Studies to give your doctor

[Ðekel]

thank you Laura.

will do.

 

[SeekinTruth]

I'm pretty sure I had read this before. But a couple of things jumped out at me. First, is it true about butter (and presumably ghee) that these hormones, including insulin growth factor are concentrated in it? If so, many of us are consuming lots of ghee and butter here on the forum on our version of the Paleo diet. Also, according to Sally Fallon in the video "The Oiling of America" the U.S. used to eat huge amounts of butter and also lard until the early decades of the 20th century. But the very first heart attack ever recorded in the U.S. was in 1921, after these other vegetable oils, etc. started coming on the market and campaigns were started to have people use Crisco instead of lard and margarine instead of butter, etc. But if they consumed so much butter in the U.S. (she mentions that in the 18th and 19th century, America was known as the "butter nation") shouldn't they have had VERY high rates of cancer, especially breast cancer?

Another couple of things that jumped out from this article is that casein and it's very negative health affects is not mentioned at all. That's very strange to talk about the evils and poisons of milk and not mention casein, isn't it? And the other thing was the claim of animal proteins leading to the leaching out of calcium from bones seems like a bogus claim. First of all, we evolved eating almost exclusively animal protein and fat and the cultures whose diet is still primarily that have pretty much no diseases, including osteoporosis -- in fact there's been several studies that show that this diet actually gives much better bone density and into old age. And there was an article posted a while ago on SOTT that said that animal protein does NOT lead to leaching minerals from bones, but in fact vegetable proteins DO.

Just thought I'd mention all this and see what other people think.

 

[Maat]

thank you Laura.

will do.

Maybe you already know it but this tool could really help you in your task :

_http://www.ncbi.nlm.nih.gov/pubmed/

 

[Ðekel]

Maat,

actually i didn't know of this tool and it looks like it could be very helpful indeed, thank you ! :)

SeekInTruth,

i too noticed that the article left out Casein ! which, i agree, is weird.
I added it here though on its other merits.

plus, Endymion has posted very insightful info on this thread that discusses Casein quite a bit.
more to take to your doctor !

about the butter, you raise a good question.
i'm going to add it to my list of research topics and update with any findings.

 

[Sinapi]

Hi all,

I apologize for not posting more studies from TASLCL. I've been distracted a lot lately, especially since school is starting soon. Instead of skimming the book, I've been trying to read it more slowly to better understand the context of Phinney and Volek's work. So far, I've only categorized 30 out of 140 citations... that's bad, I know. I'll try to get everything done by next week at the latest.

Thank you for posting that study, Endymion! The author's work is very insightful, and I agree that it will be very useful, particularly the version with citations.

There are a lot of good studies listed in the various books we have on our reading list, so perhaps that is a place to start. Find the study, the link to it, paste it in here if you can get the whole thing, along with the link so the person can print it from the original site. The more mainstream the site, the better.

Laura, I am able to paste a lot of studies (except from JAMA) but aren't you worried about violating copyrights? I just wouldn't want to put everyone in legal trouble for pasting text from a journal that requires a subscription.

Maat,

actually i didn't know of this tool and it looks like it could be very helpful indeed, thank you ! :)

SeekInTruth,

i too noticed that the article left out Casein ! which, i agree, is weird.
I added it here though on its other merits.

plus, Endymion has posted very insightful info on this thread that discusses Casein quite a bit.
more to take to your doctor !

about the butter, you raise a good question.
i'm going to add it to my list of research topics and update with any findings.

PubMed is definitely a useful tool, and I wish you luck with finding studies. :) Sometimes, however, PubMed will only have an abstract available, especially if the results are preliminary. Other times, under the abstract, there is the LinkOut button that posts links to the full study. Sometimes you'll get lucky and they'll have a full article for free available. Other times, like here: http://www.ncbi.nlm.nih.gov/pubmed/6865775 , it'll link to a journal that requires a subscription. In those cases, if you want, I'd be happy to send the full article to you if I can access it, particularly from either Springerlink or Science Direct.

 

[mada85]

about the butter, you raise a good question.
i'm going to add it to my list of research topics and update with any findings.

Have a look at this post of Laura's.

 

[Laura]

Laura, I am able to paste a lot of studies (except from JAMA) but aren't you worried about violating copyrights? I just wouldn't want to put everyone in legal trouble for pasting text from a journal that requires a subscription.

Fair Use is "discussion and study" as long as author is attributed and link is provided to the original.

Copyright does not prohibit all copying or replication. In the United States, the fair use doctrine, codified by the Copyright Act of 1976 as 17 U.S.C. Section 107, permits some copying and distribution without permission of the copyright holder or payment to same. The statute does not clearly define fair use, but instead gives four non-exclusive factors to consider in a fair use analysis. Those factors are:

1. the purpose and character of your use
2. the nature of the copyrighted work
3. what amount and proportion of the whole work was taken, and
4. the effect of the use upon the potential market for or value of the copyrighted work.[26]

In UK and Canada: Fair dealing uses are research and study; review and critique; news reportage and the giving of professional advice.

 

[Ðekel]

Endymion,

thank you.


Laura,

Fair Use is "discussion and study" as long as author is attributed and link is provided to the original.

Quote from: wikipedia
Copyright does not prohibit all copying or replication. In the United States, the fair use doctrine, codified by the Copyright Act of 1976 as 17 U.S.C. Section 107, permits some copying and distribution without permission of the copyright holder or payment to same. The statute does not clearly define fair use, but instead gives four non-exclusive factors to consider in a fair use analysis. Those factors are:

1. the purpose and character of your use
2. the nature of the copyrighted work
3. what amount and proportion of the whole work was taken, and
4. the effect of the use upon the potential market for or value of the copyrighted work.[26]

In UK and Canada: Fair dealing uses are research and study; review and critique; news reportage and the giving of professional advice.

very good to know this.
is it the same for printed material ?
since we would like whomever is interested to present the material to their health practitioners.

i could check this out but i'm sure you would already know ?

 

[Sinapi]

Thanks for clearing that up, Laura. :) TransientP, it should apply to printed material as well, since the law was written prior to the World Wide Web.

I have yet to read Chapter 8 in the book, which deals with the cholesterol business. But I have found links to most of the studies on insulin resistance, which are important as well. Also, I'll work on formatting articles individually and then posting them. Then, I'll edit the lists to give a quick link to the actual study posted directly on the forum.


PART 2

Note: An "*" next to the number means that I can get the full article through a subscription, a "**" means that I can't, although there may be an abstract, and no asterisk at all means that you can get the full article by clicking the link.

Also note that by "Relevance", I'm just quoting where the study was cited in the book. If the paragraphs that I'm copying confuse you, or if you need more context, flip through the book to the page numbers I give at the end of each paragraph. This particularly goes for the chapter on Insulin Resistance, as the authors tend to backtrack to studies that were mentioned many pages ago.

(24)

Author: Siri -Tarino

Title: Meta-analysis ofprospective cohort studies evaluating the association ofsaturated fat with cardiovascular
disease.

Relevance:

" [...] scientists have begun to take a second look at the 50-year old idea that dietary saturated fats are harmful. Yes, it has been shown that saturated fats in animal or human diets can raise blood cholesterol under some circumstances. However, we now know that some forms of blood cholesterol are either not harmful or even protective (like HDL cholesterol), and a well-formulated low carb diet containing a fair amount of saturated fat has been shown repeatedly to raise blood levels of this 'good cholesterol: Moreover, three studies published in the last year have examined carefully collected dietary records of huge populations who were followed for decades. In all of three of these recent studies,
there was no connection between saturated fat intake and either the frequency of heart attack or death [24-26]." [pgs 40-41]

Link: http://www.ajcn.org/content/91/3/535.full.pdf+html

(25)

Author: Yamagishi

Title: Dietary intake of saturated fatty acids and mortality from cardiovascular disease in Japanese: the Japan
Collaborative Cohort Study for Evaluation of Cancer Risk (fACC) Study.

Relevance: See above.

Link: http://www.ajcn.org/content/92/4/759.full.pdf

(26)

Author: Jakobsen

Title: Major types of dietary fat and risk of coronary heart disease: a pooled analysis of 11 cohort studies.

Relevance: See above.

Link: http://www.ajcn.org/content/89/5/1425.full.pdf+html

*(27)

Author: Phinney

Title: The human metabolic response to chronic ketosis without caloric restriction: physical and biochemical adaptation.

Relevance:

"Adaptation is the process through which whole organs in the body forgo glucose (from muscle to brain) and switch to burning mostly fat for fuel. The combination of gluconeogenesis and adaptation together is what allowed a group of bike racers studied by Steve Phinney to eat no visible carbohydrate for 4 weeks and still show up and perform well in their second exercise test[23]. But in light of Stefansson's do-or-die performance in the 1928 Bellevue Study (Chapter 2), this was no big surprise.

"So what does this mean? It means that we should not confuse our body's ability to maintain a normal blood glucose with our dietary carbohydrate intake. When humans are adapted to a low carbohydrate diet, blood sugar levels and one's carbohydrate intake are completely independent of one another. In fact, keto-adapted humans maintain better glucose levels across feeding, fasting, and extremes of exercise than when fed a low fat, high carbohydrate diet[23, 27]. [pg 48]

[...]

"Another factor known to influences our body's need for protein is the mix of carbohydrate and fat that provides most ofthe energy in our diet. However, the magnitude of this factor is very dependent on timing. In short term studies, taking away dietary carbohydrate and replacing it with fat reduces our body's efficiency in using protein. Put another way, when you first take away dietary carbs, you need more protein to maintain muscle and other protein-containing tissues. But when you observe a human over a number of weeks of adaptation to a low carbohydrate diet, most of this initial inefficiency in protein use goes away[27]. Thus, once you are keto-adapted, your body's need for protein isn't much higher than during a 'balanced diet'. This is a key fact in our understanding that low carbohydrate diets used in the long term do not need to be particularly high in protein [pg 59-60]

[...]

"At rest, skeletal muscles prefer fat for fuel, using glucose only when insulin levels are high and blood sugar needs some place to go. During sustained exercise, fat is still the preferred fuel at intensities up to 50-60% of that muscle's maximum continuous effort. Above 60% of maximum effort, glucose (or stored glycogen) progressively assumes a dominant role, although this dominance is attenuated when individuals are given a few weeks to adapt to a low carbohydrate diet [23, 27]." [pg 65-66]

Link: http://www.sciencedirect.com/science/article/pii/0026049583901051

(28)

Author: Chatham

Title: Lactate --the forgotten fuel!

