Does a high animal protein/fat diet forestall obesity?

Don Matesz had an interesting blog post the other day that I tweeted:  Grass-Fed Animal Products Prevent Obesity and Cardiovascular Disease?  He writes:

Not for Mongolians.

Mongols eat a diet largely composed of milk products, meat, and fat from free-ranging, organic, grass-fed animals. They consume few plant foods because few edible plants grow in the cold continental climate of Mongolia. The climate forced them into a natural experiment in low-carb nutrition based on grass-fed animal products.

I have an interest in Mongolians because there's definitely some influence of these people in my husband's ancestral line.   I went looking for any peer review literature that might address the Mongolians and found an interesting article.  But before that, I also found some other info.  Don points out in a note to WAPF (presumably aimed at their promotion of raw milk) that the Mongols boiled their milk and made cheese from it.  But one of the accountings of the diets comes from the WAPF site:  Diet of Mongolia.  

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Protein, Insulin-like Growth Factor-1 (IGF-1) and Glucose Homeostasis

I've blogged previously on the LoBAG diets for treatment of diabetes.  These diets are higher in protein that standard recommendations - 30% vs. 15% - with varying carb content (20,30 & 40% have been studied).  With both of the lower carb diets, this group has achieved good improvements in HbA1c levels in relatively short time (5-10 weeks).  In comparing their diets  they observed:

Increasing the protein content of the diet from 15 to 30% resulted in an 35% increase in IGF-I regardless of whether the carbohydrate content was 40%, 20%, or 30% as in the present study. Thus the dietary protein-induced increase in IGF-I is independent of the amount of dietary carbohydrate and fat.

I believe the near-OCD obsession with insulin in the LC community overshadows the vast body of research on other hormones and peptides that's out there and their role in metabolism.

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The Metabolic Advantage of Fructose

Is fructose making us fat?  Apparently the answer is no if you get your fructose in the form of candy!

Thanks to MM for sending me this paper.

Candy consumption was not associated with body weight measures, risk factors for cardiovascular disease, or metabolic syndrome in US adults: NHANES 1999-2004 

For the purposes of this study, candies were defined as follows:

Sugar candy consists of sugar in crystalline form or semisolid (amorphous) forms with other ingredients including flavors and colors; examples include peppermint, lollipops, licorice, and gum drops. Chocolate candy is a mixture of processed cacao, cocoa butter, and sugar and often contains other ingredients, including milk, fruit, nuts, and caramels.

 This group analyzed 3 sets of NHANES data to look at candy consumption defined as:

Candy consumers were defined as those participants consuming any amounts of candy/confection except gum and were placed in 1of 3 overlapping consumption groups: (a) any candy (including chocolate candy and sugar candy), (b) chocolate candy only, and (c) sugar candy only

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Elevated Free Fatty Acids: Detrimental?

As many of my readers know, I've been challenged lately on my beliefs on NEFA.  So I thought I would summarize my thinking on this in a post rather than having several comments scattered amongst a few threads.   I'm not going to be referencing my post here at this time (it's too time consuming to do so at the moment).  If/when I have the opportunity to do so in the future, I'll do a bumped update.  

These are my thoughts based on extensive research of the peer review literature on this topic, in almost all cases, considered review of full text articles including reading as many supporting citations in major reviews as possible.  Over the past year I have read at least a hundred such articles.

Elevated non-esterified or free fatty acids (NEFA/FFA) are a symptom associated with insulin resistance, Metabolic Syndrome (aka Syndrome X) and Type II diabetes.  The overwhelming evidence in the literature points to elevated NEFA being more than just associated with these conditions, but rather the initiating step in their development..   

