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Thursday, July 30, 2015

Insulin Resistance ~ Taubes v. Frayn aka Adiposopathy 101

I thought in the interim of doing something more formal, I'd bump this post from October of 2010.  Keith Frayn, for newer readers, is recently retired prominent Oxford scientist who wrote one of the books Gary Taubes likes to use pictures from these days in his lectures (you're welcome Gary, if only you'd read the book more thoroughly).    Metabolic Regulation.  {as textbooks go this one is relatively economical though I probably wouldn't recommend it unless you've got some scientific background in the subject ... or a lot of patience, because it should be manageable if tackled in smaller doses }

He lays out the basics of Adiposopathy - pathological fat - sick fat - though doesn't use the term.  The evidence for this is overwhelming, and although this is just an outline of sorts, it only needs some clarifications and fleshing out with evidence of various components and the mechanisms involved.  In that regard, much progress has been made enforcing the hypothesis continuing to this day.  

I've left my original post largely unchanged except with a few formatting changes for ease of reading.



Original Publish Date:  10/24/2010

Let's start with a discussion of :

Adipose tissue and the insulin resistance syndrome

(Another contribution from that "English Guy" ... Keith Frayn ...  note the date:  2001)
Obesity is associated with insulin resistance. Insulin resistance underlies a constellation of adverse metabolic and physiological changes (the insulin resistance syndrome) which is a strong risk factor for development of type 2 diabetes and CHD. The present article discusses how accumulation of triacylglycerol in adipocytes can lead to deterioration of the responsiveness of glucose metabolism in other tissues. 

 

Lipodystrophy, lack of adipose tissue, is also associated with insulin resistance. Any plausible explanation for the link between excess adipose tissue and insulin resistance needs to be able to account for this observation.
Adipose tissue in obesity becomes refractory to suppression of fat mobilization by insulin, and also to the normal acute stimulatory effect of insulin on activation of lipoprotein lipase (involved in fat storage). The net effect is as though adipocytes are ‘full up’ and resisting further fat storage.
Thus, in the postprandial period especially, there is an excess flux of circulating lipid metabolites that would normally have been ‘absorbed’ by adipose tissue. This situation leads to fat deposition in other tissues.
Accumulation of triacylglycerol in skeletal muscles and in liver is associated with insulin resistance. In lipodystrophy there is insufficient adipose tissue to absorb the postprandial influx of fatty acids, so these fatty acids will again be directed to other tissues. This view of the link between adipose tissue and insulin resistance emphasises the important role of adipose tissue in ‘buffering’ the daily influx of dietary fat entering the circulation and preventing excessive exposure of other tissues to this influx
That abstract explains the somewhat paradox of the "metabolically obese thin people".   One function of adipose tissue is as a buffer of sorts to maintain appropriate circulating lipid levels.  This is important because of the basic physics of  immiscibility (non-mixing) of aqueous and non-polar liquids (think water and oil).   The over-stuffed adipocyte model makes sense even from a common sense point of view.  If you think about blowing up a balloon, it gets harder and harder to push more air into it the larger and more filled with air it becomes.  Also, the mechanical integrity of the balloon deteriorates the more we stretch it.  When you look at an adipocyte, they sort of resemble balloons.  The "metabolic stuff" is located near the membrane on one side (other cells have nuclei more central to the cell and mitochondria and other organelles throughout), sort of like the air inlet on a balloon.  One can expect the stuffed cell to have diminished integrity, etc.



