Elevated Free Fatty Acids Further Impair Glucose Tolerance in IGT but not NGT

High concentrations of nonesterified fatty acids (NEFA) are a risk factor for developing type 2 diabetes in Pima Indians. In vitro and in vivo, chronic elevation of NEFA decreases glucose-stimulated insulin secretion. We hypothesized that high fasting plasma NEFA would increase the risk of type 2 diabetes by inducing a worsening of glucose-stimulated insulin secretion in Pima Indians.
The subjects were 151 Pima - 107 with normal glucose tolerance (NGT) and 44 with impaired glucose tolerance (IGT) at the outset of the study.  At the outset none of the subjects had been diagnosed with frank diabetes.  These subjects were part of a study on pathogenesis of diabetes in the Pima and returned for annual visits to have various tests performed.  Of note, offspring of diabetic mothers were excluded from the analysis, thus the NGT group did not include this "at risk" group. 

In this study, they used data from the outset and the last follow-up visit.  Apparently some stayed in the study longer than others, the average length of study was almost 6 years ranging from just 7 mo. to 15 years.

By their last visit, 8/107 = 7.5% of NGT's and 16/44 = 36% of IGT's had progressed to a diabetes diagnosis.

Parameters assessed:  
  • fasting plasma NEFA concentrations (free fatty acids)
  • body composition
  • insulin action (M)
  • acute insulin response (AIR, 25-g IVGTT)
  • glucose tolerance (75-g OGTT) 
Note:  Cross-sectional comparisons refer to comparisons between the groups at a single time point.  Longitudinal comparisons refer to comparisons within the groups "before" and "after".


Initial Results:
  • Within the NGT group at outset, high fasting NEFA were negatively associated with AIR (controlling for other variables)
  • Within the IGT group at the outset, no such association was demonstrated.
Comparing Initial/Final:
  • For the NGT group, high fasting NEFA  at the initial visit were not associated with change in AIR. 
  • For the IGT group, high fasting NEFA  at the initial visit were associated with a decrease in AIR, the association persisted controlling for sex, age at follow-up, time of follow-up, change in percent body fat and insulin sensitivity, and AIR at the initial visit)

Some thoughts:

My regular readers know that NEFA are my sort-of pet issue.  I first came to this subject looking at a lot of the information on controlling/treating T2 diabetes and IR (let's limit this to those who have progressed to some degree of IGT) with a low carb diet.  What I was surprised to find is that:
  1. Not only are blood glucose levels elevated in IGTIR & T2, but so too are plasma NEFA levels.  
  2. Both hyperglycemia and elevated NEFA can be "toxic" - glucotoxicity has a twin = lipotoxicity
  3. Hyperglycemia seems to be an end-stage manifestation based on the writings of major researchers in this field such as Frayn, McGarry, and Boden.
Try as they may, carbs in the absence of fat do not seem to lead to the development of diabetes through the route proposed by low carbers:  Basically that repeated post-prandial glucose excursions lead to hyperinsulinemia thereby wearing out the pancreas.   

So to me, I still see the utility of LC diets to lose weight.  So long as we're in caloric deficit, the elevated NEFA seems to be turned over through increased oxidation, etc.etc.  And VLC can be a way to get regain glycemic control more rapidly than other approaches.  

But I've long wondered about whether just lowering glucose levels wasn't just masking the progression of the disease.  Let's be clear here.  *I* am defining diabetes and IGT as β-cell dysfunction.  This is the underlying defect that separates the frank diabetic/IGT from the non-diabetic/NGT.   However our gluco-centric view of the disease would prevent us from diagnosing it in, say, the traditional Inuit as their bodies are unlikely to endogenously produce too much glucose.   Even Dr. Davis has come around to admit that VLC doesn't "cure" diabetes ... more put it into remission.  