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Hypertension, Insulin and Free Fatty Acids (Part I)

Obesity Hypertension Is Related More to Insulin's Fatty Acid Than Glucose Action

Although resistance to insulin-mediated glucose disposal has emerged as a link between abdominal obesity and hypertension, abnormalities of nonesterified fatty acid metabolism may play a greater role. ... Fatty acid concentration and turnover were markedly more resistant to suppression by insulin in obese hypertensive than in lean or obese normotensive individuals. ... The data indicate that blood pressure is related to the effects of insulin on fatty acid metabolism. The findings raise the possibility that resistance of hormone-sensitive lipase to insulin participates in elevating the blood pressure of abdominally obese hypertensive subjects by increasing fatty acid concentration and turnover.

I'm C&P'ing the entire Introduction because it contains live links to background references some readers may be interested in.

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Insulin Is an Anti-inflammatory and Anti-atherosclerotic Hormone

Insulin Is an Anti-inflammatory and Anti-atherosclerotic Hormone  (full text free until end of the month)

Fasting hyperinsulinemia is associated with an increased risk of atherosclerotic complications of heart attack and stroke. This has resulted in the concept that insulin may promote atherosclerosis in spite of the absence of any evidence that insulin is atherogenic either in the human or in experimental models. Recent evidence shows that insulin exerts vasodilatory, anti-platelet and anti-inflammatory effects at the cellular level in vitro and in the human in vivo. Since atherosclerosis is a chronic inflammatory process of the arterial wall, insulin may be potentially anti-atherosclerotic in the long term. More recent data on experimental atherosclerosis in the mouse shows that (1) insulin administration reduces the number and the size of atherosclerotic lesions in apo E null mice and (2) in IRS-2 null mice, the interruption in insulin signal transduction results in enhanced atherogenicity. Finally, the use of a low dose of insulin infusion in patients with acute myocardial infarction has been shown to markedly improve clinical outcomes, both in diabetic and nondiabetic patients. Our own most recent data show that a low dose infusion of insulin in patients with acute myocardial infarction induces a reduction in nflammation (C-reactive protein and serum amyloid A) and oxidative stress, and promotes fibrinolysis. We conclude that insulin is anti-inflammatory and potentially antiatherogenic and may be of use in the treatment of cardiovascular inflammatory conditions.

It seems that the demonization of insulin has followed much the same path as the correlation = causality logic of LDL and atherosclerosis.  Elevated LDL correlates with CVD, but there is not a whole lot of actual evidence demonstrating that the LDL itself directly causing atherosclerosis.   LDL remains a fairly reliable marker for determining risk (though it must be considered along with other factors), and whatever the flaws (and there are many) in cholesterol theories, this shouldn't be ignored out of hand.  If A causes B, and A causes C, then someone with B likely has C.

So with the insulin, we have hyperinsulinemia correlating with CVD, but as stated in the abstract above, there's little evidence that it causes it directly.  The "A" in this scenario seems to be elevated free fatty acids (NEFA/FFA) leading to "B" = hyperinsulinemia and "C" = atherosclerosis.  But in this case the correlation/causation connection may be even more convoluted.  Because there's an intermediate factor in all this -- the ever-increasingly apparent root of all evil: insulin resistance.  The way I see it is this:  Fat stores exceeding an individual's storage capacity lead to IR of the fat cells and/or excessive release of NEFA.  Elevated NEFA induces IR in peripheral tissues.  It is cellular resistance to insulin's inhibitory roles  in these cells that ultimately lead to metabolic dysfunction and/or cell damage/death.  In this regard, the relationship is not so much one of insulin not being the cause of atherosclerosis, etc., but the resistance masks the fact that it would appear that insulin is actually protective against it!  

Inflammation, shmimflamation!  :

Atherosclerosis is an inflammatory process.7 All the major classical risk factors for atherosclerosis, hypercholesterolemia, diabetes, hypertension, smoking, and menopause are associated with (and probably cause) inflammation. If high insulin levels are atherogenic, one would expect it also to exert part of its negative effect on the vessel wall through inflammatory processes. Recent evidence which we shall now review shows that just the opposite is the case, i.e., that insulin is anti-inflammatory.

