin is a growth hormone). Insulin plays a key role in the manufacture of cholesterol from glucose, both by up-regulating transport of glucose into the cell and controlling manufacture of HMG-CoA reductase, and enzyme required to transform HMG-CoA into cholesterol (side note: statins block manufacture of HMG-CoA reductase). And there's a pile of other functions as well.

When insulin binds to an insulin receptor, it not only causes a chemical signal to be sent. The entire insulin/receptor complex is also absorbed by the cell (endocytosis), removing the insulin from circulation. A condition in which there is too much insulin in the blood (hyperinsulinemia) could thus result either from too much insulin being produced in the pancreas, or from a relative lack of insulin receptors. Correspondingly, insulin resistance (the failure of cells to respond to the insulin signal) could result from a lack of insulin receptors, a failure in the chemical signal chain, or from some other molecule (like a lectin) physically blocking the insulin receptor.

We should also realize that insulin does it's thing via it's effect on genes. Genetic differences can thus imply diferent responses to insulin. Genes carry the code to manufacture proteins, and a rather small difference in gene activation by insulin can result in large visible differences between individuals. This is particularly true for fat storage. We'll see below how insulin triggers manufacture of lipoprotein lipase (LPL) which is necessary for fat storage. A small difference in the amount of LPL made in response to insulin results in a small difference in net amount of fat storage. But whether that small difference results in net negative or positive storage could determine whether or not an individual will become obese.

On to the point. Insulin controls fat storage primarily through three pathways:
  1. Up-regulation of lipoprotein lipase (LPL)
  2. Down-regulation of hormone sensitive lipase (HSL)
  3. Up-regulation of glucose transporters.
The basic unit of fat is a fatty acid. Fatty acids are not water soluble, as anyone who has tried to mix oil and water knows. Blood is mostly water, and having fat droplets wandering around your blood vessels is not good. So fats need some other water soluble molecule to transport them around in the blood. Individual fatty acids can be transported bound to a molecule of albumin, but this mostly occurs for fatty acids released from fat cells. Dietary fats and those made in the liver are carried mostly as triglycerides in large molecules called lipoproteins. Triglycerides are also the storage form of fat in fat cells. A triglyceride is composed of three fatty acids stuck to a glycerol backbone.

Triglycerides are too large to pass across the cell membrane. In order for fatty acids to get in/out of a fat cell, they must be freed from the triglycerides. Enzymes which perform this task are called lipases. Lipoprotein lipase (LPL) acts on lipoproteins in the blood to free fatty acids for transport into the fat cells. Hormone sensitive lipase (HSL) acts on triglycerides inside the fat cell, freeing fatty acids for transport out of the fat cell. The precise mechanism by which the fats actually make it across the cell membrane isn't entirely clear. Cell membranes are largely made of fatty acids themselves (in the form of phospholipids), so it's like that free fatty acids passively diffuse across the cell membrane (whereas water soluble substances, like glucose, generally require the help of a transport molecule). There is also evidence of fat transporter molecules, though these may be more important in cells like muscle that may need energy faster than can be supplied by passive diffusion.

The fatty acids inside the fat cell, regardless of their origin, are candidates for esterification, which just means they can be incorporated into triglycerides. This in turn requires a supply of glucose to manufacture the glycerol backbone (actually a molecule named glycerol-3-phosphate, or alpha glycerol phosphate; we'll use G3P). Insulin is necessary to effect transport of glucose from the blood inside of the fat cell, and also up-regulates a key enzyme (G3P dehydrogenase) required to form G3P from glucose.

Insulin increases LPL and decreases HSL. The relative concentration of fatty acids inside and outside of the fat cell are thus governed by insulin, as well as the availability of lipoproteins in the blood. Fatty acids tend to move from high concentration to low. If insulin is low, HSL activity is increased, fatty acids tend to build up in the cell and diffuse out to the blood. If insulin is high, LPL activity is increased, fatty acids build up outside the cell and tend to move in. Once inside the cell, insulin governs the relative rate at which fat is stored, not only through HSL, but also by effecting glucose transport and regulating G3P dehydrogenase.

There are other metabolic pathways which affect this process. Some, like de novo lipogenesis, are also regulated by insulin. Others, like acylation stimulation protein (ASP), appear to be independent of insulin. There are ongoing arguments as to the relative importance of the various pathways, but I think the evidence is pretty clear that insulin is king of the hill when it comes to fat storage. For instance, Type I diabetics, who make little or no insulin, basically lack the ability store fat. If ASP were important in humans, Type I diabetics should be able to store plenty of fat (since one of the symptoms of Type I diabetes is ravenous hunger, I think we would have observed this). Any Type I diabetic who injects insulin, however, is familiar with the "fat pad" that forms at the injection site, due to (ta da) the high concentration of insulin in that area.

