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Is the Insulin Theory of Obesity Over?

Kevin Hall, PhD, says his most recent metabolic ward study combined with the paper his team released over the summer falsifies the insulin-carbohydrate theory of obesity.

The insulin theory of obesity, in short, posits that higher carbohydrate diets increase insulin secretion, which then drives fat storage and essentially “starves” muscles and organs of energy. This causes increased hunger and overeating. The reason a low-carb diet works, according to the theory, is that the lowered levels of insulin allow for the body to begin metabolizing fat and increase energy expenditure. Some, though perhaps not all, proponents of the theory think that the reason this works is due to a “metabolic advantage” of a low-carbohydrate diet – ie a person on a low carb diet burns greater calories than a person eating a diet higher in carbohydrate.

In Dr. Hall’s study published in Cell over the summer, he showed that two-groups, in a crossover trial of two diets – one high carbohydrate and one moderate – found that those on the reduced carbohydrate diet experienced significantly lower 24-hour energy expenditure and sleeping energy expenditure, while the low-fat group saw no change in expenditure from baseline.* Interestingly, the low-fat group also lost a greater amount of fat compared to the lower carbohydrate group.

This most recent study, which should be published in a few weeks, goes one step farther. In this study, a group of 17 overweight and obese men were put onto a controlled, high carbohydrate, calorie-controlled diet for a month and then switched to a very low carbohydrate high fat diet (80% calories from fat) for a second month. After participants were switched to the low carbohydrate diet, they experienced a small increase in energy expenditure that decreased then disappeared over the four week duration. This, Hall explains, essentially disproves the idea of the metabolic advantage.

Additionally, this short-term increase in energy expenditure on the low carb arm was consistent with the predicted change modeled in the study Hall's team released over the summer. In that study, which created a mathematical model based on the outcomes of the two-week diets, Hall predicted that that a ketogenic (5% carbs) diet would increase energy expenditure by about 100 kcals/day. In essence, both a very low fat and a very low carb diet create very small increases in energy expenditure.+

Hall said, "I think the combination of these two studies on the metabolic side of things basically falsifies the carbohydrate insulin hypothesis."

It is important to note, Dr. Hall adds, that the studies "only falsify the predictions of the carb-insulin model with respect to body fat and metabolism changes," but, "still could be true regarding hunger/appetite." This model, since the diet arm was calorie controlled, could only test for metabolic effects and could not account for ad libitum intake.

Yesterday, Dr. Yoni Freedhoff had the opportunity to speak with Dr. Kevin Hall during his poster presentation at the International Congress on Obesity (ICO). They livestreamed an explanation of the study and the poster on Periscope.

While both Dr. Freedhoff and Dr. Hall agree that there is no metabolic advantage for low-carb diets, they also discuss the possibility that the primary benefit of a lower carbohydrate diet is an increase in satiety. And if low-carb diets do have positive impacts on satiety, they can cause spontaneously lower caloric intake in an ad libitum diet.

Dr. Freedhoff had this to say about the conversation: "Putting hypotheses aside, if you're considering ketosis as a means to lose weight, don't forget that if you stop your diet, just as with any diet, the weight you've lost is almost certain to return. So with whatever diet you choose, you'd better be damn sure you like it enough to keep with it forever."

See the video and poster below or and the transcript of their conversation.

Transcript of the video:

Dr. Yoni Freedhoff (YF): One of the world’s experts in metabolism and he was funded by the Nutrition Science Initiative

Dr. Kevin Hall (KF): And the NIH

YF: And the NIH to do a metabolic ward study and I am just going to ask him to talk us through what he found.

KH: Sure so basically we were really interested in the idea of trying to test this carbohydrate insulin hypothesis for obesity which posits that basically obesity is caused primarily because of high insulin levels which are driving fat into fat cells starving the rest of the body and thereby basically causing increased hunger and decreased energy expenditure.

So one of the logical consequences of that model of obesity, if it’s correct, is that if I take people who are overweight and have Class 1 obesity, if I then swap out, keep the calories the same, but swap out carbohydrates for fat. In particular if you crank down the carbohydrates really low to 5% of total calories and increase fat to 80% of total calories, that you would reverse some of these things.

And if I clamp, basically, the number of calories then I’m not going to be able to test the effects of hunger but I will be able to test the effects on energy expenditure.

YF: And so if the insulin hypothesis is the correct hypothesis, what would the expectation of the study have been?

KH: Right, so there are two predictions. One, because you decrease the number of carbs dramatically you should decrease insulin secretion. That should release the fat from the fat cells, you should therefore get increased fat loss from the body and you should also then, because you've relieved the starvation, this internal starvation, you should increase energy expenditure.

And previous folks have suggested that that should be 400-600 calories a day of extra energy expenditure

YF: And that would explain for them why ketogenic, low-carb diets would be beneficial for weight loss beyond "calorie is a calorie."

KH: Right, essentially the idea that I can eat whatever I want and I can actually eat maybe even more calories, slightly, than I was eating on a previous high carbohydrate diet yet still lose weight and body fat. You can't get that for free so you've gotta increase energy expenditure.