Here is a rather simplistic model Frayn uses to describe the development of IR:


Note that Frayn implicates energy excess in the development of obesity.  From the discussion:  
...If increasing fat storage in adipose tissue is associated with increasing insulin resistance, the simplest explanation might be something like that shown in Fig. 1; adipose tissue releases some signal (‘substance X’ in Fig. 1) that affects muscle and liver glucose metabolism (since these are the metabolic variables measured as insulin resistance)....
The most consistent evidence in favour of a candidate for substance X relates to fatty acids. (The general term fatty acids, rather than non-esterified fatty acids (NEFA), has been used for reasons expanded later.) ... NEFA release from adipose tissue is suppressed by insulin in both lean and obese individuals, but in obesity the process is ‘insulin resistant’ in that the dose–response curve is shifted to the right. NEFA release per unit fat mass is actually less in obese subjects than in lean subjects (effectively, it is down regulated by the fasting hyperinsulinaemia).  However, because of the increased fat mass, total NEFA delivery to the circulation is increased in obesity. Furthermore, if ‘lean body mass’ (including skeletal muscle and liver) is used as the denominator for NEFA turnover, then NEFA delivery to the consuming tissues is clearly increased in obesity. The ‘insulin resistance’ of adipose tissue lipolysis may be particularly relevant in relation to the delivery of NEFA in the postprandial period.  Despite high plasma insulin concentrations in response to a standard mixed meal, obese subjects fail to suppress NEFA release from adipose tissue at a time when it is completely suppressed in lean subjects.
So, in lean people, postprandial insulin *traps* fat in the cells, yet they are lean, so obviously this fails to result in net accumulation.  But in obese people, the insulin FAILS to trap the fat in the cells.  Thus there isn't this lack of available fatty acids to the hyperinsulinemic person as is sometimes portrayed by the authors of popular diet books.  
... in obesity the insulin-sensitive glucose-consuming tissues are subjected to an increased influx of fatty acids, and this increase is particularly marked in the postprandial period when adipose tissue, through ‘insulin resistance’, fails to protect other tissues from the influx of dietary fatty acids.
Frayn's description of insulin resistance is clearly of the "fat fails first" variety.  A theory consistent with the available evidence in 2001 (around the time of "Big Fat Lie", and LONG preceding the research and publication of GCBC).

So ... once again, I'm left to wonder how Taubes arrived at his version of the progression of insulin resistance in his GCBC book.  Starting on p. 394 of GCBC on Google books, (the entirety of the excerpts to follow are not available on Google, but I presume this page number corresponds to that of the hard copy).
"Over the years, prominent diabetologists and endocrinologists -- from Yalow and Berson in the 1960's through Dennis McGarry in the 1990's -- have speculated on this train of causation from hyperinsulinemia to Type 2 diabetes and obesity.  Anything that increases insulin, induces insulin resistance, and induces the pancreas to compensate by secreting still more insulin, will also lead to an excess accumulation of body fat.
That highlighted sentence is simply not true.   Neither carbohydrates nor proteins are associated with insulin resistance.  Indeed the only carb associated with IR at all is fructose, and fructose is also the one carb that doesn't elicit an insulin response.  

Taubes goes on to discuss James Neel "revisiting" his thrifty-gene hypothesis and how in 1982 Neel rejected it, instead suggesting three scenarios of physiological responses to excessive glucose pulses.   The first scenario involves a disproportionate quick insulin response.  The second involves the development of IR so that a proper insulin response fails to clear glucose from the blood.  But Taubes seems to focus on the third:
Neel's third scenario is slightly more complicated, but there's evidence to suggest that this one comes closest to reality.  Here an appropriate amount of insulin is secreted in response to the "excessive glucose pulses" of a modern meal, and the response of the muscle cells to the insulin is also appropriate.  The defect is in the relative sensitivity of muscle and fat cells to the insulin.  The muscle cells become insulin-resistant in response to the "repeated high levels of insulinemia that result from excessive ingestion of highly refined carbohydrates and/or over-alimentation," but the fat cells fail to compensate.  They remain stubbornly sensitive to insulin.  So, as Neel explained, the fat tissue accumulates more and more fat, but "mobilization of stored fat would be inhibited."  Now the accumulation of fat in the adipose tissue drives the vicious cycle.
Note:  Neel's exact words are presented in quotations, Taubes' words fill in.  Based on my fact-checking of some of Taubes' other references, I'm not at all sure Neel actually stated that fat becomes IR last.  But, presuming Taubes' characterization of Neel's work is accurate, this is clearly counter to Frayn's work above.  (See also The Progression of Insulin Resistance and Fat Fails First?)   However do note that even Neel's sequence of events begins with over-eating of carbs and/or in general.  This is counter to the whole "but why do we overeat" nonsense, and the whole "fat accumulation drives us to overeat, not the other way around".  IOW, Taubes inadvertently (as he does numerous times in GCBC) provides references/evidence counter to his unnecessary "alternate hypothesis",  and Critical Conclusion #5.
This scenario is the most difficult to sort out clinically, because when these investigators measure insulin resistance in humans they invariably do so on a whole-body level, whic is all the existing technology allows.  Any disparities between the responsiveness of fat and muscle tissue to insulin cannot be measured.