Relevance: The authors (Phinney and Volek) previously mention the significance of the Cori cycle, where, during intense exercise, glucose in the muscles breaks down into lactic acid, which, subsequently, dissociates into the lactate ion and the hydronium ion. The lactate ion is then transported into the liver, where it is turned back into glucose, and then the cycle repeats. It's important because they claim that it is a frequent misconception that lactate causes muscle fatigue during exercise, while it is actually due to the increase in hydronium ions in the muscles. Furthermore, they say that, due to the fact that the liver creates energy by oxidizing its own fat and can thus convert lactate back into glucose, the entire process actually improves one's performance during exercise. They go on to say that:

"Lactate is preferred by heart muscle cells over glucose, and during endurance exercise lactate can provide as much as 50% ofyour heart's energy need [28]." [see pg 66 for a more detailed discussion]

Link: http://jp.physoc.org/content/542/2/333.full

*(29)

Author: Forsythe

Title: Comparison oflowfat and low carbohydrate diets on circulating fatty acid composition and markers of inflammation

Relevance: Basically, both this study and [30] say that low carb dieters have lower saturated fat in the blood than low fat dieters. [29] in particular notes that low carb dieters had less inflammation than low fat dieters, although it notes that both dieters' inflammation improved greatly after dieting. [pg 70-71]

Also, these studies say that low-carb dieters have higher levels of HUFA in their bloodstreams. See pg 84 to read about the relevance of that.

From [pg 85]:

"In the above study of people with metabolic syndrome [29], we also did a panel of tests for biomarkers of inflammation. And despite the relatively small size of the study group and the notorious variability of these biomarkers, every one of the 16 indicators of inflammation went down in the group on the low carbohydrate diet. Although some of these reductions were not statistically significant when assessed seperately, the important observation is that they all went down. For that to happen purely by chance, it's like flipping a coin and getting heads 16 times in a row (which has a probability of happening once in 65,000 tries).

More importantly, that study also included a randomized comparison group given a low fat, high carbohydrate weight loss diet, and compared to their results, the low carbohydrate group had significantly greater reductions in 6 of the 16 inflammatory markers. In contrast, none of the markers were significantly lower in the low fat compared to the low carb group. In simple terms, what this means is that both energy restricted diets tended to reduce inflammation in people with metabolic syndrome, but that this effect was significantly greater with the low carbohydrate diet.

These results are consistent with other published studies comparing low carb to low fat diets. Not all low carb diet studies have shown significant reductions in biomarkers like eRP or IL-6, but many have. We suspect the variable results seen in other studies may be due to both questionable compliance with the assigned diet, plus the diets not being low enough in carbohydrate to achieve these anti-inflammatory effects."

Also see page 87... really, this study is referenced so much that I'd say it's a keeper at this point.


Link: http://www.springerlink.com/content/r1x1143pl42737u8/

(30)

Author: Forsythe

Title: Limited effect of dietary saturated fat on plasma saturated fat in the context of a low carbohydrate diet.

Relevance: See above.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974193/?tool=pubmed

(31)


Author: Matthews, D.R.

Title: Homeostasis model assessment: insulin resistance
and beta-cell function from fasting plasma glucose and insulin concentrations in man.

Relevance:

"A much simpler method is to simultaneously measure blood glucose and blood insulin levels and then estimate insulin sensitivity using an equation
based upon insulin clamp data. For example, one of the first methods to estimate insulin resistance published in 1985 was called the homeostatic
model assessment (HOMA)[31]. It is calculated as the product of fasting blood glucose x fast blood insulin divided by 22.5. Higher values indicate insulin resistance and lower values insulin sensitivity. Although these calculations of insulin sensitivity (or resistance) are just estimates, in most cases their correlation with the clamp data is reasonably good (e.g., r=0.8). While this leaves a degree of uncertainty when testing an individual, it provides a much more robust measure when assessing the response of a group of subjects to a change in diet." [pg 79]

Link: http://care.diabetesjournals.org/content/25/7/1177.full

**(32)

Author: Kannel, W.B., K. Anderson, and P.W. Wilson

Title: White blood cell count and cardiovascular disease. Insights from the Framingham
Study.

Relevance:

"About 20 years ago, it was noted that people with persistently high biomarkers of inflammation (e.g., CRP and IL-6) were at increased risk of heart attack[32, 33]. And then ten years ago this observation was extended to type-2 diabetes as well. This perspective has led us to regard inflammation as a potential underlying cause of insulin resistance and type-2 diabetes [34, 35]. Further, we now have evidence that insulin is associated
with inflammation[36, 37], setting up a vicious cycle fueled by repeated ingestion of insulin-inducing carbohydrates.

Since the primary factor that drives serum insulin is dietary carbohydrate, this in turn raises the controversial possibility that dietary carbohydrate intake
drives both inflammation and high blood insulin levels, both of which in turn promote insulin resistance. Does it work this way in everybody? Of course not, because we know that the other key variable is genetics. But we have just begun to scratch the surface of which genes (or gene combinations)
predispose people to become 'carbohydrate intolerant:" [pg 81-82]

Link: http://jama.ama-assn.org/content/267/9/1253.abstract

(33)

Author: Ridker

Title: C-reactive protein
adds to the predictive value oftotal and HDL cholesterol in determ ining risk offirst myocardial infarction.

Relevance: See above.

Link: http://circ.ahajournals.org/content/97/20/2007.long

(34)

Author: Pradhan

Title: C-reactive protein, interleukin 6, and risk ofdeveloping type 2 diabetes mellitus.

Relevance: See above.

Link: http://jama.ama-assn.org/content/286/3/327.full.pdf This one was a freebie! :D

(35)

Author: Hu

Title: Inflammatory markers and risk ofdeveloping type 2 diabetes in women.

Relevance: See above.

Link: http://diabetes.diabetesjournals.org/content/53/3/693.full.pdf

(36)

Author: Buyken

Title: Carbohydrate nutrition and inflammatory disease mortality in older adults.

Relevance: See above.

Link: http://www.ajcn.org/content/early/2010/06/23/ajcn.2010.29390.full.pdf

(37)

Author: Khatana

Title: The association between C-reactive protein
levels and insulin therapy in obese vs nonobese veterans with type 2 diabetes mellitus.

Relevance: See above.

Link: http://onlinelibrary.wiley.com/doi/10.1111/j.1751-7176.2010.00296.x/full

(38)

Author: Borkman

Title: The relation between insulin sensitivity and the fatty-acid composition ofskeletal-muscle phospholipids.

Relevance:

"In 1993, the New England Journal of Medicine published a study demonstrating that highly unsaturated fatty acids (HUFA; e.g., arachidonate and docosahexaenoate [DHAJ] in muscle membrane phospholipids are tightly
correlated with insulin sensitivity[38]. Specifically, this means that the more ofthese HUFAs there are in the muscle membrane, the more insulin sensitive the muscle. This observation subsequently has been corroborated and extended by multiple other studies. For example the significant correlation between muscle HUFA and insulin sensitivity was shown to be specific to the phosphatidylcholine phospholipids which predominate on the outer layer of the muscle membrane[39]. This is interesting from the perspective that it implies a role for the background fatty acid composition of the membrane per se, rather than the protein components inserted into it (like insulin receptors or glucose transporters). In other words, figuratively speaking, what the 'fabric' of the wall itself is made of is very important for glucose transport -it's not just about the number of switches (i.e. receptors and transporters) inserted in the wall.

How these HUFAs get into muscle membranes is a very complex process involving both diet composition and metabolism of the various essential fats after they are eaten. This process is discussed in detail in Chapter 9. For the purposes of this chapter, both dietary intakes of either the essential
fatty acid precursors or their final products are important. However, there is increasing evidence that some individuals have impaired ability to convert essential fatty acid precursors into HUFA[40].

As a rule, HUFA are a bit less prone to be burned for fuel than shorter fatty acids, so on average the body tends to hang on to them. But there is another way that they can be destroyed besides being beta-oxidized (i.e., burned for energy). As mentioned above, HUFA have lots of double bonds, and this makes them very susceptible to damage by oxygen free radicals (also called reactive oxygen species or ROS). The potential role of oxidative stress degrading membrane HUFA and thus promoting insulin resistance has yet to be fully explored, but it may be very relevant to this chapter. Here's why." [pg 82-83]

...

In the first study {[29]}, the subjects were selected because they had metabolic syndrome, so as a group, they had underlying insulin resistance. After 12 weeks of the low carb diet, their insulin resistance improved by 55%, and this occurred at the same time as their blood HUFA levels were increasing. This observation does not prove that rising HUFA levels were a direct cause of the improved insulin sensitivity, but this is certainly consistent with the observations of Borkman et al [ 38]." [pg 84]

Link: http://www.nejm.org/doi/full/10.1056/NEJM199301283280404#Top=&t=articleTop

(39)

Author: Clore

Title: Skeletal muscle phosphatidylcholine fatty acids and insulin sensitivity in normal humans.

Relevance: See above.

Link: http://ajpendo.physiology.org/content/275/4/E665.full.pdf

*(40)

Author: Lattka

Title: Do FADS genotypes enhance our knowledge aboutfatty acid related phenotypes?

Relevance: See above.

Link: http://www.clinicalnutritionjournal.com/article/S0261-5614%2809%2900233-7/abstract

(41)

Author: Phinney

Title: Obesity and weight loss alter serum polyunsaturated
lipids in humans.

Relevance:

"Twenty years ago, we published a couple of studies showing that very low calorie ketogenic diets raised the HUFA content in serum phospholipids (the building blocks for membranes)[41, 42]. The subjects for these studies started out pretty heavy and lost a lot of weight over a number of months. But after the weight loss diet was over, they went back to consuming more carbohydrate, and their HUFA levels went back down. This occurred in spite of the major weight loss, so it looked more like a diet effect than an obesity effect per se." [pg 84]

Link: http://www.ajcn.org/content/53/4/831.full.pdf+html


**(42)

Author: Tang

Title: Preferential reduction in adipose tissue alpha-linolenic acid (18:3 omega 3) during very low calorie dieting despite supplementation with
18:3 omega 3.

Relevance: See above.

Link: http://www.nature.com/clpt/journal/v66/n3/full/clpt1999456a.html

(43)

Author: Gardner

Title: Comparison ofthe Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial.

Relevance:

"In 2007, Gardner et al published a randomized, controlled trial called the A-to-Z Study involving 4 diets lasting a year given to groups of obese women [43]. At one end of this diet spectrum was the cOrnish diet' which is very high in complex carbs and very low in fat. At the other end was the i\tkins diet' (i.e., low carbohydrate). After 6 months, the women on Atkins
had lost significantly more weight, but after 12 months they were still lower but not significantly so. Interestingly, blood pressure and HDL cholesterol
were significantly better on low carbohydrate than any of the other
diets, and this beneficial effect remained significant out to 12 months." [pg 85]

Link: http://jama.ama-assn.org/content/297/9/969.abstract Another freebie.

**(44)


Author: Gardner

Title: Insulin Resistance -An Effect Moderator of Weight Loss Success on High vs. Low Carbohydrate Diets.

