They become just as fat as normal mice, increasing their fat mass by nearly 150% in 16 weeks. There was no difference whatsoever in body weight or body fat gains between groups. I find it interesting that there's so much attention paid to the Cell Metabolism paper while this study, which is more relevant to common obesity, and published in the highest-impact journal in the world, apparently didn't make the cut.
This study, among many others, suggests that obesity and insulin resistance are related as such:
- Excess energy intake and/or fat gain leads to
- Inflammation, leading to
- Insulin resistance, resulting in
- Elevated insulin
Still think insulin causes obesity? Ask this guy what he thinks about it:
This is a photo from a paper titled "Insulin-sensitive Obesity" (2). According to the paper, that gentleman has a low insulin level similar to a lean person, and normal insulin sensitivity, despite having a body mass index of 45.2! This is true of a significant fraction of obese people, and it has been replicated in other studies (3). What differentiates insulin-sensitive from insulin-resistant obese people? Inflammation (2). Imagine that!
80 comments:
You've got it COMPLETELY WRONG Stephan.
He's a diabetic who's been rotating injecting sites between ONLY THOSE LIMITED NUMBER of SITES.
; )
Either that, or the reporters, doctors, patient and any of the journal's fact checkers lied ... it's all part of the big pharma conspiracy[0]. You know, the same guys that brought down the towers from offices in Tower 7, then "pulled it". I know it's a fact because Gary Tabues & Alex Jones told me.
so there, neener neener neener.
PS - he needs a lot more whole wheat & brown rice.
[0] as Gary Taubes tells us, those doctors are just plain dumb ... but smart enough to pull a conspiracy to make the world fat
small typo, 2nd to last sentence: the apostrophe-ed (or is it 'ed) "s" doesn't belong.
> What's differentiates insulin-sensitive from insulin-resistant obese people?
feel free to delete this comment when you're done with it.
So if you're insulin sensitive and obese, is the insulin released in response to the carbs you consume or not?
Why it seems there might be some variety of ways in which people can become obese. Fancy that.
There still seems to be a role for insulin in most of them though.
Hi Stephan,
I've been preoccupied for the last few days, but I thought I would check in and see how the discussion of the paper is going. Ironically, I have been actually writing a textbook. Don’t worry, it is not on obesity. It is on the role of calcium in signal transduction. Writing textbooks is a massive pain in the ____ by the way. Anyway, I think it is a good time to re-write the textbooks on obesity, but probably not for the reasons that people who read your blog (in agreement or disagreement) think. I also think your argument for not adjusting our collective thinking on the relationship between insulin and obesity is not very convincing. From what I can tell between the two posts (part 1 and part 2) it comes down to two things.
1) Your first statement - “When carefully considered, this evidence suggests an alternative explanation for the results of Dr. Mehran and colleagues.” … which I interpret to mean that you think there is another interpretation of our results. I scrolled down and I didn’t see the alternate interpretation... We fed mice a high fat diet basically their whole lives and one group of mice had a reduction in the Ins1 gene (all mice were lacking Ins2). The mice with reduced Ins1, and therefore reduced fasting hyperinsulinemia, failed to gain weight due to an increase in energy expenditure via the reprogramming of white fat to express Ucp1 (and other metabolic changes). This means that two alleles of Ins1, and by extension hyperinsulinemia, was a requirement for the weight gain. I don’t see another interpretation, and neither did the reviewers, editors or any of the dozens of experts who have seen the work. I’m actually quite curious, please let me know what I missed in the data.
There are many questions that come from our work, obviously, and these will need to be followed up. Additional studies will need to: address other obesigenic diets, examine whether this occurs acutely when diets are changed in adults, and test the effects in the context of the Ins2 gene, etc, etc. There is much more coming and obviously I have the benefit of unpublished data when interpreting the current published data.
I would not dismiss the role of insulin so quickly just because people are using the link between insulin and obesity to advocate for diets that I guess you are not a fan of. For the record, and for all the people out there in blog land, our study did not address diet. In fact we made our mice fat with a high fat diet (triple the fat and half the carbs). Although we would predict that any fattening diet would show the same results, this hypothesis remains to be tested directly. There is an apparently very common misconception out there that diets high in fats and proteins can’t cause an increase in insulin, either chronically or acutely. This is not correct, especially in the chronic sense where the basal levels of secreted insulin essentially represent a steady leak of insulin that is proportional to beta-cell mass. In rodents, and perhaps in young humans, a high fat diet (and maybe any type of calories) can increase beta-cell mass (via the effects of autocrine insulin signalling). This results in increased basal hyperinsulinemia. Remember, our mice were fed a high fat diet from weaning until 1 year. The equivalent experiment in humans would take 1 year olds and feed them a high fat diet until they were 40, without exercise. As far as I am concerned, the question of which diets increase basal insulin more in humans in the long run (months to decades) is open. Some diets are expected to be exceptionally insulin-stimulating, but none would stimulate no insulin as far as I know.
Also, for the blog land record, our results are not incompatible for important roles for the brain and food intake in obesity (there is room for lots of modulators of something as complex as energy homeostasis). I understand from a recent looking webpage that you work in Michael Schwartz’s lab in Seattle (we probably know a lot of the same people at U W), so you must have a strong interest in the brain. I’m working with quite a few neuroscientists up here and there may even be important roles for insulin produced in the brain. The critical experiments remain to be done. Also, for the person who posted on the blood brain barrier. There is a new paper in the most recent issue of Cell that basically says the BBB is plastic (flexible). Gone are the days of people saying emphatically that such and such doesn’t cross the BBB. Sometimes it might cross, sometimes it might not.
2) Your second line of thought seems to be a bit of a deflection, paraphrased as “There are a bunch of knockout mice and human situations where insulin resistance, hyperinsulinemia, obesity and glucose intolerance can all be dissociated from each other.” Yes, of course, but this is beside the point and I think you might be confusing your readers a little. Yes, one can apparently knock both JNK genes out of macrophages and selectively modulate insulin resistance and hyperinsulinemia, without affecting obesity. So what? These were very short term studies, in adult mice and the results are not as straightforward as you suggest to your readers. First, the Cre used knocks genes out of more than the macrophages, including the brain and heart (according the Jax informatics information on this strain). They never checked to see if there was an effect on JNK levels in beta-cells. It is not inconceivable that JNK might have multiple functions in multiple tissues, some of which oppose each other. This gives a complex phenotype and difficult interpretation. In the case of our model, we carefully show that Ins1 is just in the pancreas, so at least we know the full extent on our manipulation. Importantly, we are manipulating insulin directly, not indirectly. This allows us to draw direct conclusions about insulin. The data in the Han paper allows the authors (and you) to draw direct conclusions about JNK1 and JNK2. Everything else is correlation. There are some other peculiarities of their mice. For example, the clamp studies show significant changes in insulin resistance in the control diet and this is not reflected in the IPGTT, ITT or insulin secretion. Seems like several effects layered on each other. At any rate, I fail to see how papers showing that insulin resistance and obesity can be uncoupled by pleiotropic manipulations in signalling pathways or cytokines disproves our observations about insulin. Did you suggested that a double-conditional knockout of JNK-kinase is more relevant to human obesity than changes in insulin secretion? There are no humans with a double conditional knockout of anything. There are lots of humans with genetic differences in insulin secretion (see all GWAS studies published to date on type 2 diabetes and work on the the VNTR alleles linked to juvenile obesity). I think it is very important to note that our protection from obesity in old mice was observed at a time when insulin sensitivity and glucose tolerance were completely normal. As far as I know, ours is the only such model. Perhaps this is why we were able to see such a clear effect.