So, lots of concepts and big words in the above. The takeaway is simple: more insulin means fat cells store fat; less insulin means fat cells release fat. The equilibrium point (at which you're neither storing nor releasing) is thus largely determined by average insulin levels. We should then be able to predict the effect of various lifestyle changes from their effect on insulin. Let's see how that works out for some commonly recommended reducing strategies.

Low Carbohydrate Diet

This ought to be a no-brainer. Of all macronutrients, carbohydrates have the largest direct effect on insulin levels. Protein also stimulates a little insulin release, but nothing like a quantities of readily available carbohydrate (dietary protein also stimulates release of the hormone glucagon, which tends to counteract insulin's effect of driving glucose from the blood into fat cells, thus reducing fat storage). By itself, fat does not stimulate insulin release (in fact it seems to decrease it mildly). But fat does cause release of hormones like CCK, which amongst other things cause the pancreas to release more insulin for a given stimulus of glucose or amino acids (this is called the "incretin effect"). So eating fat and refined carbohydrates together (which is most food in the Western diet) ought to really crank your insulin. High average insulin means more fat storage - look around any public place if you want to see this in action.

Conversely, removing carbohydrates from the diet should drastically reduce average insulin levels (unless you have some non-dietary problem, like an insulin-producing tumor, in which case you've got bigger problems that being fat). The decrease in insulin should move the body away from fat storage to fat release. Since this fat is now available for energy, appetite should decrease and/or activity should increase spontaneously. All of these effects have been observed repeatedly in both animal and human studies.

Low Calorie Diet (Starvation)
Suppose we just cut calories across the board. Say your nominal caloric intake was 2400 kcal/day, including an average of 300g of carbohydrates. Leaving fructose out of the equation (fructose does not directly stimulate insulin release, but does cause the liver to become temporarily insulin resistant, the net effect of which may be to increase average insulin levels), that's equivalent to about a cup and a half of sugar each day (the gut rapidly breaks down "complex carbohydrates" into glucose for absorption into the blood). Since the total amount of glucose in a normal person's blood is about 1 tsp, this 1.5 cups should have a drastic effect on average insulin levels, as the body works very hard to keep blood glucose in a narrow range (too much or too little glucose in the blood will kill you in a hurry).

Now, let's not change what we eat, just how much. We'll go from 2400 kcal/day down to 1600 kcal/day. That implies we're now eating 200g of carbohydrate per day, implying that average insulin levels should drop significantly. Again, this should result fat loss, since we've decreased insulin from the level that promoted our previous equilibrium. And that's precisely what's seen: starvation diets result in fat loss. However, that 200g of carbohydrate still promotes a fair amount of insulin secretion. We would thus expect initially rapid fat loss, tapering off over time, and finally stalling at the new equilibrium point. And once the fat stops coming out of the fat cells, your body is literally starving, and will likely make you fall off the wagon, so to speak. As your body has become used to lower levels of insulin (i.e. your insulin sensitivity has increased), resuming previous levels of carbohydrate and fat consumption should result in rapid weight gain, overshooting your previous equilibrium point. Which, again, is exactly what is seen.

Low Fat Diet

The low-fat diet is an interesting case, and what is called "low-fat" often involves both calorie restriction and the trading out of refined carbohydrates for more whole food sources, which tend to have less effect on blood sugar and thus insulin. Both latter effects of course will drop your average insulin, and result in some fat loss. The interesting thing here is that reduction in dietary fat should also reduce secretion of incretin hormones like CCK, and thus further reduce insulin. So low-fat diets "work", as is often observed. In fact, I would predict it works better than just generically cutting calories. I don't know if this has been observed. The confusion most people have is the idea that eating fat makes you fat, and thus erroneously conclude reducing fat makes you thin. But all of this action is ultimately effected by insulin.

And that's the rub, because it means it is difficult (and probably unhealthy) to eat low-fat forever. If you don't eat much fat, then you need carbohydrates for energy (using too much protein for energy results in nitrogen poisoning). If you get those carbohydrates from the usual sources, like bread, rice, or pasta, your insulin will go up, and you'll get fat again, whether you eat fat or not (note that excess dietary carbohydrate is converted to fat by the liver). Successful maintenance of a low-fat diet means getting carbohydrates from sources which are slowly digested, and/or maintaining a high enough level of physical activity to burn off excess glucose and enhance insulin sensitivity (more on this below).

