Glucose and NEFA: From Dysfunctional Metabolism to Toxicity

This post started out as a comment in response to Paul Jaminet's mention of a post on this blog in his Around the Web post yesterday.  It got rather long so I decided to move it here.  In the interest of more rapid publication, I'm not going to be doing a whole lot of referencing in my discussion here, but if you're interested in a particular statement please indicate so in the comments section and I'll try to track down the reference(s) I have in mind.  Paul writes:
Every once in a while someone writes to ask me if they should fear a high-fat diet because of CarbSane’s writings on lipotoxicity. I reply that lipotoxicity only appears after metabolic syndrome has developed and, while it may drive the transition from obesity to diabetes, it is not a cause of obesity, and not a danger to people who don’t have metabolic syndrome. Also, the implications for diet are not obvious, since carb intake suppresses NEFA clearance from the blood and enhances glucotoxicity. The literature commonly speaks of “glucolipotoxicity” to describe this compounded toxicity problem. CarbSane hasn’t always been clear on these points, so it’s good to see an excellent post from her covering the basics.
Thanks for the shout out Paul!

So the statement that got my mind in motion this rainy Sunday was this:  "carb intake suppresses NEFA clearance from the blood" .  I'm not sure if this is a typo or not, but it is actually the opposite that seems to be true.  And here's where Gary Taubes gets things right (if taken woefully out of context).  Carbohydrates stimulate insulin release and insulin's action on the fat cell is two fold - it stimulates NEFA uptake by stimulating esterification (it will also further stimulate ASP -- thus ASP-stimulated esterification -- in addition to that stimulated by dietary fat/chylomicrons).  Secondly, insulin will suppress NEFA release from the fat cells.  

Insulin is, after all, mostly just a traffic cop in the metabolic system.  It does not appear to have much impact on  metabolic rate, rather it regulates which fuel the cells are "burning" for energy at any given time.  To simplify matters, let's just deal with oxidation (burning) of glucose and free fatty acids (NEFA) and ignore protein and ketones (and alcohol).  

Circulating glucose levels are regulated by insulin as follows:
  • When glucose levels are high, by facilitating clearance from plasma/uptake into cells and "disposing" of it.  Glucose disposal is through one of three paths:  
  1. glycolysis - burning for energy, otherwise known as oxidative disposal
  2. glycogen synthesis - otherwise known as non-oxidative disposal
  3. de novo lipogenesis - where the products of excessive glycolysis are converted to fatty acids.  
In those with impaired glucose tolerance, the defect appears to be in path (2) and perhaps it is as simple as having glycogen stores chronically "topped off".  We have limited glycogen stores in which to stuff large quantities of glucose.
  • Insulin suppresses gluconeogenesis and glycogenolysis (breakdown) in the liver and release of glucose into circulation when circulating levels are high.
It is because of the rather limited storage buffer capacity that glucose is given preference in the heirarchy of fuel usage.  One of insulin's primary jobs in policing fuel selection is to stimulate uptake and both oxidative and non-oxidative disposal.  But it also acts to suppress beta-oxidation, aka the burning of fatty acids for fuel.  This is where the whole LC canard of shutting down fat burning comes from.

All of this is fine and dandy until the NEFA get out of control.  The supply of fatty acids to the cells is not supposed to come from dietary fat.  Dietary fat is packaged in chylomicrons with distinct signalling proteins so that cells (especially fat cells it appears) can distinguish it from other triglycerides (e.g. VLDL).  Fat is constantly being released from adipocytes in the form of NEFA and re-cycled back into triglyceride form both by peripheral tissues or re-uptake into fat cells themselves.  The level of NEFA is regulated primarily by insulin's suppressive action on lipolysis by hormone sensitive lipase (HSL) in fat cells.  In the fasted state, NEFA are higher, but in normal people, following a mixed meal, they are knocked down to "baseline" rather quickly.  Keith Frayn phrases this as release clamped down to near-zero in normal individuals.  In this graphic from the post of mine Paul was referring, we see this occurring after a large breakfast and smaller lunch five hours later.
Following a mixed meal, the metabolic state of fuel delivery is shifted towards one of almost entirely glucose. As glucose is disposed of, NEFA release ramps up to meet fuel needs as metabolism switches towards fat burning. 

I believe the evidence is overwhelming for Keith Frayn's (and many others') hypothesis for the etiology of insulin resistance initiating in the fat tissue.  As adipocytes fill and grow in size they lose insulin sensitivity.  This leads to failure to suppress NEFA release following a mixed meal, and as Frayn has also shown, in the obese, there appears to be a considerable contribution to NEFA from dietary fat due to impaired trapping.  Fatty acids liberated by lipoprotein lipase (LPL) intended for storage in the adipocyte essentially escape into circulation in larger amounts.  The result of these two in concert leads to heightened delivery of NEFA to the cells at a time when they need most to be accepting the glucose delivery.  