By the way, Science and Cell Metabolism are both respectable journals, so I wouldn’t worry too much about which is more ‘high-impact’. I prefer to measure the true impact of the paper about 10 years after it is published. I have quite a few that have stood the test of time. There are many papers in J Physiol, JBC, Biochem J etc that are classics and many, many papers in Science and Nature that are never heard from again. I would encourage the readers to judge the data in each paper without considering the journal, or even the authors.
1) Your first statement - “When carefully considered, this evidence suggests an alternative explanation for the results of Dr. Mehran and colleagues.” … which I interpret to mean that you think there is another interpretation of our results. I scrolled down and I didn’t see the alternate interpretation... We fed mice a high fat diet basically their whole lives and one group of mice had a reduction in the Ins1 gene (all mice were lacking Ins2). The mice with reduced Ins1, and therefore reduced fasting hyperinsulinemia, failed to gain weight due to an increase in energy expenditure via the reprogramming of white fat to express Ucp1 (and other metabolic changes). This means that two alleles of Ins1, and by extension hyperinsulinemia, was a requirement for the weight gain. I don’t see another interpretation, and neither did the reviewers, editors or any of the dozens of experts who have seen the work. I’m actually quite curious, please let me know what I missed in the data.
There are many questions that come from our work, obviously, and these will need to be followed up. Additional studies will need to: address other obesigenic diets, examine whether this occurs acutely when diets are changed in adults, and test the effects in the context of the Ins2 gene, etc, etc. There is much more coming and obviously I have the benefit of unpublished data when interpreting the current published data.
I would not dismiss the role of insulin so quickly just because people are using the link between insulin and obesity to advocate for diets that I guess you are not a fan of. For the record, and for all the people out there in blog land, our study did not address diet. In fact we made our mice fat with a high fat diet (triple the fat and half the carbs). Although we would predict that any fattening diet would show the same results, this hypothesis remains to be tested directly. There is an apparently very common misconception out there that diets high in fats and proteins can’t cause an increase in insulin, either chronically or acutely. This is not correct, especially in the chronic sense where the basal levels of secreted insulin essentially represent a steady leak of insulin that is proportional to beta-cell mass. In rodents, and perhaps in young humans, a high fat diet (and maybe any type of calories) can increase beta-cell mass (via the effects of autocrine insulin signalling). This results in increased basal hyperinsulinemia. Remember, our mice were fed a high fat diet from weaning until 1 year. The equivalent experiment in humans would take 1 year olds and feed them a high fat diet until they were 40, without exercise. As far as I am concerned, the question of which diets increase basal insulin more in humans in the long run (months to decades) is open. Some diets are expected to be exceptionally insulin-stimulating, but none would stimulate no insulin as far as I know.
Also, for the blog land record, our results are not incompatible for important roles for the brain and food intake in obesity (there is room for lots of modulators of something as complex as energy homeostasis). I understand from a recent looking webpage that you work in Michael Schwartz’s lab in Seattle (we probably know a lot of the same people at U W), so you must have a strong interest in the brain. I’m working with quite a few neuroscientists up here and there may even be important roles for insulin produced in the brain. The critical experiments remain to be done. Also, for the person who posted on the blood brain barrier. There is a new paper in the most recent issue of Cell that basically says the BBB is plastic (flexible). Gone are the days of people saying emphatically that such and such doesn’t cross the BBB. Sometimes it might cross, sometimes it might not.
Guyenet,
Regarding your argument regarding the rare obese gentleman with normal insulin:
Does finding a black swan suggest that all white swans are a myth?
Obviously there are many possible causes of obesity, not just one. But the most common by far seems to be hyperinsulinemia. And the large majority of obese people have abnormally high insulin, as you know.
JJ
You have missed something. If insulin is constantly present it causes insulin resistance, as you know. What your paper suggests is that high insulin must alternate with low insulin to avoid obesity. Periodic absence of insulin allows adipocytes to 'rest' and maintain their function.
I believe you have some unpublished data saying exactly this. You told CarbSane 'the mice that are fed only in a small window of time are protected from the hyperinsulinemia'.
There is something else you have missed. A high fat diet can cause magnesium deficiency. Mg deficiency means calcium overload, which has been observed in obese human adipocytes and investigated by Zemel, who tells us Ca promotes lipogenesis and inhibits lipolysis.
Andreas Eenfeldt
Your blog says this: 'Is too much insulin the cause of common obesity? Yes, most likely. ..In humans the main cause of elevated insulin is eating too much junk carbohydrates. ..low carb diets consistently outperform other diets for weight loss. It's the insulin, stupid.'
I imagine you mean by junk carbohydrates, those which have had their magnesium removed. But then why not just eat those that haven't? Here's a paper about magnesium deficiency in obese children.
RESULTS
Serum magnesium was significantly lower in obese children... Serum magnesium was inversely correlated with fasting insulin... Dietary magnesium intake was significantly lower in obese children... Dietary magnesium intake was inversely associated with fasting insulin...
CONCLUSIONS ...Obese children consumed a higher percentage of total calories from fat and a lower percentage of calories from carbohydrates. Fiber intake was lower in the obese group... potential causes of lower serum magnesium in obese youth include reduced magnesium absorption secondary to higher fat intake and lower fiber intake. ...several human studies have shown that fermentable oligo- or polysaccharides enhance magnesium absorption...
http://www.ncbi.nlm.nih.gov/pubmed/15855585
So it looks like hyperinsulinemia is a symptom of Mg deficiency rather than the cause of obesity. And that a low-carb diet high in fat and low in fibre could make things worse.
"Does finding a black swan suggest that all white swans are a myth?"
Nope, Eenfeldt, it simply establishes that colour (black or white) is no longer a characteristic of swaniness.
So what was your point, or were trying to be intellectually superior in that you too had read the Clever Phoenician?
One thing about the Johnson et al research I don't understand is this.
The mice are hyperinsulinemic. They are also insulin sensitive.
Yet their BG levels are normal.
Have they developed, by being raise in a high-insulin environment, some other way of lowering BG levels?
Do they have hyperglucagonemia to match the hyperinsulinemia?
Most people who eat a huge amount of food get fat. Some people who eat a huge amount of food don't get fat.
This doesn't prove that overeating doesn't cause obesity.
What we need to learn from the insulin-sensitive obese people is *why* they don't develop insulin resistance.
Andreas – good point on the Swans.
LeonRover – white is still a characteristic of most swans, just not an absolutely defining characteristic. Just like there is no absolute defining characteristic of human obesity or diabetes.
Jane – You say “If insulin is constantly present it causes insulin resistance, as you know.” I’m not sure we know this to be true, at least in all contexts. See swan comments above. As for alternating between high an low, the mice with reduced insulin were lower virtually all of the time.
The data about feeding windows is from another recent Cell Metabolism paper “Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet” by the Panda group. I’m not convinced that changes in circulating calcium translate into the changes in intracellular calcium that might regulate fat. And as noted above, calcium is what I am writing a text book about at the moment.