The article goes on to summarize such research.  I'll let the more science minded read that for themselves (heck, I'm just too lazy at the moment to do a decent summary), but this section concludes with:

In view of the anti-inflammatory and vasodilatory effect of insulin, insulin resistance may be expected to be pro-inflammatory and a proconstrictor state. This indeed is the case.  Obesity,31 type 2 diabetes,32 and other insulin resistant states, such as polycystic ovary syndrome (PCOS),33 are pro-inflammatory and are associated with abnormal vascular reactivity and platelet hyperaggregability.  (clumping & clotting)

........... Insulin sensitizers have been shown to exert anti-inflammatory43–46 and anti-atherosclerotic effects.47,48  Thiazolidinediones (TZD) exert anti-inflammatory effects at the molecular and cellular levels. 

The article goes on to conclude as follows:

These facts, should encourage us to increase our understanding of these novel effects of insulin so that

(1) we have an improved conceptualization of inflammation in states of insulin resistance and the relationship of these states to atherogenesis;

(2) we explore the potential therapeutic role of insulin in inflammatory conditions, such as acute myocardial infarction; and

(3) we investigate novel potential therapeutic application of insulin sensitizers such as thiazolidinediones as anti-inflammatory agents.

I broke these out in more bullet form to address them.

(1)  I take this to mean the lipid hypothesizers need to rethink as much as the carbohydrate hypothesizers do. Both need to re-think the role of dietary composition (and total intake) in terms of its impact on insulin SENSITIVITY, not insulin per se.

(2)  Insulin is, as Martha Stewart would say, a GOOD thing.  There's much promise in using it.  Insulin therapies have evolved from slow acting secretagogues (substances that enhance insulin secretion), to pumps delivering a more consistent, physiological basal level in T1's etc.

(3)  OK, I'm probably in agreement with many who disdain the whole "this gives us more reason to look into more drugs" angle, but we have to be pragmatic about it.  A Type 1 does not make insulin.  In that regard, whatever technology allows them to mimic insulin levels in a normal person, I would be grateful for it.  Type 2 is a far more varied diagnosis as the degree of irreversible damage (as opposed to suppressed function) cannot be assessed with mere fasting glucose levels or tolerance tests.   If you're hyperinsulinemic, you still have functional beta cells.  Temporarily giving them a rest with LC while you lose weight and reverse the IR that is causing the elevated insulin is a great strategy.  But if you cannot adhere to this, or if LC doesn't result in the desired weight loss, then it may well be worthwhile to at least temporarily look into pharmaceutical intervention that allows for insulin to "do its thing".  I wonder, even, if insulin might be helpful to the hyperinsulinemic T2 -- enough exogenous insulin may keep the pancreas from having to work overtime to produce the elevated levels that your body is telling it to anyway.  There's nothing about the hormone that is deleterious!!!!!!!!

Adiposopathy v. Obesity ~ I

I just came across the following article, and haven't quite digested the whole thing just yet.  Still, it is interesting so I thought I would share it here.  This post will be about the most curious topic in this paper, but I hope to revisit this in a series of future blog posts (hence the "I" in the title).  

Adiposopathy Is a More Rational Treatment Target for Metabolic Disease than Obesity Alone

Near as I can tell, the lead author, Harold Bays, is the doctor who coined the term "adiposopathy" or "sick fat".  

Adiposopathy is pathologic adipose tissue dysfunction that may be initiated and/or exacerbated by fat accumulation (adiposity) in genetically susceptible patients [1••].  Adipocytes are metabolically active and adipose tissue is an important endocrine organ (Table 1) [2••]. Abnormalities of adipocyte factors contribute to dysmetabolism (Fig. 1), and adiposopathy [1••,3•] promotes some of the most common metabolic diseases encountered in clinical practice, including type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia.

This is a summary paper focusing on the fact that it is dysfunction of the adipose tissue rather than the amount of adipose tissue that is responsible for Metabolic Syndrome.  Thus explaining your "metabolically obese thin people" and "metabolically normal obese people", etc.   The focus, as the title implies, is MetS treatments that target the fat cell dysfunction rather than simply the person's fat mass.  