Physical Activity

We've all heard the old chestnut that to effect fat loss you just need to "eat less and exercise more". We've seen above how calorie reduction can affect insulin levels. But does exercise do the same thing?

Interestingly, the answer is a qualified "Yes". Let's start with an extreme case (which, as it turns out, forms the basis for the very successful "slow burn" type exercise regimens). Muscle stores glycogen, a form of starch, for use as quick energy. The glucose to make that glycogen gets into the muscle cells via the action of insulin. In the case of muscle cells, insulin stimulates the cell to move a preformed store of GLUT4 molecules to the surface, so glucose can be rapidly absorbed from the blood. Now suppose you completely exhaust the muscle of its glycogen stores. What do you suppose its response will be?

Not surprisingly, the cell cranks out more insulin receptors in an effort to rebuild it's energy. After all, you might need that quick energy to escape the next hungry lion that crosses your path. So exercise increases insulin sensitivity of muscle, and we learned above that when insulin binds to an insulin receptor the cell absorbs the whole complex. So, independent of diet effects, we expect exercise to reduce average insulin levels; further, in doing so, the muscles also clear out some glucose. Both of these effects should lead to some degree of fat loss. Any increase in net physical activity should result in this effect to some degree. Your muscle cells will only make insulin receptors if they need to. If you start as a total couch potato, and then start walking a mile a day, your muscles need to adapt to even this small increase in activity (walking a mile burns about an extra 100 kcal).

And of course, that's what people see. How many friends have you known that started a new exercise regime and rapidly lost some weight? This is often accompanied by pronouncements like "I can eat anything I want, as long as I exercise enough". That's true, at least to the point where the new fat storage/release equilibrium is reached, at which point fat loss stops. Since the individual is no longer getting positive feedback of fat loss for their physical exertion, they usually cut back or quit, but continue eating "anything I want", and of course just get fat again.

And all of this ignores the elephant in the living room, which is overall metabolic regulation. If you use more calories than are totally available to you from food and storage (remember that high insulin makes stored fat unavailable), you should get hungry. Further, the body knows what it wants, and will try very hard to make you eat it. If you burn up the muscles' store of carbohydrate, the resultant temporary increase in insulin sensitivity will drop your blood sugar. Your brain senses that drop, and tells you to go eat some carbohydrates. People often "reward" themselves with a food treat after a workout, or maybe have a sugary energy drink or similar. Of course, this tends to defeat whatever gain in insulin sensitivity your exercise created.

The Challenge

The examples above, I believe, illustrate explanatory power of the insulin hypothesis, bringing many approaches which seemed disparate or opposed (like low fat vs. low carb) under a single explanation. My challenge to you, O Gentle Reader, is to provide counter-examples. Are there fat-loss strategies that cannot be explained by the insulin model? Give it your best shot in the comments.


Dexter said...

I have a few friends that have spent hundreds if not thousands of dollars on the Nutri System weight loss program. All achieved remarkable weight loss of 30 to 60 pounds. But as soon as they went off the system, they all regained the weight plus 10-15 pounds in 6 to 8 weeks.

Nutri System says they use low glycemic (LG) carbs...which apparently do not stimulate a alot of insulin production.

It appears one must maintain the LG foods for a lifetime in order to keep the weight off...which seems to be very difficult in our food abundant society.

And finally the role of widely available fructose and high fructose corn syrup appears to be a major landmine in the SAD.
any weight loss program.

A great lecture about sugar and fructose being poison by an MD at UCSF....

Asclepius said...

"My challenge to you, O Gentle Reader, is to provide counter-examples"

I can't!

There are some curious examples of localized fat loss such as lipodystrophy that would be worthy of investigation - but I'd wager insulin is involved somewhere along the line.

A very enjoyable post.

Drs. Cynthia and David said...

Very nice post. I can't think of any counterexamples.

As for exercise, I always think it's strange that I can feel tired and blase and hungry, then go for a run, and hunger vanishes, energy re-emerges. I know it's just hormones, but they are doing something- adrenaline releases fatty acids from fat cells for fuel; glucagon kicks in and the liver releases glucose. And it seems to require a certain level of intensity, but not necessarily "high" intensity. Too slow, and I will be bored, yawning and hungrier even though theoretically the lower intensity exercise burns more fat (as a percentage of substrate used). After a few hours, I will get hungry again, but it usually takes at least 2-3 hours. Of course a visit afterwards to Starbucks for a mega sweet frappe or mega muffin would wipe out the fat loss, but people don't seem to get that part.