FALSE

I could list many MANY more.   Dated in the 90's and such.  This is a big problem with GCBC that I've had since I first heard someone extol its virtue of highly referenced extensive research.  SOOOOOO much of that is 40+ years old, and Neel's work referenced here was over 25 years old at the time of GCBC's publication.  

Insulin Resistance – What Is It and How Do We Measure It?  This is an equine publication from 2009, but a review of older works.  

Clearly the understanding of IR and it's progression pre-dated GCBC.  If only Taubes had bothered to do such research?  Perhaps Taubes hadn't yet heard of or become acquainted with Keith Frayn?  Unfortunately he can't claim that b/c he cites Frayn in GCBC.  

I can only conclude that this is an example of the "scholarly incompetence" Taubes seemingly prefers to cop to.  Or could it be selling books?  LOL ... how dare I suggest that!

23 comments:

malpaz said...

awesome post leaving me dazed and confused....

Sanjeev said...

>> extol it's virtue of highly referenced extensive
>> research. SOOOOOO much of that is 40+ years old,

Made me guffaw.

I tried to have a reasonable discussion of Taubes some time ago. I should have known that despite their protestations "reason" was not high on their priority list when the first response to my suggestion to look at the book critically was

"clearly you have not read the book"

Anyway, a while later I basically made this point ... most of the research he cites is old, old, old.

the response to this was:

"... nonsense. there are studies cited right up to the date the book was published"

I guess they missed where I wrote "most" ... even if one study had been done the day before GCBC hit the store shelves, that says nothing about the bulk of the citations.

CarbSane said...

Yeah, and at least one more recent reference (2003 Reshef) counters Taubes' theories.

Most of the basic insulin stuff is from a 1965 TEXT (this is critical, as my bio texts from the mid-to-late 80's are woefully outdated ... texts are notoriously erroneous, even the old ones). Clearly he didn't read Frayn's more current work ... or he did and ignored it. I'm far from done exposing how Taubes selectively cites experts adn science.

I was harangued into buying a copy of this book by the "you need to read the book" crowd. But I know that had I dared to reference such a work in the manner Taubes did I would have been run out of grad school and/or given a very low grade for a research paper at any college level.

Wonder just how much worse the "lay person friendly" version will be!! :)

Colby said...

This post on the thrifty gene hypothesis and a recent paper made me visit this section of his book to see what he says. I found a glaring example of selective citation (or maybe he just didn't look into it well enough).

Taubes sets up the chapter to show that various cultures go through malnutrition/subnutrition upon poverty (by contact with settlers for example) then experience an increase in obesity, diabetes, etc. He discusses the thrifty gene hypothesis (that certain cultures may be more susceptible to obesity because they evolved to efficiently process nutrients) and the lack of support of it in the research- even by its creator, Neel. I agree with him on this- analyses that i've seen on ethnographic data from hunter-gatherer cultures does not suggest they experience feast/famine as we would imagine. Taubes takes this to mean that it has to be the introduction of carbs that trigger hyperinsulinemia that is causing these cultures to experience obesity and diabetes epidemics. He uses the Pima as one example of a culture that experiences malnourishment then a sharp obesity and diabetes increase upon contact with Western foods.