Sick fat appears to be related to adipocyte hypertrophy -- an enlarged fat cell:

It has been known since the 1970s that adipocyte hypertrophy increases the lipid/protein ratio of the adipocyte (through a relative consistency in protein content coupled with increased fat content) [13], decreases the responsiveness of adipose tissue to insulin [14], and increases the risk of metabolic diseases such as T2DM [15] and dyslipidemia, even if adipocyte hypertrophy is found in only slightly overweight individuals [16]. In fact, adipocyte hypertrophy is more closely linked to metabolic abnormalities, such as insulin resistance, than is an increase in total body fat [17].

An increase in fat cell size represents a failure of adipose tissue to adequately proliferate and differentiate [18] (as found with obesity and T2DM [19]) and, therefore, a failure to inadequately accommodate a further increase in energy influx [20]. Adipocyte hypertrophy may indicate a resistance or inability to store triglycerides beyond some maximal amount [21]. 

(This is consistent with the Critical Visceral Fat Theory I blogged on previously.)

For this post, I want to focus on the discussion of one of the pharmaceutical treatments:  PPAR-gamma agonists.  (Here's a LINK to general information on these drugs --  thiazolidinediones or “glitazones.” -- Actos and Avandia).  I'm not promoting pharmaceutical therapy, and Avandia has seen a lot of negative press of late, but nonetheless I find the mechanism of action of these drugs to be interesting.

These compounds appear to "cure" sick fat by stimulating the proliferation of new, small, young adipocytes and/or promote the death (apoptosis) of dysfunctional hypertrophied large fat cells.  Since SCAT has a greater ability to differentiate, and VAT cells are more metabolically active, this seems to have differential effects on the two types of adipose tissue.  These drugs tend to cause fat mass gain in SCAT, and loss in VAT, but appear to be most effective in the patients who are fatter to begin with and who gain more fat.  Yes, you read that right.  

From an adipose tissue metabolism standpoint, PPARγ agents have been shown to reduce free fatty acids [23••,91], increase adiponectin [92–94], and reduce leptin [93] (although not consistently so [95]), with unconfirmed effects upon resistin [95,96], IL-6 [97], and tumor necrosis factor-α [95,97]. Thus, it appears that many of the favorable effects of PPARγ agents upon glucose metabolism and adipocyte function may be most related to improvements in free fatty acid metabolism

I've seen diabetics list these meds in their treatment regimes and yet be on weight loss regimes.  In some ways this seems counter productive.  One way to try to cure sick fat is to try to reverse the dysfunction by emptying out the cells.  Another, it appears, would be to replace sick adipocytes with healthy ones.  While weight gain may be the last thing a person wants, I know I probably would resist it were I diabetic, it is interesting to consider.  

The Progression of Insulin Resistance

Vascular function, insulin resistance and fatty acids  (I'll blog on the vascular focus of this paper shortly, but this post is focusing on the bolded statements in the abstract).

Abstract

Over the past 10 years it has become clear that intact vascular function, especially at the level of the endothelium {cells lining the blood vessels}, is paramount in the prevention or delay of cardiovascular disease. It has also become clear that insulin itself, in addition to its metabolic actions, directly effects vascular endothelium and smooth muscle.  Insulin, at normal physiologic concentrations, causes changes in skeletal muscle blood flow in healthy, insulin-sensitive subjects. Insulin’s effect on the endothelium is mediated through its own receptor and insulin signalling pathways, resulting in the increased release of nitric oxide. Insulin’s vascular actions are impaired in insulin-resistant conditions such as obesity, Type II (non-insulin-dependent) diabetes mellitus and hypertension, which could contribute to the excessive rates of cardiovascular disease in these groups.  Insulin-resistant states of obesity and Type II diabetes show a multitude of metabolic abnormalities that could cause vascular dysfunction. Non-esterified fatty acid levels increase long before hyperglycaemia becomes present. Raised non-esterified fatty acids impair insulin’s effect on glucose uptake in skeletal muscle and the vascular endothelium and thus could have detrimental effects on the vasculature, leading to premature cardiovascular disease.