Gretchen – The blood glucose levels are eventually normal, but there is a period of rapid growth where we get glucose interolerance and impaired fasting glucose. We interpret this to mean that the mice are very close to not having enough insulin for glucose homeostasis but that they squeak by eventually with just what they need. The excess insulin not needed for glucose homeostasis can then be obesigenic. As for other hormones, I wish we had more samples so we could study dozens of candidates. We will have to wait for the next round of studies.
"Mice" "squeak by"
Like your metaphor - if deliberate.
Andreas,
what makes you think that hyperinsulinemia is the main cause of obesity ?
infact, obesity is probably the main cause of hyperinsulinemia.
I think macronutrients are almost irrelevant when addressing the cause of obesity. What matters is the quantity and quality of the food being eaten.
Hi Dr. Johnson,
Thanks for stopping by again.
First of all, I did not intend to imply that Cell Metabolism is an inferior journal, only that it gets less exposure than Science. Cell Metabolism is an excellent journal and it’s an accomplishment to publish there. I basically agree with your perspective that a paper in CM has as much potential to advance science as a paper in Science or Nature.
I fully understand (and appreciate) that you didn’t make any statements about diet in your paper. That part of it originated from the usual media and Internet discussion of your results.
Let’s get right to the heart of the matter here. You said “you think there is another interpretation of our results. I scrolled down and I didn’t see the alternate interpretation”. I felt I was quite clear in my post. The alternative interpretation is that you created a model of insulin deficiency, which tells us about a pathway that must be intact for obesity to occur (similar to the FIRKO), but says nothing about the normal pathophysiology of obesity.
The core problem is that obese people do not suffer from an excess of insulin action, because in obesity, insulin resistance and insulin secretion increase in parallel. That’s why obese people don’t typically develop hypoglycemia or low circulating FFA levels—if anything insulin secretion isn’t quite keeping up with insulin resistance. The point is that there’s a normal relationship between insulin secretion and insulin sensitivity that is preserved in obesity (if anything, total insulin action on glucose and FFA metabolism are diminished, not increased). To understand whether the hyperinsulinemia of obesity is a causal factor in fat accumulation, what you need to do is suppress both insulin resistance and hyperinsulinemia simultaneously, such that the normal relationship between the two is preserved, as it is in both leanness and common obesity.
As I said, this has been done repeatedly, and the results show that hyperinsulinemia makes little or no contribution to fat gain. You suggested that the recent JNK finding in Science could have been an experimental artifact. The ap2 knockout, TNF-alpha knockout, iNOS knockout, CCR2 knockout, and clonidine-treated dogs showed exactly the same thing. Since these were all done using different methods, the likelihood that they’re all due to experimental artifact is basically nil.
You said “This means that two alleles of Ins1, and by extension hyperinsulinemia, was a requirement for the weight gain. I don’t see another interpretation, and neither did the reviewers, editors or any of the dozens of experts who have seen the work. I’m actually quite curious, please let me know what I missed in the data.” I’m not disputing the fact that insulin deficiency can suppress fat gain. It’s the same thing you see in diabetes. What I’m disputing is the interpretation of this finding presented in your paper. Your paper suggested that hyperinsulinemia “drives” diet-induced obesity, and that hyperinsulinemia precedes insulin resistance in the pathophysiology of obesity. This is not the same thing as saying that intact insulin signaling is required for the development of obesity, which it clearly is, as demonstrated by your results, the FIRKO mouse, and uncontrolled diabetes. However, the interpretation of the data presented in your paper, that hyperinsulinemia “drives” diet-induced obesity, and that hyperinsulinemia precedes insulin resistance, is not compatible with the multiple papers I cited above (ap2 knockout, TNF-alpha knockout, iNOS knockout, CCR2 knockout, myeloid JNK knockout, and clonidine-treated dogs). How else do you explain the finding that suppressing insulin resistance completely suppress hyperinsulinemia in these models?
The relevance of the picture of the obese man is this: you stated that “hyperinsulinemia was a requirement for the weight gain” in your study. If this were true in humans—if hyperinsulinemia were truly required for weight gain—you would not expect to see 20% of obese people walking around with normal circulating insulin. It cannot be required for obesity. Of course, this example in and of itself does not eliminate the possibility that insulin could be playing some role. But it does eliminate the possibility that hyperinsulinemia is required for obesity.
Thanks for stopping by and I look forward to your thoughts on this.
Hi Andreas,
Insulin sensitive obese people are not rare; the prevalence of insulin sensitive obesity ranges between 10 and 30% depending on the paper. In response to your question, here's what I said to Dr. Johnson:
"The relevance of the picture of the obese man is this: you stated that “hyperinsulinemia was a requirement for the weight gain” in your study. If this were true in humans—if hyperinsulinemia were truly required for weight gain—you would not expect to see 20% of obese people walking around with normal circulating insulin. It cannot be required for obesity. Of course, this example in and of itself does not eliminate the possibility that insulin could be playing some role. But it does eliminate the possibility that hyperinsulinemia is required for obesity."
This example alone does not prove that insulin has nothing to do with obesity, just as pictures of diabetic guys with fat bellies does not prove that insulin is involved in common obesity. I understand that you have a more nuanced view of obesity that involves multiple factors, and I appreciate that. But there are people who think that hyperinsulinemia is THE cause of obesity. The fact that a substantial fraction of obese people do not have elevated insulin disproves that.
I find it amazing that Stephan apparently believes that insulin is not part of the control loop that controls FA flux into and out of adipose tissue.
People throw insulin resistance around as if it is a disease in itself - failing to realize that someone that is obese needs a bit of insulin-resistance to help direct the flux of fat out of adipose tissue if they ever want to lose weight.
There is another way to think of this: in electronics we talk about control loops with both negative and positive feedback. Looking at the feedback signal is often confusing as the feedback signal can be tiny if the loop gain is high. (It only takes enough feedback to change the output).
In the case of adipose tissue the signals are summed to determine the direction and magnitude of the FA flux. Looking at the absolute level of a single feedback signal is not going to illuminate understanding of what is going on. In other words, as in an audio amp, the feedback signal is not just the inverse of the audio.
If we look at the signals controlling adipose FA flux, the level of insulin has to be seen in relation to the level of insulin sensitivity, leptin, sympathetic stimulation etc.
Insulin obviously is central to this control loop. If Stephan wants to disprove this, he can culture some adipocytes, and measure the net flux of FA in response to insulin. Better yet, why not check out some of the existing research.
As is the normal situation in most biological systems, we have overlapping control loops - thus a single point mutation is less likely to be lethal.
(BTW Large amounts of dietary PUFA inappropriately increases insulin sensitivity ( I discourage the use of the negative term 'insulin resistance' ) - which has a similar effect of elevated insulin. The quintupling of PUFA in the diet correlates well with the obesity pandemic. )
Enough of this silliness -
Hi Karl,
You said "I find it amazing that Stephan apparently believes that insulin is not part of the control loop that controls FA flux into and out of adipose tissue."
You have completely misunderstood what I wrote. Please re-read my posts.
Stephan, It would be instructive to post the photo from the same article showing the pattern of IR fat deposition which is quite different.
What do you think about the argument that says subcutaneous fat is benign as far as health goes?
Stephen the Insulin-sensitive obesity paper is very revealing I think.