In a later chapter (page 402 in the book), he brings up fetal programming- but only one part of it that I can find. He only mentions that heavier women tend to have heavier babies and so on. He describes a "vicious cycle" of obesity and intrauterine programming that would increase obesity and diabetes risk, attributed to refined carbohydrates and sugars. He writes "The extreme instance of this phenomenon today is the Pima Indians, whose incidence of diabetes is among the highest of any population in the world. (...) Pima born to mothers who were diabetes have a two- to threefold increased risk themselves of becoming diabetic as adults, and so have a two- to threefold increased risk of passing diabetes on to their own children..." the "vicious cycle (...) can explain much of the post-World War II increase in Type 2 diabetes among the Pima ..."

Except it has been known since 1994 that the relationship between birthweight and diabetes is U-shaped! That is, women who are malnourished, such as experienced by the Pima have babies that are lower birthweight and at an increased risk of diabetes compared to normal weight babies (and about the same risk as babies born heavy in this study) http://www.bmj.com/content/308/6934/942.abstract

Studies continue to confirm this (there are many epidemiological and several animal) that suggest that a malnourished intrauterine environment amplifies the development of insulin resistance and obesity when an energy-abundant diet is available.

In my opinion- the true trigger for the dramatic increase in health endemics in these select populations would be better explained by malnutrition (in which Taubes describes about all of them) which may epigenetically alter progeny to be at an increased risk of diabetes and obesity from the introduction of an (ample) Western food environment. There are also hints of reductions in protein intake and such that has an important role in total calorie intake.

Even if this does not totally account for the dramatic changes in these cultures, it cannot be completely neglected, as Taubes does with it.

I am going to explore this in more detail and write up a blog post on it.

CarbSane said...

I'll look forward to that post Colby. Taubes is a cherry picker extraordinaire.

James Krieger said...

CarbSane,

You may be interested in this study:

http://www.ncbi.nlm.nih.gov/pubmed/19114707

This study shows that triglyceride synthesis in adipose tissue is not down-regulated on a carbohydrate-free diet, refuting the notion of anyone who claims that fat cannot be synthesized in the absence of carbohydrate. In fact, fat synthesis was equivalent when a high carbohydrate diet was compared to a carbohydrate-free diet.

Russell said...

Sorry for butting in (as a layman), but from what I'm gleaning, both of you (James + CS) are reduced-carb proponents, but you differ with Taubes over WHY carbohydrate-reducing correlates with lower obesity... is that right?

CarbSane said...

@Russell, I guess I would describe myself as a person who follows a low to now more moderate carb diet and would recommend them for weight loss. I guess one could call me a proponent of a moderate carb lifestyle. I don't know that I would agree with "carbohydrate-reducing correlates with lower obesity". I think James' position is more that LC is ONE way to lose weight.

What I've learned from my own experience and observations, however, is that *diets* and gimmicks rarely work. Atkins' original book was full of gimmicks (fat mobilizing substance that mysteriously disappeared in later versions, ketosis = huge amounts of calories wasted) and anecdotal boasting like folks eating 5000 cal/day - e.g. more than they ate before - and losing weight like crazy. So as much as Dr.A. did for the "cause" by championing how LC was not bad for the heart but rather healthy, he is also responsible for a lot of the bad rep this WOE has to this day. His second book was a bit better, and The New Atkins is better still, however it still contains those darned gimmicks. Yeah, I guess you have to do that to sell a diet book, but it fuels extremism. I would also agree that at least a faction of the LC community has developed a new type of eating disorder.

Just as fat was demonized in LF circles, so too have carbs been demonized in LC circles, often way more vehemently. And Taubes is responsible for "educating" too many low carbers with inaccurate information. And he's still lecturing this.

IMO, repeating gimmicks and playing rebel without a clue ultimately harms the cause of having the mainstream medical establishment embrace this WOE. There is so much science demonstrating the benefits of at least a lower carb lifestyle, why package it up in bad science? I cringe whenever I hear how all doctors should read GCBC.

So then you get the "I don't care why it works, it does". What about when it doesn't?

@James: Thanks for that link. That seems to confirm a 2005 related study I have in the "hopper" so I'll add this to that upcoming blog post.