If it is true that NEFA levels rise before blood glucose becomes elevated, then perhaps a screening for pre-pre-diabetes should involve measurement of this blood biomarker?  

What causes elevated NEFA?  It's largely not dietary fats as these are mostly transported as chylomicrons, although there's some indication that in an obese person more FFA's escape re-esterification in the fat cells.  However NEFA levels are largely regulated by their release from adipose tissue in the ever-present FFA/Triglyceride cycling.   The release of NEFA is policed by the inhibitory action of insulin, and this role of insulin has been described as protective.

So if elevated NEFA is the first symptom in the cascade, and an indication of impaired insulin inhibitory action on fat stores, then is the progression of IR proposed by Taubes totally wrong?  Taubes contends that peripheral tissues develop IR first followed by organs and finally adipose tissue.  This statement in this article would indicate that it's the other way around.  Elevated NEFA would indicate some degree of insulin resistance of the fat cells.  Insulin is not largely involved in storing fat, it is involved in its release.  But what causes this?  Hmmmm.... over-stuffed fat cells perhaps?  As circulating NEFA's rise these induce insulin resistance skeletal muscle and perhaps the liver as well so that it pumps out too much glucose.  

It seems more and more apparent to me that carbohydrate consumption per se has relatively little to do with the development of IR.  It naturally occurs in certain phases of life (puberty, aging) but most of us are able to compensate for mild IR by increasing insulin production.  To be fair, it's not dietary fat that necessarily causes it either, although there's still the question of higher IMCL just from eating a higher fat diet and the potential for IMCL derived diacylglycerol and/or ceramides to induce IR in skeletal muscle cells.   Using our insulin does not appear to cause us to become resistant to it.  Indeed the opposite seems to be closer to the truth as low carbers are advised to "carb up" for several days prior to taking an oral glucose tolerance test so as to restore their insulin responses to as normal as possible.

I propose that the fat accumulation leads to elevated NEFA leads to peripheral IR and other deleterious effects on the liver and pancreas.  Only  chronic carbohydrate overfeeding seems to contribute to increases in fat mass, but net fat accumulation will still largely be contributed by dietary fat.  IOW fat accumulation leads to IR leads to hyperinsulinemia.   Fat accumulation is, in the end, dictated by energy balance.

Sudden Cardiac Death and Free Fatty Acids

Here is the Heart Rhythm Society's Definition:

Sudden cardiac death (SCD), also called cardiac arrest, is used to describe a situation in which the heart abruptly and without warning stops working, so no blood can be pumped to the rest of the body. It is responsible for half of all heart disease deaths.

Sudden cardiac death occurs when the heart’s electrical system malfunctions. It is not a heart attack (also known as a myocardial infarcation). A heart attack is when a blockage in a blood vessel interrupts the flow of oxygen-rich blood to the heart, causing heart muscle to die. So if the heart can be compared to a house, SCD occurs when there is an electrical problem and a heart attack – when the problem is the plumbing.

Later in that summary it is stated that 75% showed evidence of prior heart attack, and 80% evidence of CVD.  So that leaves 25% with no evidence of prior heart attack and 20% with no CVD.

So I do a little math:
*  SCD deaths occurring in people with no prior cardiac event that caused discernible damage to heart:
                 (0.5 of all CD's are SCD's) *( 0.25 no prior heart attack) * 100 = 12.5%
                 That's one out of every eight.
* SCD deaths occurring in people with no evidence of CVD
   (presumably athersclerosis/blockage/etc. but could also include other heart problems):
                 (0.5 of all CD's are SCD's) *( 0.20 no evidence of CVD) * 100 = 10%

                 That's one out of every ten.