But let's say that one adopts a VLC diet at the onset of a diabetes diagnosis.  They lose some weight, they get off all meds, and BG control is good.  The longer and longer one adheres to such a diet, however, the worse their response to an occasional carby food.  I fully believe that an NGT person can actually become IGT with long term low carbing.  And equipped with a gluco-meter and a goodly dose of par(TYP*)anoia you'll never be able to increase carb intake, because (a)  it takes a little time to upregulate all the glucose handling, insulin stimulating mechanisms, and (b) if you're still eating high fat you've got a physiological case of IR masquerading as a pathological one.

So controlling one circulating metabolic substrate level (glucose) at the expense of the other (NEFA) has, for some time now, seemed to me to at least be worthy of reconsideration, if not outright misguided.

The authors state:
[Our] findings in people with NGT indicate that fasting plasma NEFA concentrations are not a primary etiologic factor for β-cell failure. However, in subjects who have progressed to a state of IGT, chronically elevated NEFA seem to have a deleterious effect on insulin-secretory capacity.
I'll address the first statement first because that seems to go counter to that which Frayn puts forth (among others).  The Pima, as most readers of this blog probably know, are highly susceptible to diabetes.  Yet, despite the soaring rates in that community, still not all Pima become obese and not all obese become diabetic.  So there's perhaps a different proportion that are genetically susceptible in that population.  Most of these have been removed from the NGT group because they are already IGT.   This was further refined by omitting offspring of diabetics.   The age range of the participants was 18 to 50 y.o. which is quite a range - it would be interesting to repeat this with - say - NGT's 18-28 and follow for the same length of time, like 10 years.  "Adult onset" diabetes used to be seen in older populations.   I think the wording of the authors' conclusion are a bit overstated.  Just my opinion there.

But the second sentence is important, because that's who so many who seek refuge from hyperglycemia with low carb are ... already IGT.  The effects of NEFA appear to be direct - just like those of hyperglycemia.  In other words, while I've not seen as much in the way of plausible ways by which, say, LDL particles themselves directly *cause* atherosclerosis (as opposed to simply being biomarkers), there is literally a deluge of data implicating NEFA directly interfering with metabolic processes/signalling/etc.    This means that it really doesn't matter the source or underlying cause of the elevated NEFA that is the issue, but the NEFA itself.  Therefore, if NEFA is elevated by your VLC diet, or by your excess adiposity or by your genetically "defective" fatty acid metabolism - the result may well be the same.  And IF you're already IGT, NEFA levels correlate with reduced  β-cell function down the line.  If your diet contributes to this in addition to genetics and adiposity, is it a prudent choice?


Anonymous said…
' I fully believe that an NGT person can actually become IGT with long term low carbing.'

But, if a person becomes IGT with long term low carbing, how will that be interpreted?

I'm thinking the person will say, 'See, I was right to low carb. I was ALWAYS IGT (years of eating a 'bad' diet) and I've been coping with it until now, successfully, with my low carb diet. Now, it's just out of control, but I successfully controlled it until now! Time to go even lower in carbs.'
Jay said…
Carbsane said:
"I fully believe that an NGT person can actually become IGT with long term low carbing."

This study should reassure you then, because their conclusion is:

"In subjects with NGT, we found no association between high fasting plasma NEFA concentrations and change in AIR independent of change in percent body fat and insulin sensitivity. This makes it unlikely that increased plasma NEFA concentrations represent a primary etiologic factor of β-cell dysfunction in the natural history of type 2 diabetes. "
"In conclusion, our data did not confirm the hypothesis of an etiologic effect of elevated plasma NEFA on the development of type 2 diabetes, especially not one that was due to a change in AIR. In fact, we propose that chronically elevated plasma NEFA have a deleterious effect on insulin-secretory capacity only in subjects with IGT. "
Jay said…
carbsane said:

" Let's be clear here. *I* am defining diabetes and IGT as β-cell dysfunction. This is the underlying defect that separates the frank diabetic/IGT from the non-diabetic/NGT."

This seems to be their assumption too.

"To assess the relationship between elevated plasma NEFA concentrations and acute insulin response (AIR) in individuals with a preexisting β-cell defect, we performed the same analyses in subjects with IGT."