Relevance:

"After publishing this initial paper in JAMA, Dr. Gardner went back and examined his data based upon the subjects' insulin levels before they started dieting. "Vhen the women on each diet were divided into three subgroups (tertiles) based on baseline insulin resistance, the results were striking. In the low carbohydrate diet group, weight loss was similar in the most insulin sensitive (l1.7Ibs) and insulin resistant (l1.9 Ibs) women. However weight loss with the high carbohydrate (Ornish) diet was much greater in the insulin
sensitive (9.0 Ibs) than the insulin resistant (3.31bs) women.

Thus the most insulin sensitive sub-groups of women experienced a similar
weight loss when assigned diets either high (9.0 Ibs) or low (11.7 lbs) in carbohydrate In contrast, the sub-groups that were insulin resistant fared very poorly when assigned a diet high in carbohydrate (3.3 Ibs lost) compared to a low carbohydrate diet (l1.91bs). Specifically, those women with insulin resistance lost almost 4-times as much weight when dietary carbohydrates were restricted [44]." [pg 85-86]

Link: I can't find this study anywhere, not even as an abstract!

(45)

Author: Boden

Title: Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes.

Relevance:

"What we do know is that, pretty consistently, as dietary fat percent is increased from 30% to 60% in animals and in humans, insulin sensitivity
does get worse. But once above 60% of energy as fat, which typically translates to less than 20% of energy as carbohydrates (assuming 15-20% from protein), insulin resistance turns around and starts to improve. So what's happened is that the mainstream consensus did studies of up to 60% fat, saw what looked like a straight line, and then just assumed it kept on going in a bad direction. In a word, they extrapolated themselves to a false conclusion.

But if you look at well done studies at higher fat intakes, this extrapolation
doesn't stand the 'red-face test: For example, in Dr. Guenther Boden's study of type-2 diabetics, when they cut dietary carbohydrates to 20 grams per day for just 2 weeks, there was a dramatic reduction in insulin resistance as measured by the insulin clamp technique[ 45]. Similarly, insulin
sensitivity was dramatically improved in Dr. Forsythe's subjects with metabolic syndrome assigned to the low carb diet[29]." pg 86-87

Link: http://www.annals.org/content/142/6/403.full.pdf

 

[l_autre_d]

Re: Studies for your doctor, Carbohydrate restriction and cardiovascular risk

Carbohydrate restriction and cardiovascular risk
Jocelyne G. Karam, Fiby Nessim, Samy I. McFarlane and Richard D. Feinman

found in:
Current Cardiovascular Risk Reports
Volume 2, Number 2, 88-94, DOI: 10.1007/s12170-008-0018-z

_http://www.springerlink.com/content/2510372651x456g4/

Abstract
Originally developed as a strategy for weight loss, diets based on restriction of carbohydrates were traditionally of concern because of the assumed increased cardiovascular risk if the carbohydrates were replaced with fat. It now appears that such diets are associated with an improvement in markers of cardiovascular risk, even with higher saturated fat intake and even in the absence of weight loss.
Various evidence supports this paradigm shift:

1) carbohydrate restriction improves markers of atherogenic dyslipidemia (triglycerides, high-density lipoprotein cholesterol, apolipoprotein B-apolipoprotein A-1 ratio) and reduces the more atherogenic small, dense low-density lipoprotein cholesterol;

2) high amounts of dietary carbohydrates increase de novo fatty acid synthesis and plasma triglycerides;

3) large, long-term studies of traditional dietary fat reduction continue to fail to demonstrate the predicted improvement in cardiovascular disease risk. Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. It seems appropriate to consider carbohydrate reduction as a useful, if not the preferred, alternative to low-fat diets, which have met with limited success.

PDF URL:
_http://www.springerlink.com/content/2510372651x456g4/fulltext.pdf

 

[Sinapi]

Here's the first one. Note that there may be some typographical mistakes in the paper, as well as future papers, due to the fact that this was copied and pasted from a pdf file. None of these should affect the meaning of the paper, unless it happens to be an acronym. For example, TG (triglyceride) was often changed into TO (which means nothing). If you happen to see anything like that, please say so, so that it can be corrected quickly.

Also, as you might be able to tell, I got lazy with the formatting by the end of the paper. In order for the paper not to look like a giant column, and thus save more paper, I have to manually backspace every single line. This takes a great deal of time, so, unless someone requests it, I won't be doing it again in future papers, but I'll be sure to still separate paragraphs and the like.

(4)

http://www.annualreviews.org/doi/abs/10.1146/annurev.me.44.020193.001005

Annu. Rev. Med. 1993.44:121-3/

ROLE OF INSULIN RESISTANCE IN
HUMAN DISEASE (SYNDROME X):
AN EXPANDED DEFINITION1

Gerald M. Reaven, M.D.

Department of Medicine, Stanford University School of Medicine,
Stanford, California 94305; and Geriatric Research, Education, and
Clinical Center, Department of Veterans Affairs Medical Center,
Palo Alto, California 94304

KEY WORDS: hyperinsulinemia, glucose intolerance, dyslipidemia, high blood
pressure, coronary heart disease

ABSTRACT

Resistance to insulin-mediated glucose uptake is characteristic of individuals with impaired glucose intolerance or non-insulin-dependent diabetes, and it also occurs commonly in patients with high blood pressure. The physiological response to a decrease in insulin-mediated glucose uptake is an increase in insulin secretion, and as long as a state of compensatory hyperinsulinemia can be maintained, frank decompensation of glucose tolerance can be prevented. However, it is likely that the defect in insulin action and/or the associated hyperinsulinemia will lead to an increase in plasma triglyceride and a decrease in high density lipoprotein cholesterol concentration, and high blood pressure. It seems likely that the cluster of changes associated with resistance to insulin-mediated glucose uptake comprise a syndrome, which plays an important role in the etiology and clinical course of patients with non-insulin-dependent diabetes, high
blood pressure, and coronary heart disease.

1 The US Government has the right to retain a nonexclusive royalty-free license in and to
any copyright covering this paper.

INTRODUCTION

There is now substantial evidence that resistance to insulin-stimulated glucose uptake is a common phenomenon, associated with glucose intolerance, dyslipidemia, high blood pressure, and coronary heart disease ( 1). Furthermore, these metabolic and hemodynamic abnormalities tend to cluster together in the same individual. In an attempt to emphasize these relationships I suggested several years ago the existence of a syndrome in which insulin resistance was the primary defect, associated with compensatory hyperinsulinemia ( 1). For want of a better designation, I suggested that the insulin resistance syndrome be titled Syndrome X. However, the major issue is not the best way to designate this cluster of abnormalities, but rather to be aware of their importance in the etiology and clinical course of what are often referred to as diseases of modern civilization. In this presentation an effort is made to review the evidence that has led to this formulation.

EXISTENCE OF RESISTANCE TO INSULINMEDIATED
GLUCOSE UPTAKE

Impaired Glucose Tolerance (IGT) and Non-Insulin-Dependent
Diabetes Mellitus (NIDDM)

The majority of patients with IGT or NIDDM are insulin resistant as compared to appropriately matched individuals with normal glucose tolerance ( 1, 2). In addition, normoglycemic first-degree relatives of patients with IGT or NIDDM have been shown to be insulin resistant as compared to normal individuals without a family history of NIDDM (3). Finally, there is an approximate four-fold variation in insulin-stimulated glucose uptake in individuals with normal glucose tolerance, and the defect in insulin action in approximately 25% of these individuals does not differ substantially from that of patients with either IGT or NIDDM (4). However, these insulin-resistant individuals with normal glucose tolerance are hyperinsulinemic when compared to an insulin-sensitive control group, and it appears that it is the increase in plasma insulin concentration that permits them to overcome the defect in insulin action. Ambient plasma insulin concentrations are also significantly higher in patients with NIDDM and with fasting plasma glucose concentrations of less than 8 mmol/liter than they are in individuals with normal glucose tolerance (1, 5). Significant hyperglycemia appears to develop only in patients with NIDDM when they are no longer able to sustain a state of hyperinsulinemia (1, 5). On the basis of these observations it seems reasonable to conclude that resistance to insulin-mediated glucose uptake is a common phenomenon and is present in the majority of individuals who are glucose intolerant. The degree to which glucose homeostasis deteriorates in insulin resistant individuals will vary as a function of both the magnitude of the loss of in vivo insulin action and the capacity of the beta cell to compensate for this defect.

Hypertension

Patients with high blood pressure are glucose intolerant and hyperinsulinemic when compared to a matched group of individuals with normal
blood pressure (1, 6). These abnormalities can persist despite successful drug treatment of hypertension (7), and can be seen in both obese and non obese individuals (1, 6-8). Existence of glucose intolerance and hyperinsulinemia in patients with high blood pressure suggests that resistance to insulin-stimulated glucose uptake may be present in these individuals, and this possibility has now been confirmed (1, 6, 7, 9). As with the hyperinsulinemia, the defect in insulin action is present in nonobese patients with hypertension (1, 6, 7, 9), and can still be detected when antihypertensive treatment has effectively controlled blood pressure (6, 7). The fact that insulin resistance and hyperinsulinemia can be demonstrated in patients with high blood pressure, does not necessarily mean that either of these variables play a role in regulation of blood pressure. For example, it could be argued that it is the high blood pressure that leads to the abnormalities in insulin metabolism. Although a logical alternative, it seems unlikely given evidence that neither insulin resistance nor hyperinsulinemia are seen in patients with either renal artery stenosis or primary aldosteronism (10), or in rats with experimentally induced renal vascular hypertension (11).

Dyslipidemia

The role played by resistance to insulin-stimulated glucose uptake and hyperinsulinemia in dyslipidemic states was recently reviewed in great
detail (12). There is considerable evidence that resistance to insulin-stimulated glucose uptake leads to a compensatory increase in plasma insulin concentration, enhanced hepatic very low density (VLDL) triglyceride (TG) secretion, and hypertriglyceridemia. For example, in individuals who retain insulin secretory function, particularly nondiabeties, there is a relatively linear relationship between measures of insulin resistance and plasma insulin concentration (1, 4, 5, 13), i.e. the more resistant, the greater the magnitude of hyperinsulinemia. In addition, statistically significant correlations exist between resistance to insulin-stimulated glucose uptake, plasma insulin concentration, VLDL-TG secretion rate, and plasma TG concentration in both normotriglyceridemic and hypertriglyceridemic individuals (14, 15). Furthermore, experimental manipulations that modify insulin action and/or plasma insulin concentration lead to predictable changes in VLDL-TG secretion rate and plasma TG concentration. For example, weight loss is associated with a commensurate decrease in plasma insulin concentration, hepatic VLDL-TG secretion, and plasma TG concentration (16). In contrast, feeding patients a high carbohydrate diet leads
to an increase in ambient plasma insulin and TG concentrations, and the increment in plasma TG concentration is significantly correlated with the carbohydrate-induced hyperinsulinemia (17). Based upon the observations above, there appears to be a good deal of support for the view that resistance to insulin-stimulated glucose uptake and compensatory hyperinsulinemia lead to hypertriglyceridemia in a variety of situations. Given evidence of the relationships between plasma insulin and both TG (direct) and HDL-cholesterol (indirect) concentration
( 1 , 14--19), the dyslipidemia associated with resistance to insulin-stimulated glucose uptake and hyperinsulinemia is likely to include a low HDL cholesterol concentration as well as a high plasma TG concentration.