So why do I care about this?  Because the one thing that is most predictive of SCD is elevated free fatty acids (NEFA/FFA), a characteristic of Metabolic Syndrome, Diabetes (Type I & II) ... and VLCD!!  While many with pre-diabetes/IR/Type II successfully use carbohydrate restriction to successfully control blood glucose levels,  this can be at the expense of further elevation of circulating free fatty acids.  A high fat, low carb meal can have the effect on NEFA/FFA levels that a high carb meal would have on blood glucose.

1.  Elevated plasma free fatty acids predict sudden cardiac death: a 6.85-year follow-up of 3315 patients after coronary angiography

Aims Sudden cardiac death (SCD) is the most common fatal cardiovascular event. Free fatty acids (FFAs) exert several harmful effects on the myocardium and may therefore contribute to SCD. We examined whether fasting FFA predict SCD in patients who had undergone coronary angiography.

Methods and results FFAs were measured at baseline (1997–2000) in 3315 patients scheduled for coronary angiography. Angiographic coronary artery disease was found in 2231 study participants. {My Note: Although this study was in men referred for angiography, roughly 1/3rd were FREE of coronary artery disease}.  After a median time of follow-up of 6.85 years, 165 SCD occurred in the entire study population. In a Cox proportional hazards model, the unadjusted hazard ratio (HR) for SCD in the fourth when compared with the first FFA quartile was 2.95 (95% CI 1.84–4.73; P < 0.001). After adjustment for common and emerging cardiovascular risk factors, the HR remained significant at 1.76 (1.03–3.00; P = 0.038). High FFA levels were also significantly associated with all-cause and cardiovascular mortality, even after exclusion of patients with SCD.

Conclusion Our study shows that elevated plasma FFAs are an independent risk factor for future SCD in patients referred to coronary angiography. These results may suggest that modulation of myocardial fatty acid uptake and/or metabolism are a possible target of treatment, but it still remains to be clarified whether high FFA levels are a cause or a consequence of pathological processes that underlie the association between FFA and SCD.

 2.  

Circulating Nonesterified Fatty Acid Level as a Predictive Risk Factor for Sudden Death in the Population

{My Note:  This study separately analyzes a subset of data from the Paris Study where no ischemia was found}

Background— In ischemic conditions, concentration of circulating nonesterified fatty acids (NEFA) is increased and has a proarrhythmic effect that is responsible for ventricular tachyarrhythmias. In nonischemic patients, high NEFA plasma concentration has been shown to be associated with frequent premature ventricular complexes and increased familial risk of cardiovascular disease, but its relation to sudden death has not been studied. We assessed the role of circulating NEFA in sudden death in asymptomatic men in a long-term cohort study.

Methods and Results— A total of 5250 men employed by the city of Paris, aged 42 to 53 in 1967 to 1972, free of known ischemic cardiac disease, and included in the Paris Prospective Study I, completed a second annual examination and had fasting plasma circulating NEFA measured. Each subject underwent a physical examination and ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers. Vital status was obtained for each subject from specific inquiries until he retired; after retirement, it was obtained from death certificates. Body mass index, systolic and diastolic blood pressures, tobacco consumption, parental history of sudden death, fasting cholesterol level, and circulating NEFA concentration were independent factors associated with sudden death during follow up (average, 22 years). When adjusted for confounding factors, circulating NEFA concentration remained an independent risk factor for sudden death (relative risk, 1.70; 95% confidence interval, 1.21 to 2.13) but not for fatal myocardial infarction.

Conclusions— Circulating NEFA concentration is an independent risk factor for sudden death in middle-aged men. Some form of primary prevention could be envisaged in subjects at high risk of sudden death.

These two articles contain a LOT of background in their full texts.  A lot of it is disturbing.  I won't copy all of it here, but some summaries.  If you click on my links to the free full text, you can follow active links to referenced studies, etc.