To me it looks like insulin sensitivity depends on your ability for your fat tissue to undergo hyperplasia. This is afterall how Thiazolidinedione's work.
Provided you can keep growing loads of new small insulin sensitive adipocytes, your insulin sensitivity will be fantastic. However, just try to lose weight while having all your fat distributed over small insulin sensitive adipocytes......mission impossible.
Hi Dr. Johnson,
One more thought. You said "I think it is very important to note that our protection from obesity in old mice was observed at a time when insulin sensitivity and glucose tolerance were completely normal. As far as I know, ours is the only such model. Perhaps this is why we were able to see such a clear effect."
You base this conclusion on ITTs that apparently were not a very good measure of insulin sensitivity. Christoph Buettner alluded to this in the accompanying editorial. It would be quite extraordinary if your old, obese, HFD-fed animals were just as insulin sensitive as your lean chow-fed animals. This would be totally at odds with the entire rest of the literature. A more likely explanation is that your ITTs were not sensitive enough to detect differences in insulin sensitivity. This seems to be the explanation that Dr. Buettner favored in the accompanying editorial.
Also, your mice had hyperglycemia in one form or another for nearly half the experiment, confirming that this is a model of insulin deficiency. The hyperglycemia resolved after 24 weeks, but who knows what kind of metabolic adaptations were occurring over this time frame.
It reminds me of the liver-specific insulin receptor knockout mice. They are extremely hyperinsulinemic (10X normal) but are just as lean as controls. They are also hyperglycemic as one would expect from the failure to restrain hepatic glucose output. But in old age, the hyperglycemia goes away and this seems to be because their livers poop out. At that point, they remain super hyperinsulinemic and lean but are no longer hyperglycemic. The point is that you can get some strange long-term metabolic adaptations in mice with insulin signaling defects.
If 20% of obese people are walking around with normal insulin, doesn't that mean the insulin hypothesis is actually true 80% of the time?
Human variability being what it is, confounders being what they are, wouldn't this be usually be considered reasonable truth of something?
Not everyone who smokes gets lung cancer, not everyone who gets lung cancer smokes, but no reasonable person considers that the claim "smoking causes lung cancer" is thereby invalidated.
Plainly obesity is a product of various pathologies, or combinations thereof, which explains why different people control weight more easily with different diets and different non-dietary therapies.
No, that only proves that the two are associated 80% of the time, not that one caused the other.
"But in old age, the hyperglycemia goes away and this seems to be because their livers poop out."
This is one explanation for the effect of some alternative diabetes miracle cures, the kind you buy on the Internet.
One Indian site said many of them damage the liver.
Stephan Guyenet said...
You have completely misunderstood what I wrote. Please re-read my posts.
Ok - if you really DO think that insulin does cause an increase of FA flux into adipose tissue - thus removing calories from circulation - isn't it obvious that an increased insulin signal ( if we hold the other feedbacks constant ) is going to increase appetite? Insulin does not have to work directly on the brain to increase appetite. If we divert calories to adipose tissues or withhold the the same calories from the diet - the result is hunger.
If I appear confused, perhaps it is the same reason that JJ isn't seeing your theory clearly laid out.
How does looking at the insulin level of a herbivore being fed a high-FAT + high-sucrose diet in mice with TNFalpha (Their adipose tissue is not going to work normally due to reduced sympathetic stimulation ) or iNOS knockout mice fed an abnormal diet possibly going to show that insulin is not connected to appetite in normal humans? It is a non sequitur.
Why not take two groups of normal mice, fed ad-lib with normal mice diets (no sucrose and a wild-normal very low fat diet(mice don't normally eat sugar and fat diets!)) and start a saline drip in one and add insulin to the drip in the second group and see which one gets fat?
Oh wait - they have been producing fat rodents with insulin as far back as the '60s - the insulin injected rodents typically double their food intake.
http://psycnet.apa.org/journals/com/61/2/189/
Hi Karl,
Again, you have totally misunderstood my point, so let me explain it once more. The key concept to understand is that total insulin action on fat cells, and on any other kind of cell, depends both on the amount of insulin around and on the cell's sensitivity to that insulin. Obese people are insulin resistant, so total insulin action is not increased despite the increase in insulin concentration. That's why they have normal FFA and glucose levels at an insulin level that would make a lean person enter a hypoglycemic coma. If their fat tissue were still insulin sensitive, they would have low FFA levels due to the elevated insulin, but in fact their FFA levels are normal to high. Do you see what I'm saying?
If you give insulin-sensitive animals large doses of insulin, as in the paper you cited, they gain fat because it causes hypoglycemia, which is a powerful trigger for food intake. But if you give them smaller doses of insulin that do not cause hypoglycemia, they do not gain fat, and often they actually lose fat. See these three papers for example:
http://www.sciencedirect.com/science/article/pii/0361923080902233
http://www.ncbi.nlm.nih.gov/pubmed/11821903
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302138/
Dear Stephan,
Thank you for the engaging conversation. I hope that the many readers of your blog will find it informative. I’ve also been trying to answer people’s questions through Twitter @JimJohnsonSci … this has been a really interesting experiment in ‘public science’ in the internet age. Apparently there will be a discussion of this topic at an outlet called “Super Human Radio” on Tuesday. No, I did not make that up ☺
“The alternative interpretation is that you created a model of insulin deficiency”
**There is no relative insulin deficiency in our models. Glucose homeostasis is intact. We have modeled two situations in the paper: 1) a high fat diet-induced hyperinsulinemia and 2) and high fat diet but without the persistant hyperinsulinemia. We did not see diabetes in the majority of mice (and never in older mice) and we did not detect insulin resistance. The insulin levels in the reduced insulin mice on the high fat diet were the same as on the regular mice on the normal diet.
“The core problem is that obese people do not suffer from an excess of insulin action, because in obesity, insulin resistance and insulin secretion increase in parallel.”
**I think this is the crux here. The problem is that “insulin resistance” is such a vague and poorly defined term as to literally have no good meaning. Family doctors define it as hyperinsulinemia. Physiologists define it as defects in glucose uptake, disposal, suppression of hepatic glucose output, FFA metabolism, etc. Biochemists define it as reductions in phosphorylated AKT (or whatever) in cells treated with ridiculous doses of insulin. I don’t dispute that many of insulin’s normal functions are impaired in a state known as insulin resistance, but insulin has so many function and so many of them are either unaffected or even hyperactive. We need a new way to think about these things. Virtually every tissue you can name responds differently in the state of ‘insulin resistance’. Even in the same cell, the PI3K/AKT side of the pathway can be impaired while the RAF/MEK/ERK pathway can be hyperactive and the mTOR pathway can be unaffected. We know a lot more about insulin signalling that we used to. Can you break insulin signalling and dissociate things with mutant mice that affect one or more arms of insulin signalling? Sure. But, I would argue that this reveals very little in terms of the true physiology of the system. The xIRKO mice are somewhat useful for considering the specific tissue where the KO happened, but I wouldn’t worry too much about their whole body phenotypes due to the cross-tissue compensation that plagues these models.
“To understand whether the hyperinsulinemia of obesity is a causal factor in fat accumulation, what you need to do is suppress both insulin resistance and hyperinsulinemia simultaneously, such that the normal relationship between the two is preserved, as it is in both leanness and common obesity. “
**I think you elegantly argued against this point! There is no ‘normal relationship’ between hyperinsulinemia and even the most loosely defined insulin resistance. As you and I have both noted, there are many models where they are uncoupled.