POSSIBLE ADDITIONS TO SYNDROME X

During the past few years evidence has appeared suggesting that there are other abnormalities, secondary to insulin resistance and/or compensatory hyperinsulinemia, associated with coronary heart disease (CHD), that could be added to the cluster of changes initially described as comprising Syndrome X. Evidence in support of these possible new additions to the syndrome is briefly summarized in this section.

Microvascular Angina

The phrase Syndrome X has been used by Kemp (20) to describe patients who seemed to have ischemic heart disease without significant coronary stenosis on angiography. Although the definition of this Syndrome X varies somewhat from cardiologist to cardiologist, the triad of typical angina by history, a positive exercise stress test, and no significant angiographic evidence of coronary artery disease is essential in order to qualify for this appellation. In the absence of angiographic evidence of large vessel disease, the cardiologic Syndrome X is often referred to as microvascular angina. Recently, evidence has been published suggesting that microvascular angina might be related to resistance to insulin-mediated glucose uptake and compensatory hyperinsulinemia. Thus, Dean and associates (21) studied 11 patients with the presumptive diagnosis of microvascular angina and 11 healthy subjects, and reported that the plasma insulin
response to oral glucose was significantly higher in the group with microvascular angina. Since previous studies from our group have defined a highly significant direct correlation in nondiabetic individuals between degree of insulin resistance and magnitude of the insulin response to a
glucose load (4,5, 13), it seems possible that individuals with microvascular angina, as a group, are insulin resistant and hyperinsulinemic. Plasma HDL-cholesterol concentration was lower and TG concentration higher in those with microvascular angina, which suggests that dyslipidemia is associated with insulin resistance and hyperinsulinemia in the syndrome of microvascular angina. We have also noted that dyslipidemia is present in patients with a typical history of angina, a positive exercise stress test, and no evidence of significant macrovascular disease on angiography (22). Based upon these preliminary data, it seems reasonable to postulate that microvascular angina is another manifestation of the insulin resistance syndrome.

Hyperuricemia

Epidemiologic studies have identified an increase in serum uric acid concentration as a characteristic finding in patients with CHD, often present in concert with glucose intolerance, dyslipidemia, and hypertension (23- 26). Given the relationships described between resistance to insulinmediated glucose uptake and the abnormalities noted to occur in association with hyperuricemia, it seemed reasonable to see if uric acid concentration also varied as a function of insulin resistance and/or hyperinsulinemia. We recently completed such a study in normal volunteers (27), demonstrating that significant correlations existed between serum uric acid concentration and both insulin resistance and the plasma insulin response to an oral glucose challenge. The relationships among these variables persisted when differences in age, sex, body mass index, and ratio of waist-to-hip girth were taken into account, and were seen in normal, healthy individuals. Based on these data, we suggested that differences in the ability of insulin to stimulate glucose uptake play a role in the regulation of serum uric acid concentration within a normal, healthy population.

Plasminogen Activator Inhibitor 1 (PAI-1)

PAI-1 concentrations have been shown to be increased in patients with CHD (28, 29), and there is evidence that this change may be a primary
risk factor for myocardial reinfarction in younger males (29, 30). The relationship between CHD and PAI-I is presumably a function of the
observation that plasma PAI-l and fibrinolysis are inversely related, i.e. an increase in PAI-1 concentration is associated with deficient fibrinolysis. There is evidence that PAI-1 levels are higher in patients with NIDDM (31), hypertriglyceridemia (29,30), or hypertension (32). The association between PAI-1 and the other features of Syndrome X raises the possibility that it also may be related to insulin resistance and compensatory hyperinsulinemia, and results published over the past five years lend substance to this notion. The relationship between PA1-1 and insulin resistance and hyperinsulinemia was recently reviewed in detail by Vague and colleagues (33), and they summarized evidence that PAI-1 and plasma insulin concentration are related in normal subjects over a wide range of body weight, in nondiabetic obese females, and in patients with NIDDM, angina, or hypertension.

Data linking changes in PAI-l concentration to insulin resistance depend upon the premise that insulin levels provide a reasonably accurate estimate of insulin action, a view that has a reasonable amount of support
(4, 5, 13). As a consequence, it seems likely that decreases in insulinmediated glucose uptake would be associated with increases in PAI-I
concentration. An increase in PAI-I concentration has also been shown to occur in the other clinical situations subsumed under the heading of
Syndrome X; thus it seems reasonable to add this abnormality of the fibrinolytic system to the cluster of changes comprising Syndrome X.

THE RELATIONSHIP OF SYNDROME X TO OBESITY

Throughout this presentation reference has been made to the fact that all of the elements of Syndrome X can be seen in nonobese individuals. The reason for including this information was the fact that obesity, per se, can lead to a decrease in insulin-mediated glucose uptake, whereas weight loss in obese individuals is associated with enhanced in vivo insulin action (16). However, obesity is not the only environmental change that can modulate insulin resistance, and level of habitual physical activity seems to be as
potent, if not more so, then obesity in this regard (34, 35). Furthermore, it is also known that exercise training can enhance insulin sensitivity, lower plasma TG and insulin levels, lower blood pressure, and increase HDL cholesterol
concentrations (36, 37).

The fact that obesity and habitual activity can modify the presentation of Syndrome X does not mean that Syndrome X is determined solely by these environmental variables. For example, in nondiabetic individuals, comprising volunteers of European and Native American backgrounds, we were able to show that less than 50% of the total variance in insulin-stimulated glucose uptake could be attributed to the combined effects of differences in age, maximal oxygen consumption, and obesity (35). Parenthetically, age made an extremely small contribution in this analysis, and the relative impact of differences in maximal oxygen consumption was at least as great as that due to variations in body weight. Thus, all of the clinical features of Syndrome X can develop independently of obesity, sedentary activity, etc. In this context, other terms used to describe Syndrome X, i.e. "the deadly quartet (38)" or the GHO Syndrome (glucose intolerance, hypertension, and obesity (39), are misleading in that they imply that obesity is an essential attribute of the system complex being
described-it simply isn't and should not be so designated.

THE RELATIONSHIP BETWEEN SYNDROME X AND
CHD

There seems to be reasonable evidence that at least some portion of those individuals fulfilling the criteria for the diagnosis of microvascular angina have true myocardial ischemia (40). Evidence has also been published indicating that an increase in PAI-l is a risk factor for CHD (28-30), presumably because of a defect in the fibrinolytic system. On the other hand, metabolic risk factors for CHD known to be associated with an increase in PAl-I, e.g. hyperinsulinemia, hypertriglyceridemia, and a low HDL-cholesterol, were not routinely measured in the studies linking the fibrinolytic system to CHD, and it is possible that they also contributed to the development of ischemic heart disease. In this context it is worth noting the report that abnormal levels of PAI-I were seen in patients with myocardial infarction and normal coronary arteries (41), providing a possible link between PAI-I and microvascular angina.

If we now focus on metabolic risk factors for CHD, it seems fair to say that the most attention has been given to the role played by an increase in LDL-cholesterol. However, it is becoming increasingly apparent that CHD can occur in the absence of hypercholesterolemia (42), and that the abnormalities subsumed under the general heading of Syndrome X appear to play a major role in the etiology of CHD. The importance of hypertension as a CHD risk factor is well recognized, making somewhat confusing the evidence that little or no reduction in CHD could be demonstrated when blood pressure was lowered in clinical trials (43). A possible explanation for this phenomenon may be that no attention was directed in these trials to the abnormalities in carbohydrate and lipoprotein metabolism now known to be associated with high blood pressure and discussed above. Although CHD is recognized as a major cause of morbidity and mortality in patients with NIDDM (44), it does not seem that risk ofCHD is limited to patients with frank diabetes. There is evidence that risk of CHD is also increased among individuals with normal glucose tolerance who have the highest plasma glucose concentration after a glucose load (45). Hyperinsulinemia is a compensatory response aimed at maintaining glucose tolerance in individuals who have a defect in insulin-stimulated glucose uptake. Unfortunately, endogenous hyperinsulinemia has been shown to be associated with an increased risk for CHD (45, 46).

The role of hypertriglyceridemia as a primary risk factor for CHD has been minimized in publications from the United States (47), but this has
not been the case in Europe (48, 49). The issue was the subject of an excellent recent review (50), and an important role for hypertriglyceridemia in the genesis of CHD cannot be easily dismissed. The combination of a high level of plasma TG and a low level of HDL-cholesterol as an important risk factor for CHD has been emphasized by results from both the Framingham and Helsinki Heart studies (51, 52), and there is abundant evidence implicating a low plasma HDL-cholesterol concentration as increasing the risk of CHD in both nondiabetics (53) and patients with NIDDM (54). Indeed, the only two lipid abnormalities consistently associated with CHD in patients with NIDDM are high plasma TG and low HDL-cholesterol concentrations (12).

CONCLUSION

Evidence has been reviewed suggesting that resistance to insulin-stimulated glucose uptake and the degree to which the endocrine pancreas responds to this defect both play important roles in the development of a variety of clinical syndromes that have in common an increase in CHD. It appears that the defect in insulin action is the basic abnormality in predisposing patients to develop NIDDM. Normal glucose tolerance can be maintained if insulin-resistant individuals are able to maintain a state of chronic hyperinsulinemia. Unfortunately, this may represent a Pyrrhic victory, and the consequences are likely to include microvascular angina, an increase in PAl-1 activity, hyperuricemia, high blood pressure, dyslipidemia, and CHD. At the present time we are witnessing an extraordinary increase in CHD and/or NIDDM in a variety of ethnic groups of non-European origin (51, 55, 56). In all of these situations resistance to insulin-stimulated glucose uptake and its known consequences appear to be present. Furthermore, the importance of these abnormalities are not confined to non-Europeans (42). Given these considerations, it seems reasonable to suggest that the various facets of Syndrome X are involved to a substantial degree in the
cause and course of the major diseases of civilization.