CarbSane said...

BTW Russell, I don't believe you've commented before so I extend a welcome to you and thank you for your question. Feel free to "butt in" any time! :)

Sanjeev said...

This jumps out at me a little bit.

> The muscle cells become insulin-resistant in response to the
> "repeated high levels of insulinemia that result from excessive
> ingestion of highly refined carbohydrates and/or over-alimentation,"

the presumption seems to be insulin will act something like steroids - too much and the body will down-regulate receptors.

What about the alternative - muscles that never exercise CANNOT take up glucose, insulin notwithstanding.

It's not high levels of circulating insulin that cause insulin insensitivity, it's the muscles' response to being chronically over-filled with glycogen.

CarbSane said...

One thing that clouds understanding of skeletal IR is that we have what Peter/Hyperlipid calls (if I recall correctly) physiological IR, and dietary excess induced IR. PIR is the body's way of sparing glucose for the tissues that need it. DEIR seems to occur mostly with fat excesses, and is exacerbated by chronic excesses. We always burn some carb and some fat. When carbs are plentiful, we burn them off. In excess we convert to glycogen, but even this doesn't seem to promote insulin resistance because large excesses still allow for glycolysis and then the resulting AcCoA is converted to fat through DNL. Neither the glucose nor the amount of insulin seems to be as important here as the amount of fatty acids hanging around the cells. If those aren't needed they are partially metabolized and these metabolites are subject to oxidation, etc. Whatever the exact mechanism, it almost certainly is a "full up cell" that loses its insulin sensitivity. It just seems from what I've been reading, the "full up" is fat, not carb/glycogen.

Ned Kock said...

This reminds me a bit of Unger's theory of lipotoxicity. What do you think of it?

I wrote a post about it, but am still trying to reconcile it with some of the empirical evidence I've been seeing:

http://healthcorrelator.blogspot.com/2010/08/lipotoxicity-or-tired-pancreas-abnormal.html

It does look like a promising way of looking at the development of diabetes type 2.

CarbSane said...

This is one of the things I've blogged on a lot here. I find the focus (obsession) over just one manifestation of IR (hyperglycemia) in the low carb community to be a case of tunnel vision. The other elevated circulating metabolic substrate (the NEFA's/FFA's) are elevated in obesity, insulin resistance and diabetes.

Interestingly, and here is where I take issue with Taubes' integrity and credibility, I've yet to come across much in the way of actual studies (rather than decades old hypotheses) demonstrating the "tired pancreas" theory. And yet I've come across so very many that implicate elevated NEFA resulting in (or coinciding with) lipotoxicity as being the link. See for example (if you haven't looked back already):
Lipotoxicity, Adiposopathy v. Obesity, Critical VAT Theory, and Progression of Insulin Resistance.

The Unger article is interesting as was your blog post. As you can see from above (probably not even close to a comprehensive list of my contributions) implicating NEFA in IR and NOT dietary component use of insulin wearing out the pancreas.

Speaking of wearing out an organ ... how come low carbers are so quick to accept that using the pancreas for its purpose (insulin secretion etc.) will wear it out, but they have no problem adding to the multitasking of the liver (gluconeogenesis) without thinking this might just wear it out?

Ned Kock said...

> ... so quick to accept that using the pancreas for its purpose (insulin secretion etc.) will wear it out, but they have no problem adding to the multitasking of the liver (gluconeogenesis) without thinking this might just wear it out?

Not to mention the alpha-cells, which apparently are immune to wear, unlike their cousins the betas! If one uses a high protein version of LC, which is often the case, glucagon secretion is bound to increase significantly.

Interestingly, diabetes in birds is unrelated to insulin secretion. The problem is usually with glucagon secretion. But the cause seems to be similar - foods introduced into the birds diet that are not what they eat in the wild.

Mica said...

Hello, you have a very interesting blog! I wonder what you think about Schwarzbeinz and Matt Stones view that a diet to low in carbohydrates will result in adrenal fatigue, since more adrenaline and cortisol is used?

CarbSane said...