Monica Reinagel said...

I agree that "positive energy balance" is an incomplete explanation for the phenomenon of obesity and that "negative energy balance" is an incomplete prescription for weight loss. However, I think that frumpy old energy balance (calories in/calories out) plays a greater role than you give it credit for—-and that how many calories go "in" and "out" of our bodies is determined by a lot more than just biology (i.e., appetite triggers, metabolism, etc.). There are a lot of behavioral, cultural, and social issues at work too. I think it's short-sighted to consider obesity as a purely biological issue.

Dave said...


The "behavioral, cultural, and social issues" you mention are all ultimately the result of biology. The "lower" centers of the brain, such as the insula (which deals with food rewards) project to many other areas of the brain and influence behavior. The collective results of that behavior amongst interacting individuals gives rise to culture etc.

It would be strange (or so I think) if the most recent evolutionary development (our higher cognitive abilities) could somehow override the more basic survival mechanisms in place.

Dave said...

The other thing to realize is that one clearly needs to change energy balance in order to lose or gain fat. The key question is whether a simple excess/deficit in calories accomplishes this, or if it is more deeply tied up with the physiological response to different macronutrients. In turn, this illuminates the root cause, which then informs treatment decisions.

I like Gary Taubes' way of putting it: You're not getting fat because you're eating more, you're eating more because you're getting fat.

Thackray said...

Dave said:

“I like Gary Taubes' way of putting it: You're not getting fat because you're eating more, you're eating more because you're getting fat.”

Or alternately, the main stream thinking is “we gain weight because we eat too much and don’t exercise enough”. Taubes’ thinking is “what we eat (the SAD) makes us hungry and lazy”.

Re your challenge, Peter reminds us that Taubes’ spoke about the effect of nicotine “releasing free fatty acids from adipocytes”. That seems to be a somewhat different weight loss scheme than insulin restriction.


Philip Thackray

Dave said...


Yes! I was waiting for someone to drop that one.

It's interesting to consider in that context why chronically skinny people might be skinny. All other things being equal, we'd a smoker will keep compared fat off compared to a non-smoker even in the face of hyperinsulinemia. Adrenaline as the same effect, I believe. If your baseline adrenaline level is higher than average, then I suspect you'd be on of those always skinny people. That wouldn't necessarily prevent metabolic syndrome from occurring, just the most obvious symptom of obesity.

Lauren said...

One situation that has me puzzled is when overweight people strip their diet down to meat and water and still don't lose weight. While many on a ZC board tout it as the final answer to weight loss, I notice that there are sincere people over there that have given the ZC path their all and still don't lose.

I would think that eating only meat would calm insulin down enough to lose but these people that I'm thinking about- some men, some women, seemingly healthy otherwise- just don't seem to reap the benefits.

Are they eating too much? Is all that food or all that protein eliciting an insulin response? Why does fat melt away for some and not others?

Dave said...


It may depend on the origin of the problem. If some factor other than food is responsible for high insulin levels, then changing diet may not help. Some individuals have issues with other areas of metabolic regulation, such as appetite (e.g. those who do not make leptin). The success of low-carbohydrate diets in most people occurs because their appetite is naturally reduced as stored fat becomes available. But if appetite regulation isn't working right, one could eat 4000 calories a day, in which case that person would not lose fat.

Losing fat by reducing insulin through diet probably requires that your underlying metabolic problem is diet-induced hyperinsulinemia (and remember, not everyone with this problem is obese). That's a very common problem to be sure, but certainly does not apply to everybody.

Dylan said...

Hey Dave,
Great post. I think you are right on money on both, avoiding the black box approach and the insulin hypothesis. Plus, while most of the super technical stuff was over my head, your explanation was about the best I have ever read.
One thing I'd like to ask is how alcohol would play out in your model.

To your challenge: what about Kitavans? They live on a diet of about 70% carbs (granted they are non-refined food sources) and have comparable health to the Inuit.

Dave said...


Thanks for the kind words.

I haven't been able to find much on insulin resistance and alcohol consumption. I'd guess alcohol induces some level of insulin resistance in the liver, given the metabolic pathways shared with fructose. Anecdotally, I've noticed that if I got on vacation and drink a lot I start getting pudgy even if I really stick to low carb.