Literature Cited

I. Reaven, O. M. 1988. Role of insulin resistance in human disease. Diabetes 37: 1495-1607

2. Reaven, G. M., Chen, Y.-D. I., Donner, C. C., Fraze, E., Hollenbeck, C. B. 1985. How insulin resistant are patients with
noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 61: 32-36

3. Laws, A., Stefanick, M. L., Reaven, G. M. 1989. Insulin resistance and hyper-triglyceridemia in nondiabetic relatives of patients with noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 69: 343-47

4. Hollenbeck, C, Reaven, G. M. 1987. Variations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J. Clin. Endocrinol. Metab. 64: 1169-73

5. Reaven, G. M., Hollenbeck, C B., Chen, Y.-D. I. 1989. Relationship between glucose tolerance, insulin secretion, and insulin action in nonobese individuals with varying degrees of glucose tolerance. Diabetologia 32: 52-55

6. Shen, D.-C, Shieh, S.-M., Fuh, M., Wu, D.-A., Chen, Y.-D. I., Reaven, G. M. 1988. Resistance to insulin-stimulated glucose uptake in patients with hypertension. J. Clin. Endocrinol. Metab. 66: 580-83

7. Swislocki, A. L. M., Hoffman, B. B., Reaven, G. M. 1989. Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am. J. Hypertens. 2: 419-23

8. Manicardi, V., Camellini, L., Bellodi, G., Coscelli, C, Ferrannini, E. 1986. Evidence for an association of high blood pressure and hyperinsulinemia in obese man. J. Clin. Endocrinol. Metab. 62: 1302-4

9. Ferrannini, E., Buzzigoli, G., Bonadona, R. 1987. Insulin resistance in essential hypertension. N. Engl. J. Med. 317: 350-57

10. Shamiss, A., Carroll, 1., Rosenthal, T. 1992. Insulin resistance in secondary hypertension. Am. J. Hypertens. 5: 26- 28

11. Reaven G. M., Ho, H. 1992. Renal vascular hypertension does not lead to hyperinsulinemia in Sprague-Dawley rats. Am. J. Hypertens. 5: 314-17

12. Reaven, G. M., Chen, Y.-D. I. 1988. Role of insulin in regulation of lipoprotein metabolism in diabetes. Diabetes/ Metab. Rev. 4: 639-52

13. Hollenbeck, C 8., Chen, N., Chen, Y.-D. I. , Reaven, G. M. 1984. Relationship between the serum insulin response to oral glucose and insulin-stimulated glucose utilization in normal subjects. Diabetes 33: 460-63

14. Olefsky, J. M., Farquhar, J. W., Reaven, G. M. 1974. Reappraisal of the role of insulin in hypertriglyceridemia. Am. J. Med. 57: 551-60

15. Tobey, T. A., Greenfield, M., Kraemer, F., Reaven, G. M. 1981. Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics and plasma triglyceride levels in normotriglyceridemic man. Metabolism 30: 165-71

16. Olefsky, J. M., Reaven, G. M.,
Farquhar, 1. W. 1974. Effects of weight
reduction on obesity: studies of carbohydrate
and lipid metabolism. J. Clin.
Invest. 53: 64-76

17. Reaven, G. M., Lerner, R. L., Stern, M.
P., Farquhar, 1. W. 1967. Role of insulin
in endogenous hypertriglyceridemia. J.
Clin. Invest. 46: 1756-67

18. Zavaroni, I., Dall'Aglio, E., Alpi, 0.,
Bruschi, F., Bonora, E., et al. 1985. Evidence
for an independent relationship
between plasma insulin and concentration
of high density lipoprotein
cholesterol and triglyceride. Atherosclerosis
55: 259-66

19. Laws, A., King, A. C, Haskell, W. L.,
Reaven, G. M. 1991. Relation of fasting
plasma insulin concentration to high
density lipoprotein cholesterol and triglyceride
concentrations in men.
Arterioscler. Thromb. II: 1636-42

20. Kemp, H. G. 1973. Left ventricular function
in patients with the anginal syndrome
and normal coronary arteriograms.
Am. J. Cardial. 32: 375-76

21. Dean, J. D., Jones, C J. H., Hutchison,
S. 1., Peters, 1. R., Henderson, A. H.
1991. Hyperinsulinaemia and microvascular
angina ("syndrome X"). Lancet
337: 456-57

22. Shieh, S.-M., Shen, M., Fuh, M. M.-T.,
Chen, Y.-D. I., Reaven, G. M. 1987.
Plasma lipid and lipoprotein concentrations
in Chinese males with coronary
artery disease, with and without hypertension.
Atherosclerosis 67: 49-55

23. Gertler, M. M., Gam, S. M., Levine, S.
A. 1951. Serum uric acid in relation to
age and physique in health and coronary
heart disease. Ann. Intern. Med. 34:
1421-31

24. Myers, A. R., Epstein, F. H., Dodge, 1.
H., Mikkelsen, W. M. 1968. The relationship
of serum uric acid to risk factors
in coronary heart disease. Am. J. Med.
45: 420-28

25. Klein, R., Klein, B. E., Coroni, J. C,
Maready, 1., Cassell, 1. C, Tyroler, H.
A. 1973. Serum uric acid: its relationship
to coronary heart disease risk factors
and cardiovascular disease, Evans
County, Georgia. Arch. Intern. Med.
132: 401-10

26. Wyngaarden, 1. 8., Kelley, W. N. 1983.
Gout. In Metabolic Basic of Inherited
Disease, ed. J. 8. Stanbury, J. 8. Wyngaarden,
D. S. Fredrickson, 1. L. Goldstein,
M. S. Brown, pp. 1043-1144. New
York: McGraw-HilI. 5th ed.

27. Facchini, F., Chen, Y.-D. I., Hollenbeck,
C. B., Reaven, G. M. 1991. Relationship
between resistance to insulinmediated
glucose uptake, urinary uric
acid clearance, and plasma uric acid concentration.
1. Am. Med. Assoc. 266:
3008-11

28. Paramo, J. A., Colucci, M., Collen, D.,
van der Werf, F. 1985. Plasminogen activator
inhibitor in the blood of patients
with coronary artery disease. Dr. Med.
J. 291: 575-76

29. Mehta, J., Mehta, P., Lawson, D.,
Saldeen, T. 1987. Plasma tissue plasminogen
activator inhibitor levels in coronary
artery disease: correlation with
age and serum triglyceride concentrations.
J. Am. Coil. Cardiol. 9: 263-68

30. Hamsten, A., Wiman, B., Defaire, D.,
Blomback, M. 1985. Increased plasma
level of a rapid inhibitor of tissue plasminogen
activator in young survivors of
myocardial infarction. N. Engl. J. Med.
313: 1557-63

31. Juhan-Vague, I., Roul, C., Alessi, M.
c., Ardissone, J. P., Hei, M., Vague, P.
1999. Increased plasminogen activator
inhibitor activity in non insulin dependent
diabetic patients. Relationship with
plasma insulin. Thromb. HaemOSl. 61:
370--73

32. Landin, K., Tengborn, L., Smith, D.
1990. Elevated fibrinogen and plasminogen
activator (PAl-I) in hypertension
are related to metabolic risk factors
for cardiovascular disease. J. Int.
Med. 227: 273-78

33. Juhan-Vague, I., Alessi, M. c., Vague,
P. 1991. Increased plasma plasminogen
activator inhibitor 1 levels. A possible
link between insulin resistance and
atherothrombosis. Diabetologia 34: 457-
62

34. Rosenthal, M., Haskell, W. L.,
Solomon, R., Widstrom, A., Reaven, O.
M. 1983. Demonstration of a relationship
between level of physical training
and insulin-stimulated glucose utilization
in normal humans. Diabetes 32:
408-11

35. Bogardus, C., Lillioja, S., Mott, D. M.,
Hollenbeck, c., Reaven, G. M. 1985.
Relationship between degree of obesity
and in vivo insulin action in man. Am.
J. Physiol. 248: E286--91

36. Krotkiewski, M., Mandroukas, K.,
Sjostrom, L., Sullivan, L., Wetterqvist,
H., Bjornstorp, P. 1979. Effects of longterm
physical training on body fat,
metabolism, and blood pressure in obesity.
Metabolism 28: 65(}--58

37. Schwartz, R. S. 1987. The independent
effects of dietary weight loss and aerobic
training on high density lipoproteins and
apolipoprotein A-I concentrations in
obese men. Metabolism 36: 165-71

38. Kaplan, N. M. 1989. The deadly quartet.
Upper-body obesity, glucose intolerance,
hypertriglyceridemia, and hypertension.
Arch. Intern. Med. 149: 1514--
20

39. Modan, M., Halkin, H., Almog, S.,
Lusky, A., Eshkol, A., et al. 1985.
Hyperinsulinemia: a link between hypertension,
obesity and glucose intolerance.
J. Clin. Invest. 75: 809-17
40. Anon. 1987. Syndrome X. Lancet 75:
809-17

41. Verheugt, F. W. A., Ten Cate, J. W.,
Sturk, A., Imandt, L., Verhorst, P. M.,
et al. 1987. Tissue plasminogen activator
activity and inhibition in acute myocardial
infarction and angiographically
normal coronary arteries. Am. J.
Cardiol. 59: 1075-79

42. Reaven, G. M., Laws, A. 1990. Coronary
heart disease in the absence of
hypercholesterolaemia. J. Intern. Med.
228: 415-17

43. Collins, R., Peto, R., MacMahon, S.,
Hebert, P., Fiebach, N. H., et al. 1990.
Blood pressure, stroke, and coronary
heart disease. Part 2, short-term
reduction in blood pressure: overview of
randomized drug trials in their
epidemiological context. Lancet 335:
827-38

44. Fuller, 1. H. 1985. Causes of death in
diabetes mellitus. Horm. Melab, Res.
15(S): 3-9

45. Pyoriilii, K. 1979. Relationship of glucose
tolerance and plasma insulin to the
incidence of coronary heart disease:
results from two populations studies in
Finland. Diabetes Care 2: 131-41

46. Ducimetiere, P., Eschwege, E., Papoz,
L., Richard, J. L., Claude, J. R., Rosselin,
O. 1980. Relationship of plasma
insulin levels to the incidence of myocardial
infarction and coronary heart
disease mortality in a middle-aged population.
Diabetologia 19: 205-10

47. Hulley, S. B., Rosenman, R. H., Bawol,
R. D., Brand, R. J. 1980. Epidemiology
as a guide to clinical decisions. The
association between triglyceride and coronary
heart disease. N. Engl. J. Med.
302: 1383-89

48. Cam bien, F., Jaqueson, A., Richard, J.
L., Warnet, J. M., Ducimetiere, P.,
Claude, J. R. 1986. Is the level of serum
triglyceride a significant predictor of coronary
death in "normocholesterolemic"
subjects? The Paris Prospective Study.
Am. J. Epidemiol. 124: 624--32

49. McKeigue, P. M., Marmot, M. G., Court, Y. D. S., Cottier, D. E., Rahman,
S., Riemersma, R. A. 1988. Diabetes,
hyperinsulinemia, and coronary risk factors
in Bangladeshis in East London. Br.
Heart J. 60: 390--96