“This has been done repeatedly, and the results show that hyperinsulinemia makes little or no contribution to fat gain.“
**These are all correlations based on models where the investigators set up to study some different gene. We are the only ones to actually manipulate hyperinsulinemia without targeting something indirectly. Isolating insulin is the only way to tell the contribution of insulin. The only experiments that are close to this direct are the diazoxide studies of Alemzadeh where rats or humans were treated with diazoxide and lost weight. Many studies from the same era have shown that hyperinsulinemia precedes obesity and insulin resistance in classical models like the ob/ob and Zucker rat. These studies, suggests that hyperinsulinemia precedes and therefore might cause insulin resistance.
“You suggested that the recent JNK finding in Science could have been an experimental artifact. “
**Artifact is a strong word. I would have liked to see them characterized the expression domain of their Cre model a bit better. That’s all. Generally a really nice study. We did it in our journal club this week.
“I’m not disputing the fact that insulin deficiency can suppress fat gain. It’s the same thing you see in diabetes. What I’m disputing is the interpretation of this finding presented in your paper. Your paper suggested that hyperinsulinemia “drives” diet-induced obesity, and that hyperinsulinemia precedes insulin resistance in the pathophysiology of obesity. This is not the same thing as saying that intact insulin signaling is required for the development of obesity, which it clearly is, as demonstrated by your results, the FIRKO mouse, and uncontrolled diabetes. “
**We might be into the realm of semantics here.
“ If this were true in humans—if hyperinsulinemia were truly required for weight gain—you would not expect to see 20% of obese people walking around with normal circulating insulin. It cannot be required for obesity. Of course, this example in and of itself does not eliminate the possibility that insulin could be playing some role. But it does eliminate the possibility that hyperinsulinemia is required for obesity.”
**Well, I would be careful here. Cross sectional, epidemiological data are not helpful in establishing causality. How do you know that those 20% of people where not hyperinsulinemic prior to or during their accumulation of body fat? These 20% certainly don’t eliminate anything.
Stephan, I'll conclude with a question...
What type of experiment would it take to convince you that an increase in circulating insulin is required for the development of obesity?
JJ,
While trying not to stray too much from the topic at hand, do you have any opinion on whether its possible to become obese or even maintain a state of obesity while faithfully following a very low carb ketogenic diet?
@JJ
If I understand what you are saying, I think You are confirming what I said above, that we can't look at insulin level with out controlling for insulin sensitivity, leptin, sympathetic stimulation and conclude that insulin can't be a causative factor of the obesity/T2D pandemic. We need to look at all factors of this nested control loop of the FA flux of adipose tissue.
(Another way of saying this is that at some mid level of insulin, the direction of FA flux could be reversed by a change in leptin, insulin sensitivity, or sympathetic stimulation; this is a multi-input control/feedback loop - so knowing there are other inputs hardly disqualifies insulin as a factor. )
One question - I see these mice and rat studies where a large amount of the calories come from sucrose with it's fructose baggage - something that mice don't eat naturally. I know that "everyone does it", but in my mind it is an unnatural variable. Even the control diets have more fat and sugar than a wild diet and I wonder if it can be skewing results. How did your group settle on the diets used?
,.,.
I've been on a quest to find causative factors of this pandemic (I spent some time considering fructose and found some counter examples ), I'm now looking at PUFAs - in my life there has been at least a doubling of PUFA in the US diet. It is believed that PUFA's increase insulin sensitivity - if so I can see that it is possible that PUFA's could increase the FA flux into adipose
tissue.
Hi Dave,
I’m a physiologist. I'm not in the business of knowing about or recommending specific diets. I’ve never read a diet book or looked on a diet website (before a few days ago). I don’t have a horse in the race, so to speak. However, I can offer the following observations. Take from it whatever you would like.
1) We tend to oversimplify by lumping everything into 3 big boxes (fat, carbs, protein). I think there is such a thing as healthy foods in each category and these help build a healthy diet. I think we eat too many simple sugars, too many unhealthy fats, as well as salty and high processed foods. It is funny, but I never knew what a ‘paleo’ diet was until I looked it up the other day. The pictures on Wikipedia look a lot like what I like to eat. I live by the ocean and eat lots of sushi, try to eat fresh healthy vegetables, modest portions of meat, etc.
2) I think portion size, meal speed, and meal frequency are important. I have travelled all over the world, and I am convinced that these are important variables. As I have gotten older and less active, I have dropped breakfast in favor of a glass of tea. I eat a modest sized lunch (salad or sandwich or whatever), and then a small dinner. I love high-end chocolate, but I only have very small amounts and I savor it. I find it takes at least 2 months to adapt to a change in diet.
3) I think people should think carefully about anything they put in their mouth. People initially lose weight on virtually all diets because they are playing attention to what they eat (a little like the placebo effect).
4) I think diet should always be considered in the context of exercise. An appropriate diet for an elite athlete is very different that one for a sedentary desk worker. Also, background genetic and epigenetic landscape, and the metabolic context probably dictate how each person reacts to a specific diet.
If I understand your biology question correctly, you are asking me whether I think it is possible gain weight eating mostly fat and some protein. Yes. That is what we did to the poor mice in our study.
Karl,
I think I agree with you, and add that the big picture involves much more than adipocyte FA metabolism.
Our diet was not a high fat AND high sucrose version. These are often used to induce diabetes in mice, because the beta-cells fail faster. The beta-cells didn't fail in our mice and they had no trace of glucose intolerance by 1 year.
We actually chose the diet because we knew that it increased fasting insulin. We actually did not set out to study obesity. We were focused on understanding the mechanisms involved in the expansion of beta-cell mass. The observation that the mice failed to gain weight was serendipitous.
Stephan wrote to Anders "I understand that you have a more nuanced view of obesity that involves multiple factors, and I appreciate that. But there are people who think that hyperinsulinemia is THE cause of obesity"
According to Anders' multiple statements in his blog (like the blog post 'It's the insulin stupid') he does not have more nuanced view. Anders is in the same boat with Taubes & Eades and many others.
These guys turn a blind eye to the wealth of clinical data consistently showing on par outcomes in terms of weight loss on low carb diets. See for example this recent meta-analysis on low carb diets
http://aje.oxfordjournals.org/content/176/suppl_7/S44.abstract
These guys simply have a phobia to diversity and complexity. At the end, their own professional agendas override.
Low fat proponents are not any better, though.
Thank God you exist Stephan!
"If I understand your biology question correctly, you are asking me whether I think it is possible gain weight eating mostly fat and some protein. Yes. That is what we did to the poor mice in our study."
Thanks. I asked mainly because it is common among low carb gurus to credit the reduction of insulin secretion for the blunted hunger and weight loss without counting calories that often occurs on these types of diets.
Oh forgot to add, in addition the low carb gurus tend to have this belief that if you eat a minimally insulinogenic diet, one could eat say 10kcal of fat and either their body would burn it all by raising energy expenditure or excrete the leftovers without storing much of the fat.
Hi JJ
Thanks for your reply.
'..As for alternating between high an low, the mice with reduced insulin were lower virtually all of the time.'
Yes, but did you look at the short-term pattern of insulin secretion? Are the 5-10 minute oscillations normal? I can't imagine that on a high fat diet they would be.