Kitavans: I think there's little doubt humans evolved to be able to handle whole-food sources of carbohydrate. If your metabolism is healthy, you can certainly deal with slower release of carbohydrate to the blood without major insulin spikes, excess fat storage, etc. In fact, it amazes me that it takes so long for Westerners to develop metabolic syndrome given the typically large intake of high-glycemic food. Our metabolic regulatory system is remarkably robust.

Leslie said...


Don't forget that a good bit of protein will convert to glucose. Maybe the ZC strugglers have a too-lean diet, and would benefit from more fat consumption?

Olga said...

Hi Dave:

Great post! Is the reason that you need to greatly increase fat consumption on a low carb diet simply to ensure adequate calories? Could this explain the stall that occurs the closer one gets to their ideal weight? Does the body become stingy about giving up it's fat, once there is less available to shed, and does eating enough fat to mimic the amounts originally available at the beginning of the dietary change, solve the problem? So that, one should increase fat consumption as one looses weight.
Out of curiosity, on average,how much protein, carbs and fat do you eat per day? Thanks again.

Sue said...

Do we know the percentage of people who do not make leptin?

Dave said...

Hi Olga.

You need to eat something for energy. While the body can metabolize protein, it burns "dirty". Carbohydrates and fats contain only carbon, hydrogen, and oxygen, and when metabolized the end products are thus water and carbon dioxide. Proteins have nitrogen and other elements which are left behind when protein is metabolized for energy. Too much nitrogen is toxic, so it is filtered out by the kidneys and excreted. Having only lean protein as an energy source overloads the body's ability to keep up, leading to "rabbit starvation".

I think the body knows this, and that's why lean protein tastes lousy. Think steamed skinless chicken breast - yum yum. My daughter won't touch chicken sausage (trumpeted as "low fat" on the label) unless it's drowned in butter or egg yolks (or hollandaise, the combination of the two). And if you try to give my kids skim milk, they'll spit it right back in your face (seriously).

So if you're not eating carbohydrate for energy, that leaves fat. And your mitochondria don't care whether that fat comes from food or your fat stores.

I'm not sure if the body is intentionally stingy about giving up fat. It could just be an equilibrium effect: more stored fat means more free fatty acids at equilibrium. There is probably some level of stored fat and insulin at which storage is balanced by release. Drop the insulin, and the fatty acids are now free to be used for energy, until your new equilibrium is reached. "Stall-busting" strategies, such as the Atkins "fat fast", are aimed at lowering insulin further, while maintaining a caloric deficit.

I eat about 30% of calories as protein, and nearly all of the rest as fat. I have very little carbohydrate, beyond the tomato on my burger or maybe some greens. I actually don't pay much conscious attention to what I eat, beyond avoiding non-whole food carbohydrates.

There's interesting differences between how we perceive what and how much we ate vs. what actually goes in. I remember one football Sunday, we had what I thought was a massive pigout: carnitas loaded with cheese, sour cream, and guacamole. Steak with butter-based sauce for dinner, and home-made low-carb ice cream for dessert. I thought I must have had at least 4000 calories, and actually didn't eat again until dinner the next day.

But on this particular occasion, curiosity got the better of me, and I added up the previous day's meal on Came out to about 2000 kcal. I felt stuffed, but that was my body's way of telling me it had enough energy.

In my carb-eating days, I could have easily put away 4000 kcal in food and beer, and still been hungry for breakfast, because most of the calories would have been made inaccessible by the massive insulin spike. My brain thought I was low on energy, so I ate more. That's how I would up 350 lbs. There's no way I could stuff in 4000 kcal on my current diet. Ran into this the other night, in fact. It had been a hectic day, and I'd skipped breakfast and lunch. My wife and I were doing our football ritual, made up some plates of carnitas. I was very hungry and sure I'd hammer the whole thing, but wound up leaving a good chunk behind. And even by the next morning, I couldn't really think about eating any more.

Dave said...


Haven't found any numbers yet, but this abstract indicates complete leptin deficiency is "very rare", while noting that leptin excess is common in obese patients (leptin resistance apparently precedes insulin resistance in the development of metabolic syndrome).

Anonymous said...

The insulin hypothesis is interesting, but it's still just that, an hypothesis.

I'm aware of the studies that found an effect, but let's not forget all of the studies that did not find any effect of a lower GI diet or difference in insulin sensitivy/secretion.

McLaughlin T.Difference in insulin resistance do not predict weight loss in response to hypocaloric diets in healthy obese women. J Clin Endo Metab. 1999.

de Luis DA. DIfferences in glyacemic status do not predict weight loss in response to hypocaloric diets in obese patients. Clin Nutr. 2006.