50. Austin, M. A. 1991. Plasma triglyceride
and coronary heart disease. Arterioscler.
Thromb. 11: 2-14

51. Castelli, W. P. 1986. The triglyceride
issue: a view from Framingham. Am.
Heart J. 112: 432-37

52. Manninen, Y., Tenkanen, L., Koskinen,
P., Huttunen, 1. K., Manttari, M., et a!.
1992. Joint effects of serum triglyceride
and LDL cholesterol and HDL cholesterol
concentrations on coronary heart
disease risk in the Helsinki heart study:
implications for treatment. Circulation
85: 37-45

53. Castelli, W. P., Doyle, J. T., Gordon, T.,
Hames, C. G., Hjortland, M. c., et al.1977. HDL cholesterol and other lipids
in coronary heart disease. Circulation 55:
767-72

54. Welborn, T. A., Knuiman, M.,
McCann, Y., Stanton, K., Constable, l.
1. 1984. Clinical macrovascular disease
in caucasoid diabetic subjects: logistic
regression analysis of risk variables.
Diabetologia 27: 568-73

55. Sicree, R. A., Zimmet, P. Z., King, H. O.
M., Coventry, J. S. 1987. Plasma insulin
response among Nauruans: prediction
of deterioration in glucose tolerance
over 6 yr. Diabetes 36: 179-86

56. Haffner, S. M., Stern, M. P., Mitchell,
B. D., Hazuda, H. P., Patterson, J. K.
1990. Incidence of type II diabetes in
Mexican Americans predicted by fasting
insulin and glucose levels, obesity, and
body-fat distribution. Diabetes 39: 283-
88

 

[Ðekel]

zlyja,

Thanks for clearing that up, Laura. TransientP, it should apply to printed material as well, since the law was written prior to the World Wide Web.

thanks you.

great additions too !
:)

 

[Sinapi]

No problem, transientP! :)

Carbohydrate restriction and cardiovascular risk
Jocelyne G. Karam, Fiby Nessim, Samy I. McFarlane and Richard D. Feinman

found in:
Current Cardiovascular Risk Reports
Volume 2, Number 2, 88-94, DOI: 10.1007/s12170-008-0018-z

_http://www.springerlink.com/content/2510372651x456g4/

Abstract
Originally developed as a strategy for weight loss, diets based on restriction of carbohydrates were traditionally of concern because of the assumed increased cardiovascular risk if the carbohydrates were replaced with fat. It now appears that such diets are associated with an improvement in markers of cardiovascular risk, even with higher saturated fat intake and even in the absence of weight loss.
Various evidence supports this paradigm shift:

1) carbohydrate restriction improves markers of atherogenic dyslipidemia (triglycerides, high-density lipoprotein cholesterol, apolipoprotein B-apolipoprotein A-1 ratio) and reduces the more atherogenic small, dense low-density lipoprotein cholesterol;

2) high amounts of dietary carbohydrates increase de novo fatty acid synthesis and plasma triglycerides;

3) large, long-term studies of traditional dietary fat reduction continue to fail to demonstrate the predicted improvement in cardiovascular disease risk. Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. It seems appropriate to consider carbohydrate reduction as a useful, if not the preferred, alternative to low-fat diets, which have met with limited success.

PDF URL:
_http://www.springerlink.com/content/2510372651x456g4/fulltext.pdf

Sounds like a good find, l_autre_d! I have to type this in parts, though, because otherwise I get an error message:

http://www.springerlink.com/content/2510372651x456g4/fulltext.pdf

Carbohydrate Restriction and
Cardiovascular Risk

Jocelyne G. Karam, MD, Fiby Nessim, MD,
Samy I. McFarlane, MD, MPH, and Richard D. Feinman, PhD

Corresponding author
Richard D. Feinman, PhD
Department of Biochemistry, State University of New York
Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY
11203, USA.
E-mail: rfeinman@downstate.edu
Current Cardiovascular Risk Reports 2008, 2:88–94
Current Medicine Group LLC ISSN 1932-9520
Copyright © 2008 by Current Medicine Group LLC

Abstract

Originally developed as a strategy for weight loss,
diets based on restriction of carbohydrates were traditionally
of concern because of the assumed increased
cardiovascular risk if the carbohydrates were replaced
with fat. It now appears that such diets are associated
with an improvement in markers of cardiovascular risk,
even with higher saturated fat intake and even in the
absence of weight loss. Various evidence supports this
paradigm shift: 1) carbohydrate restriction improves
markers of atherogenic dyslipidemia (triglycerides,
high-density lipoprotein cholesterol, apolipoprotein
B–apolipoprotein A-1 ratio) and reduces the more
atherogenic small, dense low-density lipoprotein
cholesterol; 2) high amounts of dietary carbohydrates
increase de novo fatty acid synthesis and plasma triglycerides;
and 3) large, long-term studies of traditional
dietary fat reduction continue to fail to demonstrate
the predicted improvement in cardiovascular disease
risk. Cardiovascular disease is the leading cause of
morbidity and mortality in the Western world. It seems
appropriate to consider carbohydrate reduction as a
useful, if not the preferred, alternative to low-fat diets,
which have met with limited success.

Introduction

Recent studies suggest a substantial reversal of our
understanding of the role of dietary carbohydrate
restriction in cardiovascular (CV) risk. Long established
as a strategy for weight loss, low-carbohydrate diets are
traditionally not recommended because of the concern
that the carbohydrates will be replaced with fat, with
assumed deleterious effects on CV risk. It is now clear,
however, that replacement of dietary carbohydrates with
fat generally leads to improvement in atherogenic dyslipidemia
(raised triglycerides, low high-density lipoprotein
[HDL] cholesterol, and small low-density lipoprotein
[LDL] particles), even with higher saturated fat (SF)
and even under conditions in which no weight loss
occurs [1••,2,3]. The underlying basis of these effects is
reduction of the elevated levels of insulin that follow carbohydrate
ingestion. Insulin inhibits lipolysis, activates
lipoprotein lipase, and stimulates de novo fatty acid
synthesis. These responses bias metabolism toward fat
accretion, toward elevation of triglycerides and reduction
in HDL, and away from oxidation. Insulin per se
might be described as atherogenic [4]. Continued high
insulin stimulation effects a negative feedback system
that manifests as insulin resistance and, under conditions
of nutrient excess, hyperinsulinemia may lead to
obesity. Obesity and the insulin-resistant state further
exacerbate the effects of high carbohydrates on CV risk.
We describe recent reports that support these generalizations,
emphasizing changes in lipid markers.

Definitions

Analysis of carbohydrate restriction is complicated
by a lack of clear definitions and the association with
popular low-carbohydrate diets that recommend a level
of carbohydrate intake that varies over time [5–7].
Such diets typically specify the intake of less than
30 g/d for 2 weeks followed by variable reintroduction of
carbohydrates. The low levels are usually referred to as
very-low-carbohydrate ketogenic diets (VLCKDs). The
amount of carbohydrates that constitutes a low-carbohydrate
diet varies widely among studies. We consider
less than 130 g/d or 26% of a nominal 2000 kcal
diet as a reasonable cutoff for the definition of a low carbohydrate
diet. Carbohydrate consumption before
the epidemic of obesity averaged 43%, and we suggest
26% to 45% as the range for moderate-carbohydrate
diets. The issue is important because carbohydrate as a
nutrient is likely to have a linear effect on metabolism
but, as stimulus for insulin, one anticipates a catalytic
or threshold effect.

Diet and CV Risk

The literature includes numerous trials of low-carbohydrate
diets—as a single arm [8–10] or, more commonly, as comparisons
with low-fat diets [11–14,15••,16,17]. Tested diets
include VLCKDs and a range from low-carbohydrate to
those that might be considered high-carbohydrate diets.

The overall picture of CV risk is clear. Low-fat diets
tend to reduce total and LDL cholesterol. Carbohydrate
restriction does not have a consistent effect on total cholesterol
but tends to raise LDL, although there is great
individual variation. Low-carbohydrate diets consistently
have a more positive effect than low-fat diets on
other markers that may be more predictive of CV disease
than LDL: HDL, triglycerides, total/HDL ratios, and
apolipoprotein (apo) B/apo A-1 ratios. Abnormalities in
these markers are collectively referred to as atherogenic
dyslipidemia, usually in the context of defining metabolic
syndrome (MetS) [1••,2] (Table 1).

Ginsberg et al. [18] have summarized the importance
of triglyceride-rich lipoproteins, and numerous
trials show reduction in triglycerides by low-carbohydrate
interventions [1–3,9–14,15••,16,17]. Reduction
in triglycerides by carbohydrate restriction is one of
the most reliable outcomes of any dietary intervention
that is not specifically designed to correct a deficiency.
Somewhat ironically, given the continued recommendations
for a low-fat, high-carbohydrate diet, an
increase in triglycerides has been used as a biomarker
of compliance to a low-fat diet [19]. It also has been
demonstrated that after some period on a low-carbohydrate
diet, postprandial triglyceride response to a
high-fat challenge is reduced compared with controls or
low-fat diets [15••,20, 21].

LDL Particle Size

The apparent dichotomy between LDL and markers
of atherogenic dyslipidemia is now understood in the
context of observations that subfractions of LDL differ
in atherogenicity. Small, dense LDL particles are
considered more atherogenic than the large, more buoyant
particles. Patients with higher levels of the smaller
particles are referred to as having the pattern B phenotype.
Dreon et al. [22] and Krauss [23••] have shown
that dietary carbohydrate is the major predictor of this
pattern. Inclusion of small LDL particles in the definition
of the atherogenic dyslipidemia of MetS provides
a single marker for the identification of CV risk and
suggests a consistently overall positive effect of carbohydrate
restriction.

An alternative measure emphasizing small LDL particles
is determination of apo B. Because each lipoprotein
particle contains one molecule of apo B, total LDL would
bias the results toward larger particles. Apo A-1 is similarly
a molecular indicator of HDL. Barter et al. [24] have
presented evidence that the apo B/apo A-I ratio is superior
to other markers for prediction of CVD. This parameter,
again, is more reliably improved by low-carbohydrate
diets than by low-fat diets.

Dietary Saturated Fat

Despite persistent recommendations for low-fat diets,
total fat per se has little effect on CV risk, and the
cutting edge of the debate on macronutrients is the presumed
risk from dietary saturated fatty acids (SFAs).
The concern originates with early epidemiologic studies
that have been strongly criticized [25,26] and are now
somewhat anachronistic. Associations of dietary SF
and blood cholesterol have been demonstrated [27] but
show large individual variation: cholesterol sometimes
increases after reduction of SFAs. Long-term trials,
particularly from the Women’s Health Initiative [28•],
show no effect of dietary SF on CV incidence, and the
overall perspective on risk of dietary SFAs is ambiguous
at best [29]. Recent prospective studies have even
demonstrated benefit in replacing carbohydrates with
SF: decreases in small atherogenic LDL [30] and, most
dramatically, reductions in the progression of coronary
atherosclerosis with higher SF [31].

