Insulin Doing Its Thang! And Still No Starving Cells

In comments yesterday, Wayne/ProudDaddy wondered whether triglycerides might be the bad guy instead of NEFA based on this study from Keith Frayn's research group: Adipose tissue fatty acid metabolism in insulin-resistant men.
Aims/hypothesis  Increased NEFA production and concentrations may underlie insulin resistance. We examined systemic and adipose tissue NEFA metabolism in insulin-resistant overweight men (BMI 25–35 kg/m2).
Methods  In a cohort study we examined NEFA concentrations in men in the upper quartile of fasting insulin (n = 124) and in men with fasting insulin below the median (n = 159). In a metabolic study we examined NEFA metabolism in the fasting and postprandial states, in ten insulin-resistant men and ten controls.
Results  In the cohort study, fasting NEFA concentrations were not significantly different between the two groups (median values: insulin-resistant men, 410 µmol/l; controls, 445 µmol/l). However, triacylglycerol concentrations differed markedly (1.84 vs 1.18 mmol/l respectively, p < 0.001). In the metabolic study, arterial NEFA concentrations again did not differ between groups, whereas triacylglycerol concentrations were significantly higher in insulin-resistant men. Systemic NEFA production and the release of NEFA from subcutaneous adipose tissue, expressed per unit of fat mass, were both reduced in insulin-resistant men compared with controls (fasting values by 32%, p = 0.02, and 44%, p = 0.04 respectively). 3-Hydroxybutyrate concentrations, an index of hepatic fat oxidation and ketogenesis, were lower (p = 0.03).
Conclusions/interpretation  Adipose tissue NEFA output is not increased (per unit weight of tissue) in insulin resistance. On the contrary, it appears to be suppressed by high fasting insulin concentrations. Alterations in triacylglycerol metabolism are more marked than those in NEFA metabolism and are indicative of altered metabolic partitioning of fatty acids (decreased oxidation, increased esterification) in the liver.
They selected relatively small samples (10 each) from larger pools in a group of "registrants" for study if you will.  At first look, this study gives one pause over the role of NEFA in the development of IR and T2 diabetes.  But on closer examination ... "not so fast"! 
Comparisons were made between a group with low and a group with high fasting insulin concentrations, taking this as a proxy measure of insulin resistance. To ensure clear separation between groups, men selected for the control group had fasting insulin concentrations below the median for the entire OBB population (51.6 pmol/l). They were compared with men with fasting insulin concentrations within the upper quartile of the whole OBB population (above 76.2 pmol/l).
Here's what they ended up with:

Very interesting to note that the only parameters in which these two groups are statistically different are fasting insulin, HOMA-IR,  and fasting triglycerides; waist circumference makes "honorable mention" at p of 0.06.  

These Men were HyperInsulinemic, Not Insulin Resistant

The authors write:
Another way of looking at our results would be that compensation for the increased fat mass occurs in the insulin-resistant group, through increased insulin concentrations, bringing about a normalisation of NEFA concentrations.

As highlighted previously, hyperinsulinemia was used as a proxy for IR, and by HOMA-IR they would be called IR.  But are they?  Well ...
HOMA-IR = (Glucose x Insulin)/K         K = constant, depends on units used
But this highlights a considerable drawback of this diagnostic parameter.  In this case, look at the glucose between groups:  5.55 mmol/l for IR vs. 5.61 mmol/l for Controls (p=0.97 ... in other words, "identical").  So these men are hyperinsulinemic, but not "prediabetic" by FBG standards!  Two things to point out here:
  • Controls were overweight but not hyperinsulinemic
  • Study group was hyperinsulinemic but not IR
The insulin is doing it's thang!  The study group has high insulin that keeps circulating glucose and NEFA levels in check.  Plain and simple.  I discussed this in What Does Insulin Regulate Anyway?  And in the case of the men in this study, insulin was doing its job.  I suppose one could say they are "pre-resistant" in that higher levels of insulin are required to achieve the same result, but they are not "resistant" in that their cells still respond to insulin.  Here's insulin, glucose and NEFA for fasting and following a mixed meal (Figs 1a,b 2a)  In all graphs the IR study group is dark circles, open squares are controls.