DAS SK.Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial. Am J CLin Nutr. 2007.

Aston LM. No effect of a diet with reduced glycaemic index on satiety, energy intake and body weight in overweight and obese women. Int J Obes. 2008.

Sichieri R. An 18-mo randomized trial of a low-glycemic-index diett and weight change in Brazilian Women. Am J Clin Nutr. 2007.

Raatz SK. Reduced glycemic index and glycemic load diets do not increase the effects of energy restriction on weight loss and insulin sensitivity in obese men and women. J Nutr. 2005.

Raben A. Should obese patients be counselled to follow a low-glycaemic index diet? No. Obes Rev. 2002.

It's far from being about to be a theory!

Pretty good read tho, thanks!

Dave said...

"It's far from being about to be a theory!"

I think that depends on how you define theory.

At any rate, remember there is no absolute truth in science. We instead consider the weight of the evidence. A few contradictory studies swing things a bit the other way, but I believe that the evidence still strongly favors the insulin hypothesis. And there's really no viable alternative hypothesis, i.e. explaining how you gain and keep significant fat without the effect of insulin.

Anonymous said...

To me a theory is something proven that had stood the test of time. It still can change, but everyone seems to agree that this is it.

I agree with you that in science we must weight the evidence, and that's why i've provided these studies wich put weight on the other side of the balance.

As far as having a viable hypothesis, the calorie-in/out, albeit not complete and fully understood, still exaplain a lot of things.

If weight loss is the concern, have people eat less and move more, and they will lose weight. Now keeping it off is something else and optimizing body composition is something else too. But blaming insulin for everyone is a mistake.

I've read Good Calories and Bad Calories, and maybe insulin as some role in some people, but obvisouly not in everyone. Just as much as cortisol can bother some peoples, or hypothyroidism some others.

But denying the calorie equation as Taubes does is an error. Calories do count and will always do.

The insulin hypothesis does the same mistake that the fat hypoethesis did : it puts the blame on a single factor whereas obesity is multifactorial.

Such a complex phenomenom cannot be approch with a narrow solution.

But it's still important to consider every aspect of the equation and see if ultimatly, with the client in front of us, it can make a difference or not.

Dave said...

Taubes does not deny the calorie hypothesis, rather the assumption that calories in/out are independent.

The role of insulin in fat storage definitely fits your definition of "theory". The role of calories independent of macronutrient composition does not.

shortrib said...

Thanks, Dave, for this article. Some tidbits here after reading the comments...

I think I finally understand the whole process of insulin and fat storage even though I've been "living it" for nearly two years! My diet is quite similar to yours. :) IOW, I don't worry about it. It's specifically NOT micromanaged.

But one thing I'm still not clear on - what exactly does it mean when a person is insulin resistant? Does that mean that fat storage is no longer happening? or is it that more insulin than is required to handle the carbs pumps out, causing more fat storage? I read Taubes but can't remember.

I have a friend who is overweight and tried Atkins and only lost 1-2 pounds during the induction phase. She was thoroughly through with anything low-carb at that point. She also said she felt sick eating all that meat. I don't know specifically what she ate since she didn't want to talk about it. :/ I wonder now if she didn't eat enough fat.

I do a "boot camp" at my gym (just fer fun!). I nearly fell over when the trainer told people to eat a piece of fruit to "recover" after the class!

Also...I loved your thoughts on biology shaping culture. Wondered if the Kitivans eat carbs that have been fermented or altered in some way? I read somewhere that ancient cultures ate carbs that way to make them more digestible. But they'd still be carbs so...

Dave said...


"Insulin resistance" is really tissue specific, even down to the (generally not well-understood) mechanism by which resistance occurs. Basically it means the tissue in question does not respond to the insulin signal, but the exact how/why is still an open question. In metabolic syndrome, I'd guess it is the liver and/or muscle tissue which become insulin resistant first, both being major glucose sinks. If you're gaining fat, your fat tissue is not yet insulin resistant. Once your fat tissue becomes insulin resistant, there's no place left to put excess glucose and fat, so you wind up with high blood sugar, high triglycerides, etc.

Note that with the prevalence of metabolic syndrome, the term "insulin resistance" is often used to denote a disease state. Some level of insulin resistance is physiologically normal, i.e. you become more insulin resistance while you sleep to keep your blood sugar stable. Similarly, a higher fat level in your blood triggers some insulin resistance. If you're an omnivore, you need a little extra insulin resistance when fat is plentiful, since you're probably not eating much glucose.