The Limitations of “You Are What You Eat”

The assumption underlying dietary recommendations that,
for example, limit SFA is that the physiologic distribution of
nutrients will be a reflection of consumption. On the other
hand, even if it is assumed that plasma SFA is deleterious,
metabolic transformations may have substantial impact; the
idea that high dietary SF will lead to high plasma SF is not
supported by studies that impose carbohydrate restriction
at the same time. Volek et al. [15••] compared a VLCKD
(carbohydrate-fat-protein: 12%:59%:20%) with a low-fat
diet (56%:24%:28%) in people with MetS. After 12 weeks,
SFAs in triglycerides and cholesteryl ester were lower in the
VLCKD group than in the low-fat group despite a threefold
higher intake of dietary SFAs (and a higher baseline value)
in the VLCKD group. King et al. [32] also found an elevation
in plasma SFAs on a low-fat, high-carbohydrate diet.
The likely increase in total triglycerides suggests further
limitations of such a diet [33].

In general, whereas dietary lipids may play a role
in changing the plasma lipid profile [34], the resulting
plasma profile does not predictably mirror the dietary
pattern. Increases in total fat, for instance, might be
expected to show changes in lipid pattern, but the major
result of the study by Raatz et al. [35] was the small difference
in fatty acid distribution between a low-fat and
high-fat diet. Similarly, Cassady et al. [36] found that
two groups consuming low-carbohydrate diets differing
in dietary SFAs showed little difference in plasma stearic
or palmitic acid.



Figure 1. Cardiovascular risk factors
increased by high-carbohydrate diets and
improved by carbohydrate restriction
(also see Figure 3 in Volek et al. [2]). The
major effect is to increase adipocyte and
hepatic triglycerides, leading to increases
in very-low-density lipoprotein (VLDL). The
exchange of triglycerides and cholesterol
leads to triglyceride-rich phospholipids,
which are further processed to small,
dense low-density lipoprotein (LDL), or
cleared decreasing levels of high-density
lipoprotein (HDL). Tissue differences are not
shown. ACC—acetyl–coenzyme A (CoA)
carboxylase; FA—fatty acid; FAS—fatty acid
synthase; HSL—hormone-sensitive lipase;
SFA—saturated fatty acid.


De Novo Fatty Acid Synthesis

High levels of dietary carbohydrates lead to fatty acid synthesis
[37]. Because the effects can be reduced by the type
of carbohydrate and by exercise, it was generally believed
that fatty acid synthesis was not a major player in human
physiology. Recent studies, however, suggest that it may be
important, especially in the context of insulin resistance.
Volek et al. [15••] found that maintenance of plasma SFAs
in the low-fat group was due at least in part to decreased de
novo fatty acid synthesis, with the VLCKD group showing
reduced levels of palmitoleic acid (16:1n-7), an indicator of
fatty acid synthesis; it appears that newly synthesized SF,
palmitic acid, may be immediately acted on by the stearoyl–
coenzyme A desaturase. A study in C57BL/6 mice showed
that a ketogenic diet increased expression of adenosine-5'-
monophosphate (AMP) kinase corresponding to a decrease
in acetyl–coenzyme A carboxylase, the initial enzyme in
the fatty acid synthase pathway, compared with controls,
and most resembled animals subject to caloric restriction
[38]. Petersen et al. [39•] showed that insulin-resistant
subjects on a high-carbohydrate diet biased carbohydrate
disposal toward fatty acid synthesis and away from glycogen
storage. Interestingly, Schwarz et al. [40] found a
strong correlation between de novo fatty acid synthesis and
increased triglycerides.

 

[Sinapi]

I have to apologize, all. I can't post the full article because I keep getting, "The following error or errors occurred while posting this message:
The message body was left empty." I can't even paste two paragraphs from the study, even if I reformat everything! What's going on?

In the meantime, here's the original version _http://www.mediafire.com/?j432jzbvkxkycxv and a text version _http://www.mediafire.com/?m4348u4f4yc4tqr if you are interested.


EDIT: Sorry guys, I honestly didn't notice the attachment options until today. So, if you don't want to give my mediafire account hits, you can view them right here.

 

[Sinapi]

Hi everybody,

First of all, I'd like to apologize for not posting in a while. My college schedule has a heavier workload than I thought it would have, so I've had to put this on the back burner, and I have no idea when I'll fully finish this. This part only contains references from Chapter 8, the one dealing with saturated fat and cholesterol in relation to a low-carb diet. I think that the articles here are very important, and, thankfully, many of them are free. I also want to try to continue pasting text from the articles I have linked to again. If I'm unable to post large articles, like what happened last time, I'm going to post about it in the tech support forum.

Also, whenever I figure out how to do so, I'll link to all the different parts in this topic in each list.

PART 3

[46]

Author: Ridker

Title: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.

Relevance:

"The majority of cholesterol circulates in our bloodstream as 'low density lipoprotein cholesterol' (LDL-C), making it the prime target of drug and lifestyle strategies to prevent heart disease. While the widespread use of statins (a class of drugs used to lower cholesterol by inhibiting its production) has shown a certain degree of success in reducing cardiovascular risk, there is considerable uncertainty that cholesterol lowering per se is the primary source of this benefit. It has been argued that other mechanisms independent of reducing LDL-C (e.g., anti-inflammatory effects) may account for much ofthe clinical efficacy ofstatin drugs[46]. And yet, despite this causal uncertainty, the proposed link between blood cholesterol and heart disease has been the driving force behind dietary recommendations to restrict cholesterol and saturated fat." [pg 89]

Link: http://www.nejm.org/doi/full/10.1056/NEJMoa0807646#t=articleTop

[47]

Author: Volek

Title: Modification of lipoproteins by very low-carbohydrate diets.

Relevance:

“Plasma LDL-C responses to low carbohydrate diets can be variable in magnitude and direction. In well controlled experiments, the serum LDL-C level in response to a very low carbohydrate diet may increase, decrease or stay the same. In side-by-side comparison to low fat diets, LDL-C levels are usually higher in response to low carbohydrate diets[47] . This is one of the favorite talking pOints of low carbohydrate diet critics.” [pg 91]

They go on to say that it doesn't necessarily matter how much LDL-C you have, but rather the size of the particles. Big and fluffy LDL-C (Pattern A) is better than small and dense LDL-C (Pattern B), the latter of which can end up accumulating as plaque in your arteries (see reference [50]).

Link: http://jn.nutrition.org/content/135/6/1339.full

[48]

Author: de Lorgeril

Title: Mediterranean Diet, Traditional Risk Factors, and the Rate of Cardiovascular Complications After Myocardial Infarction: Final Report of the Lyon Diet Heart Study

Relevance:

“First, the presumed causal link between 'total' LDL-C and heart disease is tenuous. Cholesterol reductions induced by statin drugs may be associated with reduced cardiovascular risk, but when it's a low-fat diet that lowers LDC-c' and it's compared to a higher fat diet, guess which did a better job at lowering the REAL incidence of heart disease? In 1994, the Lyon Diet Heart Study [48) was terminated prematurely at 27 months due to a dramatic decrease in mortality in the group that consumed a 40% fat Mediterranean-type diet compared to a group that was prescribed the American Heart Association's 'prudent diet: This dramatic difference in heart disease and overall mortality occurred despite the fact that there were no differences in the two groups' LDL-C responses to the diets.

Even more convincing is the recent report from the Women’s Health Initiative [49] showing that dietary fat restriction in these post-menopausal women reduced LDL-C but had no effect on cardiovascular disease (CDV) outcomes (heart attack, stroke, and overall mortality) after 8 years.” [pg 91-92]

Link: http://circ.ahajournals.org/content/99/6/779.full.pdf+html

[49] (freebie!)

Author: Howard

Title: Low-fat dietary pattern and risk of cardiovascular disease: the Womens Health Initiative Randomized Controlled Dietary Modification Trial.

Relevance: See above. Also, scroll down to [51] for further reference.

Link: http://jama.ama-assn.org/content/295/6/655.full.pdf+html

[50]

Author: Lamarche

Title: The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects.

Relevance:

“Third, it is now well accepted that what we call LDL-C is, in fact, a complex mixture of lipoproteins consisting of particles varying across a range of sizes. Smaller LDL particles are more atherogenic (i.e., dangerous) than larger ones. And here’s a key fact pertinent to this discussion: low carbohydrate diets consistently and significantly increase LDL particle size irrespective of the response in LDL-C concentration. Compelling data now indicate that having more small LDL particles is associated with increased risk for heart disease [50].” [pg 92]

Link: http://www.em-consulte.com/article/79798


*[51]

Author: Friedewald

Title: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.

Relevance: This one’s mostly just for if you’re curious about how cholesterol measurement works, and how inaccurate it can be, especially if you want to discuss your cholesterol results with your doctor. You may even want to include this excerpt from the book.

“The most common way LDL-C is determined is to estimate its concentration using a formula derived from direct measurement of total cholesterol, HDL-C, and triglycerides. The equation was developed in 1972 by William Friedewald and colleagues[51] and continues to be routinely used in clinical assessment of cardiovascular risk and research studies, including those involving low carbohydrate diets. LDL-C is calculated as total cholesterol minus the sum of

HDL-C and VLDL-C.
LDL-C = Total Cholesterol -[HDL-C + (Triglycerides/5)]

A major assumption is that the ratio of triglyceride to cholesterol is constant. VLDL is estimated as equal to triglycerides (mg/dL) divided by
5. This presumed 5: 1 ratio is not constant, and the errors from this LDL-C calculation are significant [52]. In the original 1972 paper, these researchers noted that the calculation of LDL-C was inaccurate when chylomicrons were present or triglycerides were above 400 mg/dL. These essential limitations under conditions of high plasma triglycerides are widely recognized today. Less appreciated are the potential errors associated with low plasma triglycerides, a condition that is highly relevant when interpreting the LDL-C response to low carbohydrate diets since they often result in marked reductions in triglycerides.

For example, a published case report describes a man with plasma triglycerides of 55 mg/dL who had an estimated LDL-C of 172 mg/ dL using the traditional Freidewald equation. But when measured by two separate direct methods, his actual LDL-C proved to be 126 mg/dL (this was also substantiated by a normal apo B level) [53]. In a formal study of 115 volunteers with plasma triglycerides less than 100 mg/dL, use of the Friedewald formula resulted in a statistically significant overestimation of LDL-C by an average of 12 mg/dL[54].

How does this play out if you are on a low carbohydrate diet? Let's assume that a low carbohydrate diet causes a reduction of triglycerides from 200 to 75 mg/dL with no change in total and HDL cholesterol. As a result, the calculated LDL-C from the Friedewald equation would necessarily increase from 100 to 125 mg/dL. How much of this 25% increase is real and how much artifact? That can only be determined by a direct assessment of LDL-C, which most physicians do not bother to do.