The hyperinsulinemia was accompanied by elevated fasting triglycerides:  TG produced in the liver.  They used both an oral radiolabeled palmitic acid and an infusion (different labels) to "trace".  
The whole-body rate of appearance of NEFA (RaNEFA) was derived from arterial tracer: tracee ratios of [2H2] palmitate.  Steele’s equation modified for use with stable isotopes was used to calculate RaNEFA at each timepoint.
There seem to be "missing NEFA" here.  As Hellerstein demonstrated the major fatty acid source for fasting VLDL is NEFA, but he, too could not account for all of the triglycerides in the group with elevated triglycerides.  Still, the major finding in those studies was that high carb diets increased fasting VLDL by reducing clearance rates.  Here the fasting clearance rates into adipose and muscle seem comparable between groups, so the hyperinsulinemia would appear to increase the rate of triglyceride synthesis (esterifying of NEFA).  Figs 1c, 4a&b

The liver is a major organ in the extracellular "recycling" in the TAG/FA cycle, and muscle is included in that as well.  So the liver is recycling more NEFA.  What this study demonstrates is that via the action of insulin, NEFA is regulated by both reducing NEFA release (per fat mass) and increasing the "recycling" by the liver -- and perhaps the role of systemic recycling is under-estimated.  

Interestingly the hyperinsulinemia decreases postprandial triglyceride clearance -- triglycerides in this state would be chylomicrons -- so slower uptake of fat in the hyperinsulinemic state.  So much for hyperinsulinemia putting more fat into the fat cells.  But here's the most interesting thing:  

Net NEFA uptake into muscle was higher in the hyperinsulinemic men!

(Figs 1a, 2c&d).   To the left of the vertical dashed line, in the fasted state, the hyperinsulinemic men had lower NEFA output from their fat cells (per fat mass), but significantly greater net NEFA uptake into muscle.  It would appear that by some mechanism, insulin further regulates the systemic TAG/FA cycle by increasing NEFA "disposal" into muscle.   IOW the muscle is probably an oft overlooked "organ" in the regulation of TAG/FA.  I wish they had measured REE and RQ to predict the fate of these NEFA ... My best guess is that most is esterified into intramyocellular triglycerides, IMTG. In the introduction the authors say:
Plasma NEFA concentrations are potentially also regulated by the rate of removal from the circulation. An impairment of NEFA uptake by muscle has been demonstrated in obesity.


Net uptake of NEFA by forearm muscle was greater in the insulin-resistant group than in the controls in the fasting state (Fig. 2d; p=0.023), but not thereafter.  Forearm muscle absolute (unidirectional) NEFA uptake was calculated using the clearance of [2 H2]palmitate and the arterial NEFA concentration. It was not different between groups

I'm a little confused by this, if absolute uptake was the same, how is net uptake different, unless in the normal men NEFA flows back out and under hyperinsulinemic conditions, they are esterified and "trapped" in the muscle as IMTG.

But can we please, PLEASE, put this notion of starved cells to rest??  The hyperinsulinemic men had totally normal glucose metabolism and circulating NEFA levels available to be burned for fuel.  Indeed they appear to have consistently higher net NEFA uptake to their muscle cells.  

This study is consistent with the etiology of insulin resistance beginning in the fat tissue and the link to obesity.  Clearly there's some individual variation in terms of how much fat one accumulates before insulin levels rise to keep NEFA levels in check.  But I think these men are better described as insulin sensitive compensators rather than insulin resistant.  Their fat, livers and apparently muscle cells are all responsive to the effects of insulin, but more insulin is needed to keep their NEFA levels in check.  They are "pre-IR", perhaps pre-pre-diabetic.   Perhaps accumulation of IMTG, and/or associated metabolites like diacylglycerols and ceramides, eventually interferes with glucose metabolism at which point glucose uptake is impaired, and/or accumulation of TG in the liver leads to hepatic IR with lack of suppression of gluconeogenesis.  AKA insulin resistance manifested as impaired glucose tolerance, IGT, and elevated FBG.