I don't know how the Kitavans prepare their carbs, though I suspect it's more a matter lacking specific foods (fructose, maybe grains and PUFA) that trigger insulin resistance rather than a specific method of preparation. I'm also guessing the Western combo of refined carbs and high fat content is bad for insulin sensitivity. Tolerance of refined carbs requires all the insulin sensitivity you can get, and dietary fat drives things the wrong way.

High-glycemic carbs may cause the same effect, since a spike of glucose and insulin causes the liver to convert excess glucose to palmitic acid, which induces insulin resistance. The Kitavans probably eat much lower on the glycemic index.

marxist-socialist said...


i have a question. I am on a high-protein, low-carb, low-fat diet. But i would like to know if whole-eggs are fattening? Because right now i only eat egg-whites. I even have an egg-divider that i bought at the website of Sears For dividing the egg-whites from the yolks. I've been eating this way because i've read that when people are following a low-carb diet they have also to take into consideration the amount of calories. And since fats have the double amount of calories, i thought that it is rational to eat low in fat.

So my basic question again is, if whole-eggs are allowed in low carb diets of 30 grams to 70 grams of carbohydrates a day.



Dave said...


Most low-carb diets are also high-fat. Egg yolks are very nutrient dense, and I would consider the fat therein a good thing.

Personally, I think if you're counting calories, you're thinking too much.

marxist-socialist said...

HELLO DAVE: thanks for your answer !! And you are right !! I've been eating 4 egg whites and 2 yolks in my morning protein pancakes and i feel fuller, as compared to when i made my protein-pancakes with just egg whites. Another thing that i think it's good about low-carb diets is that i don't know but some how you can eat more calories on low-carb diets and still lose weight as compared to the traditional low-fat diets which are supposed to be real low in calories and fats, and make people feel hungry, tired, depressed and deprived the whole day.

Another thing i think about high protein, low carb diets is that they have anti-depressant qualities. I think it's because of the increased brain chemicals caused by higher intake of protein and fats.


Dave said...


Yes, agreed. The theory is you can eat more calories on low-carb because the calories you eat are not being locked away by insulin. Assuming your energy regulation mechanisms are all working (and I think they do in most people, provided the system isn't being bombarded by refined carbs), your total caloric intake is modulated by the fat being released internally. One shouldn't have to think about how many calories are being consumed - no other animal does.

marxist-socialist said...

Dave: hi again, and u are very right !! In fact last night i had to eat about 9 oz. of baked-chicken, that i had in the refrigerator as a snack and i didn't wake up feeling bloated at all. If i did that when i used to follow a diet higher in carbohydrates i would've waken up feeling bloated and with more bodyweight on the scale.

This country and the whole world needs an anti-carbohydrates revolution. We need a political-economic system in which corporations like Duncan Hines would make high-protein cakes made with whey and soy protein powder, instead of using wheat-flour as their basic ingredient.

And more things like that, and also the USA needs to take off the shelves of the supermarkets the excess of wheat white flour, bakery foods made out of white-flour, whole aisles devoted to breads (it's almost crazy how in this country, you can go to any Wal Mart and major supermarkets and see whole long aisles devoted to just cakes, another aisle to white-flour and another to breads. We need more subsidizing of eggs, chicken, meats, green-vegetables and less breads, potatoes, less rice and less cakes, and pancakes.


Thanx again and keep writting scientific articles about carbohydrates, insulin and low carb diets.


randy said...

Nicely presently theory, but it seems to contradicted by real world data.
When you accurately measure what peoply eat (instead of asking them) only calories seem to be determinent. High carb, low Carb don't seem to make a differenct.


If a password is required, I suggest you join.

Predictability of weight loss
W. M. Bortz
JAMA. 1968;204:101-105.

Kinsell LW Calories do count

Metabolic effects of substituting carbohydrate for protein in a low-
calorie diet: a prolonged study in obese patients.

Metabolic effects of carbohydrate in low-calorie diets.

Energy intake required to maintain body weight is not affected by
variation in diet composition

Protein metabolism during weight reduction with very-low-energy
evaluation of the independent effects of protein and carbohydrate on
protein sparing.

Is a calorie a calorie?1,2,3,4

Some Metabolic Changes Induced by Low

Fat, Carbohydrate, Salt,
and Weight Loss

Similar weight loss with low- or high-carbohydrate diets

Effect of a high-protein, energy-restricted diet on weight loss and
energy expenditure after weight stabilization in hyperinsulinemic

Is a calorie a calorie

Effects of an 8-Week High-Protein or High-Carbohydrate Diet in Adults
With Hyperinsulinemia

Ketogenic low-carbohydrate diets have no metabolic advantage over
nonketogenic low-carbohydrate diets.

