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).

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.


Colby said…
Nice post. You may be interested in a study that explored an epigenetic mechanism of insulin resistance via methylation of the PGC-1alpha promotor(regulates mitochondrial biogenesis and function) and found: "myocytes from the biopsies [of subjects with insulin resistance] were incubated with factors known to induce insulin resistance: TNF-alpha (TNF-alpha and free fatty acids stimulate accumulation of sphingolipid ceramide and various ceramide metabolites), palmitate, and oleate all induced hypermethylation of the PGC-1alpha promoter (reduce mitogenesis), whereas high glucose and insulin concentrations did not."

This would also suggest that these other factors precede high glucose/insulin and may be causal (and this study shows some good causal mechanisms, though in vitro). I blogged about the study in detail:

Also of possible interest to your upcoming vascular posts if you haven't seen it- this recent insulin receptor knockout model (specific to endothelial cells) suggests that a loss of insulin signaling accelerates atherosclerosis. It also discusses some of the other research showing insulin has both anti- and pro-atherosclerotic properties at the molecular level.
Harry said…
Hi CarbSane,

I've just been looking through your series of posts that recommend the hyper-lipid genesis of all sounds quite reasonable (to this layman).

I mentioned lipotoxicity to one of Taubes' fans (Tom McNaughton of 'Fat Head' fame) and he argued that the existence of lean Type II diabetics disproves the hypotheses that IR starts in over-stuffed adipose tissue. I'm sure there's some intelligent response to this (maybe to do with visceral fat, rather than many 'lean' people still have high levels of visceral fat)...I'd be much obliged to hear your thoughts.

CarbSane said…
Welcome Harry! I think this post of mine (and the referenced paper) speaks to the issue of lean T2's: Critical Visceral Adipose Tissue Theory

It seems that subQ fat, superficial and lower body in particular, is more protective and more capable of generating new insulin sensitive cells to store excesses than visceral. Seems very reasonable that lean folks lack enough of a buffer for lipids.

FWIW, I wouldn't take what Tom McNaughton says about anything as fact. He's a comedian and filmmaker who, to the best of my knowledge, doesn't even have a scientific background. Of course nobody has to listen to me either, except for the fact that I try to convey comprehensive reviews and well done studies intended to elucidate the mechanisms involved. The whole notion that fat cells remain insulin sensitive so that systemic IR drives fat accumulation simply isn't supported by the evidence.

Thanks for reading and joining the discussion!
LynMarie Daye said…
If you think about it, the existence of lean Type 2 diabetics actually offers support to the lipotoxicity theory. As I wrote in my blog post Fat Fails First: "Consider the fact that people with congenital generalized lipodystrophy, in whom fat cells are lacking from birth, typically develop components of the metabolic syndrome such as insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes at a much earlier age and in more severe forms than do obese humans. This is believed to happen because a dearth of fat cells causes the body to have no "safe" place for excess fatty acids to be stored, and people with lipodystrophy tend to generate excess fatty acids because they cannot make much leptin, a major adipose-derived satiety hormone, and hence have a strong drive to eat. Some of the excess fatty acids will end up being stored in the liver and muscles as well as in other non-adipose tissues (aka lipotoxicity) resulting in decreased insulin sensitivity in these organs and the metabolic syndrome."

The entire post is here:

At the very least, lean Type 2 diabetics hardly disprove that insulin resistance begins first in fat cells. They too can fit nicely into the theory.
LynMarie Daye said…
CarbSane wrote: "FWIW, I wouldn't take what Tom McNaughton says about anything as fact. He's a comedian and filmmaker who, to the best of my knowledge, doesn't even have a scientific background."

It appears you're correct:

Some of the reader comments are very dismissive of formal education: "Any fool can buy a so-called ‘education’ - a degree is just a piece of paper, after all." I don't know about you CS, but despite the fact that I had to shell out money for my science degree, I still had to earn it. It certainly wasn't handed to me on a silver platter.
CarbSane said…
Yeah, I worked for my degrees.

As for IR, in addition to citing LM's "Fat Fails First" post a few times here, I've recently posted a contribution to the understanding of this by Keith Frayn. I became acquainted with this authority on fat metabolism through Taubes. Interestingly, of all his work, he is cited in GCBC mostly for stating that "dieting is difficult", and the rest is seemingly ignored.
James Krieger said…
It's amazing how much Taubes ignores in the very work he cites.

Even in the 1980 NAS report that he cites, he selectively quotes that "overweight eat no more than lean", and ignores the previous sentence that mentions underreporting! Even underreporting was suspected in wasn't until doubly labeled water in the 1990's that it was verified.

He also misquotes Jim Levine's classic overfeeding NEAT study, saying that the researchers couldn't explain why some people did not gain weight while overfeeding. It makes me wonder if he even read this paper (or was hoping no one would ever bother to look it up), because the researchers did explain that the variations in weight gain were due to variations in upregulation of NEAT. Of course, if he had mentioned this, it would give too much credence to the concept of energy balance.
Melchior Meijer said…
James and others,

The energy must go somewhere. I don't think Taubes denies that. My interpretation of his book is that he asks why the one person starts burning like a wildfire, while the other person stores the excess in his adipose tissue (or starts building muscle like crazy, like the Asian guy in the BBC Horizon experiment led by Fredrik Nystrom).

Am I wrong?
CarbSane said…
Melchior, Taubes is all over the map on calories IMO. For example, on the one hand he states that the obese don't eat more than the lean, e.g. it is not from overeating, yet on the other hand he addresses energy balance but claims it is obesity that drives overeating. In his analysis of Shai he implies that LC'ers eat more but lose more weight, which is in direct contradiction of energy balance. He said in that lecture that one could be as gluttonous as you wanted with fat and protein and you wouldn't gain weight, again this violates physical law.

Whenever someone tries to tell me about losing weight on hundreds of excess LC calories, I ask: where do the extra fatty acids go? Occasionally I get that they are excreted. Not so. Occasionally I get that they were never absorbed. Perhaps so for some, but absorption of upwards of 95% of something like 600g fat has been demonstrated, so not likely for "normal people". This leaves storage or burning. If they are "burnt" this would be measurable in changes in RMR, TDEE, etc. It's not.

I don't see Taubes wondering why some react differently to the same diet. He seems singularly (one of his favorite words) focused on why carbs are the cause of obesity.
CarbSane said…
I'm astounded by the amount of information Taubes ignored. Apparently he succeeded in what I call "baffling with bullshit". He made GCBC so tediously long and chock full of minutia about obscure cultures, etc., most readers were tricked into equating "extensive" references with "comprehensive" references.

Frayn is a particularly glaring example of this. Taubes himself describes Frayn as a fat metabolism expert, and yet, he doesn't seem to have actually read most of that work. Worse still, he cherry picks statements even out of his cherry picked sources. Is there a word for that? LOL
Melchior Meijer said…
Dear Gary,

These questions need to be adressed. You opened many peoples eyes for the flawed science and corrupted politics that lead to the current dietary recommendations. I'm sure GCBC has literally saved lives. However, CarbSane et al are shooting some pretty convincing holes in the carbohydrate hypothesis. Although I personally don't like their sometimes offensive approach (it must have been a hell of a job to write the book and I don't believe one second that you are in it for the money), their questions are valid. Carbohydrate drives insulin drives fat accumulation seems to be too simple. Please adress their questions and help increase our insight. I think this is the place to do that, since it is the only Sane (non vegan troll invested) spot on the internet where an intelligent (albeit somewhat venomous) critique on your hypothesis is aired.