We know that adipocytes do exactly the same 5-10 minute oscillations that beta cells do. Lipolysis oscillates, which means derangements in insulin oscillatory secretion might prevent proper lipolytic oscillations and lead to fat gain.
BTW, you're right about calcium of course. Circulating calcium has the 'wrong' relation to intracellular calcium because of vitamin D. However, I think obesity researchers are neglecting the role of intracellular calcium in adipocytes. We don't even know whether lipolytic oscillations are accompanied/caused by calcium oscillations. I think they must be, but it's remarkable that we don't know. If they are, they would be very sensitive to magnesium deficiency, since MgATP pumps out the calcium.
Andreas:
That person does not have normal insulin, but has normal insulin sensitivity. There is a difference.
The guy has a lot of insulin, and the insulin does cause obesity, but only in conjunction with normal insulin sensitivity. If the person was insulin resistant he wouldn't get fat.
1. "The problem is that “insulin resistance” is such a vague and poorly defined term as to literally have no good meaning."
Amen! People will say that IR is a postreceptor defect and then say that something like cortisol or high BG results in temporary IR.
2. I think one should distinguish between "is required for" and "can cause."
I think many things can cause obesity without being required for obesity.
3. We also need to distinguish between postprandial hyperinsulinemia (caused by eating carbs or a lot of protein) and fasting hyperinsulinemia.
Reijo wrote:
"Low fat proponents are not any better, though".
Actually billions of people have lived with the absence of chronic disease with plant-based, low-fat diets. The highest recorded carbohydrate intake in a living population has been observed among the Papua New Guineans. Carbohydrates accounted for massive 94,6% of caloric intake. The result of a diet based on almost entirely on 19 different sweet potato variants, some fruits thrown in, and a rare pork feast every now and then. Fat intake <3% of calories. Protein intake 25g per day. Given these observations, a diet advocated by Dean Ornish seems to allow grandiose amounts of fat.
Traditional Diets in Asia Pacific and Implications for Health, and the History of Disease Prevention
http://healthylongevity.blogspot.fi/2012/11/traditional-diets-in-asia-pacific-and.html
Anyways, very interesting account Stephen, thanks a lot.
Ah, good ol' Peter: Never met a loose correlation he didn't fall head over heals for.
Hi Dr. Johnson,
I think we're approaching an understanding here. As I alluded to, I believe the results in your paper are accurate and I think they fit in perfectly well with the rest of the literature showing that an intact insulin signaling pathway is required for the development of dietary obesity. There is no question that disrupting the insulin signaling pathway can prevent fat gain.
However, this result does not imply that an excess of insulin action (determined both by insulin concentration and tissue sensitivity to insulin) is a causal factor in common obesity, or that hyperinsulinemia precedes insulin resistance in the etiology of common obesity.
You asked me what experiment would convince me that an increase in circulating insulin is a causal factor in diet-induced obesity. The experiment would be set up as such. Feed a fattening diet to a model that does not develop insulin resistance or hyperinsulinemia, such that insulin does not increase and the relationship between insulin secretion and sensitivity is maintained at the lean level. If obesity does not occur in animals that maintain a lean-type insulin signaling profile in the face of a fattening diet, then that would strongly suggest that the hyperinsulinemia of obesity underlies the fat accumulation observed.
However, these experiments have been done repeatedly and they show that obesity develops readily in mice or dogs that maintain a lean-level insulin signaling profile.
You asked if I think it would be possible to become obese or maintain obesity while eating a VLC ketogenic diet. There are studies indicating that mice can become obese on zero carb diets, though the evidence hasn't always been consistent on this.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488544/
As for humans, my answer is I don't know. I don't know if a person could become obese eating a ketogenic diet. It is certainly possible to maintain obesity on a ketogenic diet-- Internet discussion forums are full of such people. That said, KD does typically cause significant fat loss and apparently it has been a useful tool for some people. Whether that involves alterations in insulin signaling or not, I don't know (probably some aspects of it, e.g. improvements in blood pressure and lipoprotein profile do involve reduced insulin). As far as I know it has never been demonstrated that reduced circulating insulin plays a causal role in the fat loss, but it remains a possibility. However, it is clear that generally the more extreme the diet, the more weight loss occurs, whether it's low carb, low fat, vegan, carnivore, fruitarian, etc.
Thanks for participating. Cheers.
Ah, good ol' Peter: Never met a loose correlation he didn't fall head over heals for.
To overlook a consistent and strong correlation (eg, whenever high-fiber, low-fat diets are eaten, <15%, chronic disease prevalence is low) may result in missed opportunity for healthy longevity.
Hi again!
Stephan, you wrote “I think we're approaching an understanding here.”
I agree. This is fun.
“ There is no question that disrupting the insulin signaling pathway can prevent fat gain.”
Importantly, we did not target ‘insulin signalling’, which is a really key aspect of all of the other studies. Targeting ‘insulin signalling’ is really quite tricky, because insulin signalling is lots of things. You can hit one arm of the pathway (like Akt) and see major changes in other arm (like Erk). We have done quite a bit of signalling work in this area in beta-cells and pancreatic cancer cells. The same complexity is apparent when targeting ‘insulin signalling’ in a specific tissue. 1) the Cre is almost never specific for a specific organ (a good example we all know is the RIP-Cre) and 2) even if it was specific, the compensation from other organs can be profound and is typically un-investigated. Thus, the cleanest manipulations give the most direct answers.
“However, this result does not imply that an excess of insulin action (determined both by insulin concentration and tissue sensitivity to insulin) is a causal factor in common obesity, or that hyperinsulinemia precedes insulin resistance in the etiology of common obesity.”
Here is the remaining gap. Our results (in the controlled and artificial conditions it was conducted) do in fact show exactly that – that the excess of insulin IS required – because when we remove the excess insulin (and only the excess insulin) the obesity does not occur. Also, we clearly see hyperinsulinemia (seen within 1 week after HFD) precede both the obesity (~20 weeks after HFD) and IR (never) in our model.
“You asked me what experiment would convince me that an increase in circulating insulin is a causal factor in diet-induced obesity. The experiment would be set up as such. Feed a fattening diet to a model that does not develop insulin resistance or hyperinsulinemia, such that insulin does not increase and the relationship between insulin secretion and sensitivity is maintained at the lean level. If obesity does not occur in animals that maintain a lean-type insulin signaling profile in the face of a fattening diet, then that would strongly suggest that the hyperinsulinemia of obesity underlies the fat accumulation observed.”
OK. Perfect agreement! So, isn’t this what we did in the mice?!?
I would take it a step further and say that we need to investigate many more types of diets to ensure that the requirement for hyperinsulinemia is not exclusive to the model we used.
“However, these experiments have been done repeatedly and they show that obesity develops readily in mice or dogs that maintain a lean-level insulin signaling profile.”
All these other manipulations target insulin indirectly and/or in addition to something else. The only studies to reduce insulin genetically are ours (mice) and some seminal papers in worms and flies.
“You asked if I think it would be possible to become obese or maintain obesity while eating a VLC ketogenic diet. There are studies indicating that mice can become obese on zero carb diets, though the evidence hasn't always been consistent on this.”
Actually, I didn’t ask this. Someone asked me. I defer to your expertise here :-) and I think we completely agree.
“As for humans, my answer is I don't know.”