The important take-home message from this study might be to keep an eye on the triglycerides and fasting insulin levels.  If and when these go up, you've exceeded your personal level of fatness for a normal TAG/FA cycle and circulating NEFA levels.  What of low carb lowering triglycerides and insulin levels?  Absent weight loss, I'm not at all sure this is a preferred metabolic state.  I'm reminded of the study I blogged on a while back:  Failure of LC/HF Diets to Suppress NEFA Release.   Now this was a weight loss study (and despite all the fatty acids being liberated from their adipocyte jail cells they lost the same amount of weight on each diet) .  One has to wonder what becomes of all the excess NEFA in the weight stable state if they aren't being recycled as VLDL.

From the study:  
Weight loss was similar between diets, but only the high-fat diet increased LDL-cholesterol concentrationsThis effect was related to the lack of suppression of both fasting and 24-h FFAs.
So if your LDL is high on your LCHF diet (and trigs are low, ahem ...), your blood is probably swimming with NEFA.  Don't know what that means for the long haul, and we really don't have any long term human studies or populations to look to to know for sure.  Something to consider in terms of risk.


ProudDaddy said…
For those who may not have read my original comments, I was left wondering about TG tissue concentrations. Waist circumference (only a 6% probability that the difference was due to random chance, in my layman's interpretation of p value) might be a good proxy for liver TG since the heights were nearly identical . This would then agree with the theory that somehow reducing hepatic and pancreatic TGs will improve diabetic symptoms.

Evelyn, since you "speak the language", do you have any plans to correspond with the authors re the things you are wondering about?
Morris said…
I am somewhat puzzled by the conclusions you draw from the several conflated studies you summarize. My interest is about metabolism in normal weight people w/o clinical indications (like me). It seems that elevated NEFA’s in the fasted state are undesirable by default in your view. Why? The NEFA levels of the study subjects are high and HDL levels are low compared to normal. The subjects are overweight or obese, which suggests some metabolic dysregulation. So my question is how relevant are such studies to normal subjects. Can abnormal states be understood w/o understanding the norm?
CarbSane said…
I just received an email from someone re: NEFA and said their email to Frayn bounced back. Taubes sneeringly referred to his retirement in his CrossFit talk. I've always been reluctant to contact researchers ... maybe I'm old fashioned, but in "my day" you didn't write the researcher to express your opinion per se, and pretty much you'd have to be a "name" in the field to query/challenge/etc. However I think I'm changing my mind on that and may ask those questions I have. Can't hurt, right?
CarbSane said…
Morris, I don't think "normally" elevated NEFA is undesirable. They are normally elevated in fasting, and -- along with glucose -- during the "flight or fight" response. I don't believe looking at abnormal states can give you insights -- time and again the "dose response" in abnormal states doesn't hold up in normal states. For example HbA1c is not predictive in normal ranges, but small differences make big risk differences above a threshold that delineates diabetes.

I'm not saying these subjects didn't have some degree of dysregulation. On the contrary, that was the point if we don't get too mired in semantics. They had a degree of necessary and responsive adaptation to attain normal regulation of NEFA and glucose.
Morris said…
Evelyn. Thanks for the reply. It appears I misunderstood your take on the studies. I took the closing sentence literally. The question that remains for me is what is the healthy physiological limit for NEFA oxidation compared to glucose. In his textbook Frayn presents a calculation (Box7.1) which suggests 2/3 of total energy comes from NEFA oxidation, presumably in healthy people (he doesn’t say)
Puddleg said…
"Interestingly the hyperinsulinemia decreases postprandial triglyceride clearance -- triglycerides in this state would be chylomicrons -- so slower uptake of fat in the hyperinsulinemic state. So much for hyperinsulinemia putting more fat into the fat cells."

Well, I guess if your're hyperinsulinaemic, you won't be gettin' fat on a high fat diet then.
Why you'd practically have to eat carbs!
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