Thanks Mica and welcome! I'm not so sure about "fatigue" per se, but I do believe that perpetual VLC'ing is a stressful state for the body. That can't be a good thing IMO.

This is something I recall discussing somewhere here in the comments. If eating too many carbs compared to what we evolved to eat is no good, then eating too few carbs compared to what we evolved to eat is probably not good either. The poster culture for HFVLC eating seems to be the Inuit, but they are an adapted group of humans consuming a diet very high in O3's.

I also wonder about relying entirely on protein substrates for glucose synthesis. The calculations I've seen in terms of grams protein to make certain grams of glucose never seem to add up. I don't see how, especially the high fat contingency of the VLC crowd, lean body mass is maintained in the long run.

ttarchala said...

You provided five links in response to Taubes' assertion that "when these investigators measure insulin resistance in humans they invariably do so on a whole-body level, which is all the existing technology allows. Any disparities between the responsiveness of fat and muscle tissue to insulin cannot be measured."

Of these links:
- Three refer to animal studies, despite Taubes explicitely qualifying his claim as pertaining to humans; indeed, in the comments to the 2004 article, the author bemoans that animal studies cannot be easily put into clinical research
- One does not measure any specific tissue insulin resistance, all it does is measure whole body IR in correlation with proportions of different types of adipose tissues
- One study actually strives to measure specific tissue (skeletal muscle) insulin resistance but the method is such that it cannot easily extend to fat tissue, not to mention being extremely difficult to set up, expensive and invasive.

Therefore, your loud cry of "FALSE!" is completely unsubstantiated by the links you provided. They are obviously a result of a quick PubMed trawl.

CarbSane said...

Hi ttarchala & welcome to my blog! I just now saw two posts in the "spam" folder (I can't turn that off unfortunately), so just now published this one of the two essential duplicates. Sorry about that.

Taubes makes a blanket statement about what the state of the technology allows. Circa when? I know that animal studies only count when convenient to GT, but they ARE certainly relevant in trying to sort out the phenomenon. Work similar to Sims' 1960's/70's work on human adipocytes has also been done. Adipocytes become LESS sensitive to insulin as they become larger and that appears to be the precipitating factor for when obesity -> IR -> T2.

Perhaps a "PubMed trawl" would have been a place for GT to start, no doubt he would have found this excellent summary by Keith Frayn that should have led him down the path of further investigation. I don't have time to blog on every study I come across, but work on the progression of IR and the development of diabetes is substantial. I've come across studies looking at sensitivity of vascular endothelium, pancreatic beta cells, etc. to insulin. Some is in rodents and other animal models, but that's how we sort out some of these things. It is unfortunate that where rodents differ, we somehow accept our fat metabolism as similar (e.g. contributions of de novo lipogenesis being much more substantial in rodents) but ignore when they have been demonstrated similar (e.g. glyceroneogenesis).

Rather than look at the WHOLE of the science, Taubes picked Neels' hypothesis that most closely fit his pre-determined conclusion, found a snippet in apparent support and ignored all the rest. A familiar pattern.

Dana Seilhan said...

Did anyone miss the fact that Taubes is a science writer who has been trying to summarize science rather than formulate his own theories?

Do you really judge the validity of a theory by how old it is? So, when is gravity going to stop working?

I want to listen to your side of things... but it's kind of difficult when I can't hear what you're saying over all the logical fallacies. Sorry.

Leo said...

@Dana
Taubes summarized nothing. He mixed
cherry-picking with out of context quotes with fantasy and bad science. That's like pretending to summarize a movie while telling another, even longer, story about different characters and situations.

CarbSane said...

@Dana: Welcome! Considering that one of Taubes biggest "lines" is that he's proposing an *alternate hypothesis* I fail to see how anyone can state that he's not formulating theories.

I don't judge the validity of a theory by how old it is, I judge theories by the evidence that supports or contradicts it. If an old theory is contradicted by new evidence then it should be revised or discarded. There is simply too much evidence showing Taubes wrong and not really much if any showing him correct.

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