However, they were actually setting out to see if they could show NEFA triggering the transformation from NGT to IGT - they couldn't.

"Our longitudinal studies indicate that the transition from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) is characterized by substantial worsening in insulin-secretory function (14). Therefore, the etiologic role of plasma NEFA concentrations on decrease in insulin secretion was examined specifically in subjects with NGT."
"In subjects with NGT, we found no association between high fasting plasma NEFA concentrations and change in AIR independent of change in percent body fat and insulin sensitivity. This makes it unlikely that increased plasma NEFA concentrations represent a primary etiologic factor of β-cell dysfunction in the natural history of type 2 diabetes. "
CarbSane said…
@euler: This seems to be what folks say when they exhibit the symptoms of insulin resistance/diabetes/prediabetes. It's sort of "well imagine how much more IR/D/PD I would have been". BUT, we'll never know. And, of course, they always default back to how they were eating - which was NOT a Kitivan, traditional Japanese, or even USDA food pyramid style diet. It was the SAD. Yeah, SAD will get you there faster, of this I'm almost certain. But is VLC getting folks to the same place more slowly?
Mirrorball said…
Here is a somewhat related study:

A maintenance higher fat diet decreases β cell responsiveness when compared to a maintenance lower fat diet.
CarbSane said…
Wow! I'm efforting the full text on that one. It's not even close to "low carb high fat" either ... just from C/F% of 55/27 to 43/39.
John said…
The decreased response of pancreatic β-cells to glucose on high(er) fat is expected: elevated NEFA cause more UCP2 expression. This lowers the ATP/ADP ratio in β-cells, which reduces their insulin secretion. There is a nice review paper about uncoupling proteins and dietary fat that discusses this [1].


[1] Fisler J.S., Warden C.H. Uncoupling proteins, dietary fat and the metabolic syndrome. Nutr Metab (Lond). 2006 Sep 12;3:38. http://pmid.us/16968550
Mirrorball said…
CarbSane: "I'm efforting the full text on that one."
I've uploaded it to YouSendIt: https://www.yousendit.com/download/dkJwWWVxV3I5eFZjR0E9PQ
Bill said…
CS (and Jay),
“Hyperglycemia seems to be an end-stage manifestation”
This seems to suggest that there is a large and obvious population with normal blood glucose but impaired insulin-induced FFA suppression. Is there any evidence of this (other than vague generalizations in review papers)?
CarbSane said…
Hi Bill, I would say this population is the normoglycemic obese. Whenever NEFA is measured in a study, obesity is associated with elevated levels.
CarbSane said…
@Jay: I wasn't stating anything special as to the definition of diabetes - I just wanted to avoid the "Oh yeah, the Inuit" retort. If one defines diabetes as hyperglycemia, the Inuit probably don't have it. But do their beta cells function properly?

I can't put my finger on the study, but it's been discussed here before how FFA infusions can impair beta cell function in normal humans. So while this study showed no association (after removing those most at risk from an NGT pool of 18-50 year olds followed for 7 months to 15 years) eating a diet that would normally suppress NEFA during the day, I'm not encouraged.

The IGT group converted to frank diabetes at a 4-fold rate and there was an association. If those folks ate a VLCHF diet that does not suppress NEFA for the 12 hrs or so a day that a "normal" diet would, does that sound like a prudent strategy to you?
CarbSane said…
Thanks John - Interesting read!
CarbSane said…
BTW Jay: I disagree that this study contradicts Frayn & Boden in implicating FFA in the etiology of T2 (and others). It only shows that slightly elevated NEFA in person A vs. B may or may not be predictive of future insulin response. The fact that once one has progressed to IGT there is an association is certainly in agreement with F&B - especially when one looks at the percent progressing to frank diabetes.

Fasting NEFA also doesn't tell the whole story. This is part of Frayn's work that postprandial NEFA may be the bigger issue. Failure of adipose tissue to effectively trap FA's hydrolyzed for transport into the fat cells but that escape into circulation instead. A VLC diet will exacerbate this defect.