(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 POV. If you think about a balloon being filled with air, it gets harder and harder the more full the balloon gets to blow more air into it. 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 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 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
- Subdivisions of subcutaneous abdominal adipose tissue and insulin resistance ~ 2000
- Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2 ~ 2000
- Plasma Fatty Acids, Adiposity, and Variance of Skeletal Muscle Insulin Resistance in Type 2 Diabetes Mellitus ~ 2001
- Insulin Resistance – What Is It and How Do We Measure It?
- Tissue-specific insulin resistance ~ 2004
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 it's 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!
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