YF: And so how long, sorry, how long was this, this was a one-month setudy?

KH: This was a two-month,

YF: Two month?

KH: Two month inpatient metabolic ward study. People, 17 overweight, class 1 obese subjects, I know I just screwed up my first, people first language...

YF: That's ok that happens to the best of us. And so what were the findings, let's go through, I'm just going to shift over to, you want to use your pen to point to things.

KH: Yeah so here is the study design, basically. Two months onsite metabolic ward. The basically the first period is a baseline diet, high carbohydrate diet, 25% of total calories coming from sugar and every week they spent two days inside a metabolic chamber. And basically what we do is over the first period of time we adjust the number of calories to match what they were burning inside the chamber so that we put them in energy balance inside the chamber and then we clamp the calories for the rest of the period of time and switch them to an 80% fat 5% carbohydrate diet keeping protein clamped all the way along.

YF: And there's no opportunity to cheat here, these are people who are, sadly for them I imagine in a locked ward in a sense?

KH: They are in a locked ward in that sense, they can have visitors but they have to have their visitors in public. They have to eat all of their food in front...

YF: Who does this? Who did you find to actually do this for two months?

KH: We found 17 very motivated people to do this.

YF: It's amazing

KH: They were compensated let's just say that

YF: I bet they were, this could not have been a cheap study. So then results wise, talk us through the results.

KH: One of the interesting things was that despite the fact that we were trying to put them in energy balance in the chamber and we were actually able to do that. Um, outside the chamber they actually burned more calories. Not too surprising in retrospect but we actually were surprised by the magnitude of how many more calories they were burning outside the chambers. Upwards of 500 calories a day more outside of the chamber than insider the chamber. So what that meant was that we were feeding them more or less in balance in the chamber but we were underfeeding them outside the chamber.

YF: And that's simply because they were in the chamber and weren't doing very much?

KH: Yeah it's a small room

YF: They can't exactly exercise a great deal?

KH: Exactly. So that's the other part we tried to clamp the physical activity as much as possible. Three 30 minute sessions, fixed sessions on cycle ergometry every day for the entire period of time

YF: And I imagine unlimited bandwith for their internet connections?

KH: Yes, exactly. Lots of television lots of internet…

YF: Ok so then back to the results

KH: Ok so what happened. The blue period of time, this is the last 15 days of the baseline run-in high carbohydrate diet so they're losing weight slightly. It's a roughly 300 calorie a day negative calorie balance over all. They're losing fat over this period of time. We switch them to the low carbohydrate diet, they lose a good chunk of weight about 1.6 kilos right away. Interestingly, and I think most importantly for the carbohydrate insulin hypothesis is that the fat mass slowed.

YF: So the loss of fat mass slowed down

KH: Yes, exactly

YF: On a low carb high fat diet.

KH: Taht's correct yes.

YF: I'm assuming not what we predicted.

KH: The prediction was, you drop insulin, you increase lypolysis, you increase the amount of fat burning and therefore you should you, you should release those trapped fat from the fat cells, you reduce body fat, this is measured by DEXA.

YF: But that's certainly not hat was found here.

KH: No that's not what was found here, we actually saw a slowing of the fat loss, in fact, it took the full 28 days on the ketogenic diet to lose the same amount of fat as the first 15 days.

YF: Sorry so on the first 15 days of the control diet

KH: baseline run-in diet

YF: people lose as much fat as the study diet with the low carb high fat.

KH: That's correct, but more weight.

YF: So they lost from lean mass?

KH: Yes and in fact one of the things that we measured which is not shown on the poster, is that we measured 24-hour urinary nitrogen excretion which is an index of how much protein is being utilized that went up over the first period of the ketogenic diet so they're actually losing protein as well as water.

YF: Now, how fast was that weight loss? It looks like it's only just 2 kg over 28 days so it's basically a pound and change a week.

KH: Yeah but you can see that this period of time very shortly after introducing the ketogenic diet at time zero you get this rapid weight loss and then it's relatively stable.

YF: The only reason I was asking is having seen studies in the past where rapid loss was associated with disproportionate loss of lean tissue. So I wondered whether or not that’s what we were seeing but it doesn't seem like they lost fast enough for that to have happened.

KH: Right, I think that what you're really seeing here is you're seeing a, it's not a huge amount of protein loss. You're seeing a transient loss of protein which is essentially slowing down the fat loss transiently and then that sort of picks back up again after you 've got that transient flood of protein. And we know that insulin, for example, does suppress proteolysis so it's not that surprising based on the physiology. What I'm showing here is the the fact that we've actually done what we've said, this is 24 hour c peptide in the urine, it's an index of how much insulin is secreted in the course of the day. You can see that that drops by 50% in the ketogenic diet. So we're actually doing what we've said we were doing.