Me neither! The experiment is all but impossible to do correctly. Humans make horrible models for research…
"To overlook a consistent and strong correlation (eg, whenever high-fiber, low-fat diets are eaten, <15%, chronic disease prevalence is low) may result in missed opportunity for healthy longevity."
To overlook a myriad of confounding factors is willful blindness or stupidity. "But, but, but those people who live in an entirely different way to us ate "x" and don't SEEM to have had cancer. Must be the sweet potatoes!" The article you linked to on your site is a hodgepodge of anecdotes, poorly subtstantiated dietary reductionism coupled with religious fervour (and all the objectivity that implies). You and Don Matesz are a match made in heaven.
Don't look now, but the Swiss enjoy more longevity than Papau New Guineans ever did. Must be the sweet potatoes!
OK, I'm a comparatively stupid personal trainer,so I'm probably missing the point. As I understand it, you can put on weight by eating low GI foods, (e.g sugar), as the speed of digestion of these foods is such that your body cannot all process the energy released, and stores that which it can't process as fat. As far as I'm aware, this can happen to anyone, whatever their insulin resistance or their BMI. Presumably, insulin resistance would make this worse, but if you stuff yourslef with enough of the wrong foods, it seems that you're going to become obese, whether you're insulin resistant or not. Or is there something I've missed (quite possible!)?
The point that I think Stephan is missing is that 'normal' insulin levels depend on the other feedback loops - insulin sensitivity, leptin, sympathetic stimulation.
Weight gain/loss IS the flux of FA in/out of adipose tissue. ( Can we agree on this?) If we also agree that insulin is one of the controls - the relative level of insulin has to be included in the understanding of obesity.
My background includes work in electronic feedback loops - the effect of insulin is likely not just a simple summed input to the FA flux - as is often the case in both electronics and biology, the feedbacks can be multiplied, act as exponents etc. Thus looking at the level of one feedback component without controlling for the others can't prove your hypothesis that the pro insulin effect of carbohydrates don't have a long term (more than 3 week) effect on the average direction and magnitude of this flux.
My hunch is the reason lowcarb diets work, is that the intricate BG control loop is broken in about 40% of the public. Avoiding carbs returns postprandial BG spikes to less than 110 and reduces trygly levels to around 50.
Even if they were not helpful in maintaining a healthy weight, reducing BG to levels below levels where elevated glucose makes fats become toxic which reduces inflammation and improves overall health needs to be considered.
It is oxLDL is goes into macrophages in the intima of arteries - and one potent intervention to reduce oxLDL is to keep PP BG below 110. Adjusting carbohydrate intake to accomplish this appears a reasonable approach.
Karl, "Avoiding carbs returns postprandial BG spikes to less than 110 and reduces trygly levels to around 50."
This statement is not true in everyone, especially people with diabetes. As with clinical trials, it may be the average response to LC diet, but there are outliers.
Stephan asks if humans can become obese on ketogenic diet. Evidence from the treatment of pediatric epilepsy show that this is possible but rare. Some published patient series describe weight gain as 'side effect'. Here is one open access paper http://www.seizure-journal.com/article/S1059-1311(11)00168-3/fulltext#sec0045 and there is more at PubMed.
Karl, PUFAs improve insulin sensitivity in humans also in the context of low carbohydrate diet. RCT evidence http://jcem.endojournals.org/content/89/4/1641.long
I previously said, "What we need to learn from the insulin-sensitive obese people is *why* they don't develop insulin resistance."
Coincidentally, this came in today and purports to explain why. I only read the abstract.
http://www.nature.com/nm/journal/v18/n10/full/nm.2899.html
BTW, if anyone knows what NEET stands for, I'd be interested to know.
According to Wiki article http://en.wikipedia.org/wiki/CDGSH_iron_sulfur_domain
The CDGSH iron sulfur domain 1 protein is also referred to as mitoNEET is an integral membrane protein located in the outer mitochondrial membrane and whose function may be to transport iron into the mitochondria.
@Galina: Yes, but what do the initials NEET stand for?
Google took me not father that the article http://www.ncbi.nlm.nih.gov/pubmed/22562611
Sorry, couldn't find more.
Gadfly wrote:
To overlook a myriad of confounding factors is willful blindness or stupidity. "But, but, but those people who live in an entirely different way to us ate "x" and don't SEEM to have had cancer. Must be the sweet potatoes!" The article you linked to on your site is a hodgepodge of anecdotes, poorly subtstantiated dietary reductionism coupled with religious fervour (and all the objectivity that implies). You and Don Matesz are a match made in heaven. To overlook a myriad of confounding factors is willful blindness or stupidity. "But, but, but those people who live in an entirely different way to us ate "x" and don't SEEM to have had cancer. Must be the sweet potatoes!" The article you linked to on your site is a hodgepodge of anecdotes, poorly subtstantiated dietary reductionism coupled with religious fervour (and all the objectivity that implies). You and Don Matesz are a match made in heaven"
Thanks for your feedback, please be kind and identity any anecdotes, possible co-founders and religious fervour you encountered so I can pass the info. The kind of ecologic (and clinical data) collected from parts of Asia, Central-Africa and South-America has influenced many western scholars to conduct trials on the effects of dietary intervention to various biomarkers, gene expression, heart disease, diabetes and prostate cancer. Besides, isn't this kind of ecologic analysis of various populations exactly what paleo-folk are all about? Masai this, Inuits that.
Traditional Diets in Asia Pacific and Implications for Health, and the History of Disease Prevention
http://healthylongevity.blogspot.fi/2012/11/traditional-diets-in-asia-pacific-and.html
In regards to specific example of Papua New Guineans on their exceptionally high carbohydrate intake, these people are well studied in terms of living people and autopsies.
Epidemiological studies in a total highland population, Tukisenta, New Guinea: Cardiovascular disease and relevant clinical, electrocardiographic, radiological and biochemical findings
http://www.sciencedirect.com/science/article/pii/0021968173900313
Maybe you just perceive the blog post as "religious fervour" since you probably eat an LDL-C cholesterol elevating diet. We don't like to hear bad news about our bad habits.
Playing around with google a bit more, shows that NEET refers to the single letter amino acid code for the last 4 c-terminal residues of the protein(Asn-Glu-Glu-Thr).
Oh, Petey and his Papau New Guineans...
So good, so protective and healthy is their diet that worldwide statistics rank New Guinea at 29th in the world at a rate of about 186 deaths/100,000 folks. That's *significantly* ahead of those fat-guzzling French, Dutch, Danes, Swedes.... Must be the sweet potatoes.
If we play your game of dietary reductionism, it's pretty clear that the diets of those European countries are vastly superior to that of those in New Guinea.
@Zachary: Thanks!
““However, this result does not imply that an excess of insulin action (determined both by insulin concentration and tissue sensitivity to insulin) is a causal factor in common obesity, or that hyperinsulinemia precedes insulin resistance in the etiology of common obesity.”
Here is the remaining gap. Our results (in the controlled and artificial conditions it was conducted) do in fact show exactly that – that the excess of insulin IS required – because when we remove the excess insulin (and only the excess insulin) the obesity does not occur. Also, we clearly see hyperinsulinemia (seen within 1 week after HFD) precede both the obesity (~20 weeks after HFD) and IR (never) in our model.”