From #1:

Circulating FFAs are mainly released from triglyceride stores of the adipose tissue and serve as physiologically important energy substrates. An excess of FFA has been implicated in insulin resistance and hepatic steatosis.3,4 Furthermore, elevated FFAs are associated with atherosclerosis5 and hypertension.6 Fatty acid oxidation supplies the heart with ∼70% of its energy but an overwhelming delivery of plasma FFA to the heart, as it is observed in acute coronary syndromes (ACS) and heart failure, may contribute to myocardial dysfunction.2,7,8 High FFA and subsequent increased utilization of fatty acids for energy generation in the ischaemic myocardium may cause a ‘metabolic crisis’ in patients with CAD because fatty acid oxidation requires more oxygen when compared with the use of glucose.2,7 Apart from this, high concentrations of FFA have been shown to exert pro-arrhythmic actions.2,9,10

This study's results:  Note 1st Quartile = Fourth of subjects with lowest NEFA on up to the 4th Quartile containing the fourth of subjects with the highest NEFA levels.

I could copy the entire discussion from reference 2, but instead here's a direct link to that section:
http://circ.ahajournals.org/cgi/content/full/104/7/756#SEC3

Why does this concern me?  Well, I'm otherwise healthy, but when I ballooned up to the 260's-270's after my first stint on LC, I (not immediately, but when I was that weight for a while) developed a racing heart w/o exertion, listed as a risk factor in my first link.  This occurred sometimes in my sleep to the extent that the pounding of my heart in my ears woke me up!  After my second stint on LC I had the racing heart with relatively mild exercise -- I was in the low 200's at the time and feeling and looking pretty great at the time (I weigh more than I appear to).  Now I had a bunch of tests run that ruled out heart abnormality and wore a Holter monitor and even experienced a related symptom while wearing that.  My heart didn't skip any beats, and I've never had an abnormal EKG, but still ... every now and then, even now.

When one looks at fasting lipids, there is always the question of whether it is the circulating lipids themselves that are "causing" something, or if they are merely a symptom of underlying metabolic imbalance, some other factor or factors of which actually cause disease.  Fasting triglycerides are an example of this.  By now most have seen the differing triglyceride profiles of high carbers vs. low carbers, and excessive carb consumption does lead to elevated fasting trigs.  But most of the fat low carbers consume do not exist as trigs, and clearance of triglycerides from the blood has been shown to be faster (this makes sense, we're fat adapted).  Still ... is it the triglycerides themselves that exert a directly damaging effect?  Or is it that residual trigs indicate a metabolic imbalance?  Many of the references for NEFA seem to point to the fact that it is the LEVEL OF THESE IN CIRCULATION that is associated with negative implications or that can elicit a problem in an otherwise healthy animal/human.  A HF/VLC diet offers a double assault on NEFA levels.  Low insulin (the crown jewel of LC'ers) levels fail to suppress lipolysis, the major source of NEFA, although dietary fats contribute some.  I think this is something we should not be so quick to ignore when considering the benefits and risks of carbohydrate restriction.

Insulin resistance and the regulation of vascular tone: is insulin a vasodilator?

Insulin resistance and the regulation of vascular tone: is insulin a vasodilator?

This is a review article that discusses an action of insulin that is not normally considered, it's possible function as a vasodilator.  I wonder if this might not be the reason why some low carbers still struggle with high blood pressure even after achieving a lower weight.

... insulin-induced glucose uptake was associated with a striking increase in leg blood flow; the insulin dose-responses of blood flow and glucose extraction were very similar. These findings raised the possibility that insulin is a vasodilator hormone. In addition, the effect of insulin on leg blood flow was blunted in obese insulin-resistant patients, suggesting that vascular (in)sensitivity is a component of insulin resistance.

My summary:  There appears to be a vasodilating action of insulin, however it is unclear whether this is a direct action of insulin or through an indirect action due to insulin's influence on lipolysis.  Insulin inhibits lipolysis (not "fat burning" but merely the conversion of triglycerides to free fatty acids), so lower levels increase NEFA/FFA's