YF: We have three more graphs to muddle through for the people who are listeing in, there are 14 people

KH: 14, awesome. So really quickly, basically, the energy expenditure in the chambers is the total number of calories burned while they're spending those 2 days a week inside the chamber. You can see that the induction of the ketogenic diet does cause a slight increase, it's very slight increase.

YF: Not as much as would have been expected?

KH: Nowhere near.

YF: so this looks like to me from here, with the error bars of course, but a hundred calories a day extra on a ketogenic diet as far as burning goes.

KH: And then it goes away.

YF: K.

KH: So

YF: So again not what we would have hoped for.

KH: It wanes linearly over, exactly. And you can see that there's a big chunk of that is in sleeping metabolic rate which again wanes away over time. And then finally, they are shifting quickly to fat oxidation so

YH: So there is a question from Katherine, she wants to know if it goes completely away, but it looks like you haven't done a long enough study to necessarily conclude one way or the other? Maybe it goes back up maybe it goes down, maybe it stops.

KH: Who knows/ But I guess one would have to postulate some very interesting physiological phenomenon to suggest that it goes back up.

YF: I'm sure people will.

KH: Everybody will. IT's never going to be long enough, it's never going to be extreme enough... Interestingly from the purpose of our last paper where the complaint was that nothing that you would get an increase further augmentation of fat oxidation after the first week

YF: And so briefly though for people who hadn't seen the first paper, the first paper was criticized because it was too short.

KH: Too short and not

YF: And so the thinking was that they weren't fully induced into the

KH: They weren't fat adapted.

YF: They weren't fat adapted into the ketogenic state. So that would not be the case here because

KH: Right

YF: Most people would agree that fat adaptation occurs before two months.

KH: Or at least one month, right. So this is they're on the ketogenic diet for a one month period.

YF: Oh yes, sorry that's right.

KH: But interestingly, you'll notice that all of the adaptation occurred within the first week. So 24-hour RQ goes down and stays down. It does not take another nose dive like one might have hypothesized if you had further fat adaptation after the first week. You've got all of it within the first week. So our conclusions are, this is inpatient, controlled, isocaloric, ketogenic diet. Got small increases in energy expenditure basically at the limits of detection using current state-of-the-art methods.

Despite the rapid and substantial in insulin secretion and increase in fat oxidation we saw no augmentation of body fat loss with this low insulin diet, in fact, we saw slowing of body fat loss with the ketogenic diet. And really our data don't support any sort of large magnitude changes that are really physiologically significant in terms of augmentation of energy expenditure that have been hypothesized in the past to be the metabolic advantage of [low carbohydrate, ketogenic diet].

YF: Question from one of the people who is watching was whether or not - what the average weight or BMI was for the participants? It was 17 men with overweight or obesity, it doesn't say what those sort of were.

KH: 29 was the mean BMI they were all class 1 obese or were overweight so the range was 25-35.

YF: And so based on this, I take it that this has not increased your buy-in for the insulin hypothesis in terms of

KH: I think the combination of these two studies on the metabolic side of things basically falsifies the carbohydrate insulin hypothesis.

YF: So that is a very, very firm statement and I won't disagree with you, but it's us, when's the paper coming out, people want to know.

KH: It's a good question, so was just resubmitted to the American Journal of Clinical Nutrition after a round of relatively positive reviews so I would anticipate probably hearing something positive within the next few weeks.

YF: And there was a question was, "Does this mean the hypothesis is now over?" I suspect you would say yes.

KH: I still think that there might be something interesting to say about appetite. That was somehting that was measured very indirectly in the study, which I'm not presenting the data yet

YF: Certainly my clinical experience with ketosis would say that it does indeed help with appetite. The issue of course that I have with it is that I can't find people who want to live like that forever which is something like this requires if you want to keep the weight off forever.

KH: Right, if you're only interested in losing weight transiently then maybe a very low carbohydrate ketogenic diet is the way to go but as Yoni points out you have to be willing to do something permanently to persistently change your behavior to keep the weight off permanently

YF: Awesome, thank you Kevin, I appreciate that and our second, each of us, mutually periscope I dont' think we did that bad. Oh wait, so the question from Katherine was whether or not total protein intake - I mean I do think protein is important in satiety but I think ketosis may have a unique contribution to satiety as well at least that's been my experience but I'd love to see some head to heads in that regard as well.

KH: I think that's an interesting point; one of the things that's also been shown adnd we review this in the paper is that this is the very first time that reducing carbohydrates has been shown to increase energy expenditure even though it's a very minor amount. Everybody else who's ever shown and increase in energy expenditure with including Ludwig's group, has had to increase protein at the same time and we know that protein's thermogenic so one of the questions is, is there really a physiologically significant increase in energy expenditure that can be achieved with carbohydrate restriction, I think this basically answer the question and the answer is probably no.

YF: Terrific, my phone is about to die, Thank you Kevin!

KH: Great, thanks.

*This is a correction from the previous statement that said there was no difference in energy expenditure between the two groups. Thanks to Dr. Kevin Hall for pointing out the discrepancy.

+This clarification was added May 9, 2016

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