I think this is the crux of the issue here. Can we agree that a positive energy balance (i.e. “excess calories”) is a necessary condition for common obesity? If so, the question is, where do those calories go? It’s obvious that insulin is a major hormone regulating the balance of energy between cells and blood. “Normal insulin action” is primarily about preventing hyper or hypoglycemia, correct?
Dr. Johson, are you saying that both mice maintained normoglycemia despite only the “hyperinsulinemic” mice gaining fat mass? If so, where the heck are the calories going? Muscular tissue? Increased maintenance respiration?
Although insulin plays a role in the CNS, it still seems to me that it operates mostly on short time-scales and is supposed to be responsive to blood glucose homeostasis. Although the signaling is no doubt complex (and above my level of understanding), I fail to see why it is central to understanding common obesity. Again, my distinction is between something that is a proximal cause (likely) versus a root cause (unlikely). I guess the dispute is over what is “intact insulin signaling”? Do you think that variations in insulin signaling play a role in determining whether excess calories are disposed into fat tissue or by some other means? If so, I see what you’re getting at…
Gretchen
Yes, - I'm talking about the vast majority of T2D - some people have done so much damage with elevated BG and secondary effects of obesity that they might have to take meds. There is a large number of people that no longer need medication once they go on a low-carb diet.
@Reijo
I'm saying to opposite of conventional wisdom - while PUFAs increase insulin sensitivity - which even lowers BG short term - the problem starts when people stop getting fatter. Free FA start to leak - the insulin sensitivity once again goes down as the adipocytes are now distended - BG goes back up - the combination of high BG and FFA is toxic.
I think there are serious long term risks eating the large amounts of PUFAs in the US average diet.
"Maybe you just perceive the blog post as "religious fervour" since you probably eat an LDL-C cholesterol elevating diet. We don't like to hear bad news about our bad habits."
Thanks for your concern. Mine is fine. Of course, we know from some of the largest studies done on cardiac risk factors that LDL-C ranked about 9th on the list of stuff. Heck, psycho-social factors are a greater contributing factor to CVD than LDL-C on it's own. But you keep beating that bible, dearest.
You guys better be nice to Peter or he'll get mad and start posting under one of his other accounts (e.g., Bog). Then you'll really be sorry. :)
You see, depending on how much of a troll he's feeling like on any given day, he'll choose between multiple accounts. "Peter" for example is about a 3 out of 10 on the troll scale, whereas "Bog" is like a 9. Actually the "Bog" account got banned a while back so I guess we won't see that one. Oh well. Nevermind. :)
Karl, I see you point. Here in Finland soy, sunflower or corn oils are not an issue, we consume canola and olive oils which are very different. Our intake of n-6 PUFAs is less than 5 E %.
I don't buy your theory. PUFA is not linked to development of T2D or obesity in epidemiological studies, neither in shorter term RCTs.
Mozaffarian & Micha 2010 (Saturated Fat and Cardiometabolic Risk Factors, Coronary Heart Disease, Stroke, and Diabetes: a Fresh Look at the Evidence): "In contrast, three of four cohorts [54] observed lower incidence of diabetes with greater consumption of PUFA and/or vegetable fat [53, 55, 56]."
But who knows, perhaps one day it turns out that you're right.
@Gadfly,
having an access to well sanitized loo's, vaccinations and antibiotics are better predictors for mortality than LDL-C cholesterol. I've never claimed the opposite, however I though you were interested in chronic disease.
LDL-C is causal factor in atherosclerosis. This is well established in biomedical science. There's no atherosclerosis independent of elevated LDL-C cholesterol no matter what is your blood glucose, cigarette smoking status, weight, etc. These risk factors cannot produce plaques themselves. They can only exacerbate the damage CAUSED by elevated serum cholesterol.
Epidemiological studies on homogeneously high risk populations may find better risk estimators than cholesterol, but these should not be confused with mechanism itself. In other words, blood-pressure, cigarette smoking, elevated glucose, HDL levels may turn out to be better risk predictors than cholesterol since until very recently time-weighted exposure to LDL has not been reliable quantified. LDL-C CAUSES plaque formation throughout the life beginning in childhood.
Each 1mmol (38mg/dl) drop in LDL-C cholesterol since birth is independently associated with ~55% reduction in CHD.
Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease: A Mendelian Randomization Analysis
Background LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified.
Conclusions Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.
http://intranet.cardiol.br/coberturaonline/slides/Reduction%20in%20LDL%20Presentation%20Slides.pdf
Lipoprotein lipase Ser447Ter polymorphism associated with the risk of ischemic stroke: a meta-analysis
http://www.ncbi.nlm.nih.gov/pubmed/21816453
Take-home-message: do not mix risk predictors and mechanism of action. Socio-economic status is very good risk predictor for obesity even though it has no direct role in the pathophysiology of obesity itself.
I wrote:
^Take-home-message: do not mix risk predictors and mechanism of action. Socio-economic status is very good risk predictor for obesity even though it has no direct role in the pathophysiology of obesity itself.
Being a poor, middle-aged African-American female in Alabama, USA would translate to almost a bullet-proof risk predictor for obesity and diabetes.
Gretchen, that paper you linked is extremely interesting. I've been trying to find out what iron does in adipocytes for a long time. It seems that iron overload upregulates mitoNEET, which stops iron from getting into mitochondria. This means a shortage of iron-dependent enzymes so the cells can't burn a lot of fat and accumulate it instead. But they're healthier because their mitochondria aren't being damaged by iron, so their production of adiponectin is very good. Adiponectin prevents insulin resistance, so the animals are insulin sensitive despite being massively obese.
Oddly, lipolysis is higher, not lower, but the fatty acids are taken up again into the cell and re-esterified. So I suppose the point of the whole thing is to prevent lipotoxicity to other tissues, including pancreatic beta cells.
People do say obesity protects against diabetes. And diabetes is linked to iron overload. Perhaps one function of adipocytes is to store iron so it doesn't damage beta cells. Then mitoNEET makes sure it doesn't damage the adipocytes, and they accumulate fat so the fatty acids can't damage beta cells either.
Regarding Andreas Eenfeldts view on the cause of obesity. This was published on his Swedish site today, kostdoktorn.se. http://translate.google.com/translate?sl=sv&tl=en&js=n&prev=_t&hl=sv&ie=UTF-8&eotf=1&u=http%3A%2F%2Fwww.kostdoktorn.se%2Fvisst-sanker-lchf-mat-ditt-insulin-kraftigt%2F
He's definitely in the same boat as Taubes. I guess he just doesn't want to show it on the international stage yet.
I guess he didn't want to put it up on dietdoctor.com
I don’t have much word to say since I shared the same thought of the rest of the comments that’s here. To be honest HCG Diet works for me and that is all say. It is painless…
Book-Pal.com
Science will go on discovering many things. Meanwhile, we have some irrefutable facts: incidence of obesity in pre-industrial cultures is low to non-existent, and is the incidence of the chronic metabolic illnesses so common today. In the US, the incidence of obesity and the illneses just mentioned rise in accordance with the ascendence of the food industry. The main factors in this food industry are refined sugar, refined flour, refined vegetable oils, artifial flavors and coloring. That is really all you need to know to assure health insofar as health is related to diet. As for how this unholy mixture in industrial food plays havoc in different ways with different human beings, that will no doubt provide grist for scientific mills for many years to come.
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