Most people now have the 'LDL-C is bad and HDL-C is good' concept down pat. But there is more to the story. It is well established that not all LDL particles are created equal. Moreover, certain types of LDL have been shown to correlate with abnormal lipid profiles and promote atherosclerosis. As noted previously, the larger more buoyant LDL particles are less harmful than smaller ones. Small LDL particles reside in the circulation longer, have greater susceptibility to oxidative damage by free radicals, and more easily penetrate the arterial wall, contributing to atherosclerosis. No matter what your total LDL-C concentration, if you have relatively more small particles (referred to as Pattern B) it puts you at a several-fold higher risk for heart disease compared to people with larger LDL particles (Pattern A)[49]. And once again, this is independent of your LDL-C concentration.

How can you tell if you're pattern A or B, and how many small particles you have floating around? This is not a simple test for your doctor to do, so it's not routinely ordered by physicians, and thus it doesn't showup on standard lipid panels. The most common analytical methods use a process called gel electrophoresis, but new techniques are available based on nuclear magnetic resonance (LipoProfile Test from LipoScience) and ultracentrifugation (VAP Cholesterol Test from Atherotech).

In the mean time, the ratio of your triglyceride to HDL-C (TG/HDL-C) is an effective surrogate for LDL particle size. Values ofTG/HDL-C over 3.5 indicate that you probably have pattern B with a predominance of small LDL particles, and a ratio this high indicates there's a good chance you may also have insulin resistance[55] .” [pg 93-95]

Link: http://www.clinchem.org/content/18/6/499.full.pdf+html

*[52]

Author: Sniderman

Title: Triglycerides and small dense LDL: the twin Achilles heels of the Friedewald formula.

Relevance: See above.

Link: http://www.sciencedirect.com/science/article/pii/S0009912003001176

[53]

Author: Wang

Title: Low triglyceride levels affect calculation of low-density lipoprotein cholesterol values.

Relevance: See above.

Link: http://www.archivesofpathology.org/doi/pdf/10.1043/0003-9985%282001%29125%3C0404%3ALTLACO%3E2.0.CO%3B2

[54]

Author: Ahmadi

Title: The impact of low serum triglyceride on LDL cholesterol estimation.

Relevance: See above.

Link: http://www.ams.ac.ir/aim/08113/0014.pdf

*[55]

Author: McLaughlin

Title: Is there a simple way to identify insulin resistant individuals at increased risk of cardiovascular disease?

Relevance: See above.

Link: http://www.sciencedirect.com/science/article/pii/S0002914905007411

[56]

Author: Volek

Title: Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet.

Relevance:

“In summary, if LDL-C is your sole intended target, a low fat diet and/ or cholesterol-lowering drugs appear to make sense. But there is enough doubt to question whether LDL-C is the best target for everyone. If your target encompasses a broader range of potent biomarkers like triglycerides, HDL-C, LDL particle size, insulin resistance, or inflammatory markers, then using a low fat/high-carbohydrate diet is equivalent to dancing on the edge of a mine field, whereas a low carbohydrate diet improves all these blood borne risk markers[56].” [pg 96-97]

[...]

“The formation of LDL particles of varying sizes is intimately linked with triglyceride metabolism in the liver. When viewed through metabolic binoculars, it comes to no surprise that dietary carbohydrate has a predictable effect on LDL size. Dietary carbohydrate restriction increases the prevalence of larger LDL particles, whereas low fat/high carbohydrate diets have the opposite (and overtly harmful) effect. This inverse relationship between dietary carbohydrate content and LDL size is evident over a wide range of carbohydrate intakes[57], and it can have quite dramatic (i.e., positive) effects at very low carbohydrate intakes [56]. As people move down the carbohydrate ladder, more and more of them convert their serum lipids from pattern B {small, dense LDL particles} to Pattern A {large, fluffy LDL particles} and thus decrease their cardiovascular risk. And moving up the carbohydrate continuum has the opposite effect. In carefully controlled feeding studies, low fat/high-carbohydrate diets decrease LDL particle size, causing some individuals to shift from pattern A to pattern B[58, 59].” [pg 98-99]

Link: http://www.cnpp.usda.gov/Publications/DietaryGuidelines/2010/Meeting2/CommentAttachments/Feinman-Volek2009-170.pdf

[57]

Author: Krauss

Title: Dietary and genetic probes of atherogenic dyslipidemia.

Relevance: See above.

Link: http://atvb.ahajournals.org/content/25/11/2265.full

*[58]

Author: Dreon

Title: Low-density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men.

Relevance: See above.

Link: http://www.fasebj.org/content/8/1/121.full.pdf+html

[59]

Author: Dreon

Title: A very low-fat diet is not associated with improved lipoprotein profiles in men with a predominance of large, low-density lipoproteins.

Relevance: See above.

Link: http://www.ajcn.org/content/69/3/411.full

*[60]

Author: Kotronen

Title: Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations.

Relevance:

“An additional highly relevant aspect of plasma triglyceride is its fatty acid composition. Blood triglycerides containing saturated fatty acids are more highly correlated with insulin resistance than ones containing essential fatty acids[60]. In addition, a number of prospective and case-controlled studies associate higher proportions of saturated fats in blood lipids with increased coronary disease risk[ 61-63]. How does one come to have more saturated fat in their blood lipids? If you subscribe to the simplistic concept that you are what you eat, then you might believe that dietary saturated fats are to blame for insulin resistance and coronary disease.

However association does not prove causality. The alternative explanation is that an insulin resistant liver readily converts carbohydrate to fat (de novo lipogenesis), and the main product of this pathway is the saturated fat palmitic acid (16:0). When stressed by excess dietary carbohydrate, the liver secretes highly saturated triglyceride-rich VLDL particles. Once in the circulation, these large VLDL are readily converted to small atherogenic LDL particles. Having a lot of saturated fat in your triglycerides, therefore has little to do with your dietary saturated fat intake, but rather how much carbohydrate you eat and how effectively (or ineffectively) your body processes it (see side bar and also Chapter 9).” [pg 99]

Link: http://www.springerlink.com/content/922q1731l183021v/fulltext.html

*[61]

Author: Miettinen

Title: Fatty-acid composition of serum lipids predicts myocardial infarction.

Relevance: See above.

Link: http://www.jstor.org/stable/29508202?seq=1

*[62]

Author: Simon

Title: Serum fatty acids and the risk of coronary heart disease.

Relevance: See above.

Link: http://aje.oxfordjournals.org/content/142/5/469.full.pdf

[63]

Author: Wang

Title: Plasma fatty acid composition and incidence of coronary heart disease in middle aged adults: the Atherosclerosis Risk in Communities (ARIC) Study.

Relevance: See above.

Link: http://www.ajcn.org/content/78/1/91.long

[64]

Author: King

Title: Effect of a low diet on fatty acid composition in red cells, plasma phospholipids, and cholesterol esters: investigation of a biomarker of total fat intake.

Relevance:

"Saturated fat in the diet gets blamed for a lot of bad things. It turns out most of the harmful effects attributed to dietary saturated fat (e.g., increased heart disease, insulin resistance , vascular dysfunction, etc.) are unsubstantiated. The truth is that saturated fats only become problematic when they accumulate. And the guilty party for saturated fat accumulation, in most cases, is dietary carbohydrate.

Yes; dietary intake of carbohydrate -not saturated fat -is the major driver of plasma levels of saturated fat. Counter-intuitively, prior studies have reported lower plasma levels of saturated fat in response to diets that contained 2-3 fold greater intake of saturated fat but were lower in carbohydrate[29, 64, 65]. Even in controlled feeding studies in weight stable individuals (which necessitates a high intake of dietary fat), low carbohydrate diets decrease plasma saturated fat levels[30].

A cautious reader might suggest that the saturated fats are not showing up in our tests because they are leaving the blood and accumulating
in tissue triglycerides. But we have done this experiment in mice adapted to a low carbohydrate diet, and despite eating almost 3-times as much saturated fat as the control mice for 8 weeks, tissue levels of saturates are the same or lower in the Jow carb mice. How can this be? Clearly, humans and mice adapted to a low carbohydrate diet by becoming very adept at using saturated fats as the preferred fuel in muscles and liver. Thus, from the body's perspective, a low carbohydrate diet reduces both blood and tissue saturated fat levels irrespective of dietary saturated fat intake." [pg 100]

Link: http://www.ajcn.org/content/83/2/227.full

[65]

Author: Raatz

Title: Total fat intake modifies plasma fatty acid composition in humans.

Relevance: See above.

Link: http://jn.nutrition.org/content/131/2/231.full

[66]

Author: Shai

Title: Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet.

Relevance:

"HDL-C is one of the best biomarkers of long term cardiovascular health. Unfortunately for drug companies, however, it is a therapeutic target for which existing drugs have little efficacy. Low levels indicate Significant cardiovascular risk independent of LDL-C. The importance of HDL-C derives from its well established role as a scavenger of excess unesterified cholesterol from lipoproteins and tissues requiring transport back to the liver (i.e., reverse cholesterol transport).

HDL-C also increases bioavailability of nitric oxide (important to the regulation of vascular function and blood pressure) and has antioxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic effects, all of which contribute to its anti atherogenic properties. Almost as consistent as their triglyceride-lowering effects, low carbohydrate diets increase HDLC[
47]. The increase in HDL-C may not occur as quickly as the decrease in triglyceride, but based on empirical evidence and the results of a recent 2 year diet study[66]' this slowly developing HDL-C boost appears to be very resilient. A notable feature of this study was the gradual increase in carbohydrates over the 2 year intervention which in this case resulted in a concomitant loss of the triglyceride-lowering benefit but a persistent benefit in HDL-C." [pg 101]

On a side note, that bit about HDL-C increasing the bioavailability of nitric oxide reminded me of this article (http://www.crimetimes.org/98c/w98cp11.htm) that mentioned that a lack of a gene for the production of nitric oxide in mice led to an increase in aggressive behavior. I first mentioned that on the thread regarding possible connections between psychopathy and the vagus nerve (http://cassiopaea.org/forum/index.php?topic=25009.0), although I incorrectly implied that this article, and a few others, actually, specifically mentioned psychopathy; they only mentioned aggressive behavior. That brings me back to this abstract (http://www.ncbi.nlm.nih.gov/pubmed/12056583) that observed lower serum cholesterol in those with antisocial personality disorder (APD) and conduct disorder (CD). Those diagnoses do not automatically correlate with true psychopathy, but it's interesting to think how much our culture has become more violent since the low-fat diet became more popular. But that's still a lot of speculation.

Link: http://www.nejm.org/doi/full/10.1056/NEJMoa0708681#t=article

Thanks again for reading. :)