Dave said...


Thanks for the references. Obviously we can find plenty of studies providing evidence for alternative hypotheses - that's science. The kicker is the (largely unargued) evidence that at the cellular level, fat storage is governed by insulin. My point is that many things affect insulin. Calories obviously do count - eating any kind of a normal diet (one that includes protein), more calories mean more insulin.

The issue as I see it is not calories, carbs, etc. but rather identifying the core causes of metabolic imbalance and their remedies. Insulin appears to be the lynch-pin anabolic hormone. If it is out of wack, so are plenty of other things. Obesity is one symptom of metabolic imbalance, but focusing on that one symptom misses the bigger health picture.

Razwell said...

There sure is:

Gary Taubes ignores his own evidence. You know the photos he shows of victims of lipodystrophy? The insulin theory can't explain why they have obese lower bodies and rail thin upper bodies and vice versa. The blood insulin level is the same everywhere in the body.

Taubes is correct in attacking the Calorie Theory , but has not satisfied a complete alternative hypothesis

Dave said...


The other side of the coin is the cellular response to insulin. If for some reasons the cells stop responding to the insulin signal, then fat will preferentially be released instead of stored. Progressive lipodystrophy must be something like this (may or may not be related to insulin per se) due to its local nature.

That said, I have been thinking lately that the insulin theory needs to be qualified. Reduction in average insulin level is probably a necessary condition for fat loss, but may not be sufficient. If you ate 3000 kcal/day in fat, I suspect the other metabolic pathways and simple diffusion physics would prevent fat loss. And following on your point, it is probably more accurate to discuss the total activity of insulin, sort of the product of concentration and the cellular response. However, we likely exert the greatest control over concentration through dietary modification.

Lori Miller said...

Hi Dave, I know this is very late to the game, but your post covers something I had wondered about for some time: low-fat diets.

I used to follow a low-fat, intense exercise program. I initially lost weight and gained muscle, and then it stopped working and I gained the weight back, even though I followed the program as closely as I had before. I even cut down on calories, to no avail.

After doing some reading, I concluded that the weightlifting required in the program helped burn the insulin from the carbs, and it stopped working because my metabolism changed. Also, I was no longer building muscle; just maintaining it. This happened around age 38, when people typically get that middle-aged spread. (I wrote my humble theory on my blog for anyone who wishes to read it.)

Happy to say I'm on the low-carb train. It's worked well and makes sense to me on many levels. Some of the members on an unrelated forum I belong to are taking this route, too. I try not to be dogmatic when talking it up.

montmorency said...

Even later to the thread:

People like Robert Lustig seem to give more weight to Leptin than to insulin, suggesting Leptin is the dominant hormone.

I don't think Gary is convinced.

I was and still am a firm advocate of Gary's work (including WWGF), but I am open to the possibility that he may have got a few details wrong and that new ideas or new understandings of old ideas may have come along to supplement or in some cases replace Gary's original thinking.

This is the way science should work after all.

One of Gary's critics maintains that his view that it is the fat cells which are the first to become insulin resistant. That person says that the opposite is true, and that they are the last. And then the fat has nowhere to go. I'm not sure what is supposed to happen after that...sorry I don't have references to hand, but there are supposed to be some.

As it happens, even after reading and re-reading GC, BC, I didn't think that Gary explained IR all that clearly.

He did a better job of it in WWGF. However, that is to no avail if Gary's understanding of IR is not quite correct.

I would be interested in finding out the views of experts in the field, both allies and opponents of Gary's views generally, and of those who are neutral.


montmorency said...

On alcohol:

Robert Lustig's "The Bitter Truth" reminds us of the deleterious effects of alcohol (as well as fructose) on the liver.

I think it could be this, rather than any direct effects of insulin response that we might have to worry about.

Anecdotal evidence: When I drink a lot of red wine when I am on vacation, I don't seem to put on much, if any weight.

However, if I have longer periods of drinking red wine (I've given up beer and white wine), gradually it does have an effect, and probably not just on my weight. I suspect that it is the dreaded fatty liver beginning to be evident, and perhaps contributing to higher IR.

Chris Masterjohn's interesting articles on choline tell us that it tends to have a protective effect against fatty liver, caused by either fructose or ethanol. It's not clear whether it can actually reverse any damage already done.

Wise counsel would seem to dictate that it's best not to assume that eating lots of liver and egg yolks gives one a pass to drink oneself stupid!