Here's where things get worse.  Our cells can refuse the glucose delivery but they are limited in their ability to refuse the fatty acid delivery.  This is because fatty acids flow into cells by a facilitated diffusion mechanism.  There does appear to be some sort of transport facilitation going on (and it may be cell specific), but it is not required nearly as much as glucose requires it's transporters (the various GLUT's) for passage in.  The excessive delivery of fatty acids to the cells forces them to switch to burning them for fuel.  They also suppress glycolysis and non-oxidative glucose disposal which means that the glucose channels are essentially "clogged" and the cells refuse it.  When this happens, you get more elevated glucose spikes and lower rate of return to fasting levels ... in other words, impaired glucose tolerance (IGT).  This is peripheral IR.

The other thing that chronically elevated NEFA do is that they seem to suppress the ability of pancreatic beta-cells to mount an appropriate acute insulin response to carbohydrate.  This exacerbates the hyperglycemia.  However this action of NEFA appears to be contributing to metabolic dysfunction and not exactly exerting a toxic effect on the beta cells.  Glucose also plays a roll in metabolic dysfunction before becoming overtly toxic in that it causes the IR individual to secrete more insulin to compensate for the hyperglycemia.  Apparently this can go on for years, perhaps even indefinitely, in those genetically gifted individuals with the capability to continue this compensation.

Glucose does not appear to be very toxic in and of itself until you get to a frank diabetic state where glucose levels are chronically elevated and glycation wreaks its havoc.  The NEFA do appear to have somewhat toxic effects on the cells directly especially in the sedentary or hypercaloric state during this "metabolic mayhem" phase.  Let me explain what I mean.  In the normal person consuming an energy balanced diet the metabolism switches almost effortlessly between fat and carb burning, although in reality there's always some of each going on, and certain cells are given preference to available fuel to burn.  However in the hypercaloric or obese IR state (worsened further if still gaining weight on hypercaloric diet) cells are forced to burn fat and it seems that the buildup of diacylglycerols and ceramides as a result and ROS formation exert lipotoxic effects.  It appears that esterification to form lipid droplets of triglycerides in the cells (often referred to as intramyocellular triglycerides, IMTG, in muscle) is protective in nature.   These in and of themselves are also not detrimental as conditioned athletes tend to have high levels of IMTG yet remain exquisitely insulin sensitive.  This is explained by their high energy expenditure so when these fatty acids are burned, the DAG's and ceramides aren't produced to do their damage.  The exact mechanism by which DAG's and/or ceramides impact cell function have yet to be elucidated, but their content in the cells is correlated with chronic peripheral IR.  Still, at this point the toxicity is more "mucking up the works" than totally destructive.

So all of these dysfunctions lead to the truly toxic mix of hyperglycemia + elevated NEFA = glucolipotoxicity.  It appears that either can do damage separately, but the mix of the two is generally implicated in beta-cell apoptosis (cell death) and apoptosis of various other critical tissue cells (e.g. liver, vascular endothelium, heart, kidney) .   It's like a car that runs rough vs. one that won't start anymore.  The cell death is the ultimate manifestation of toxicity!

Thus, you want to avoid this deadly duo at all cost.  However I cautiously disagree with Paul's assessment that a high fat diet cannot be problematic in the absence of hyperglycemia.  It could be causing your cells to "run rough" to use the car analogy.  I don't see a problem with PHD if it establishes and sustains a suitably lean condition.  And the failure of VLC diets to suppress postprandial NEFA release is not an issue, IMO, on a diet containing 100 or so grams of starch.  However, since NEFA are rarely measured in lab tests, and neither is pancreatic or liver fat content routinely measured, we are all flying a bit by the seats of our pants on this issue and knowing exactly what's going on.  

I'm not a doctor or dishing out medical advice, but based on what I've been researching in this area, here's a couple of things that make sense to me.
  • In one study on VLC diets, elevated fasting (and postprandial) NEFA were correlated with LDL.  So ... if you have normal LDL you're probably fine.  And by normal, I mean a bit higher than causes most lipophobic doctors to get concerned, but not the dramatic increases some experience eating VLC.
  • Fasting or going on a VLCal diet a few days a month can't hurt to clear out any backlogged lipids.  Where there is rapid turnover, it's less likely for ROS production and such.  A mere 8 weeks of severe caloric restriction restored normal beta cell function attributed to reduced pancreatic fat in that recently published study.  
  • If you're not losing weight on VLC and/or remain significantly overweight it seems prudent to err on the side of caution.  Middle of the road approaches seem far less effective than the extremes, but high carb/low fat seems the more logical approach to long term restoration of insulin sensitivity.  
  • Live an active life or exercise.  Don't be a couch potato.
  • Perhaps do periodic "carb ups" where you ramp up carb intake slowly over a period of a week or so then test for glucose tolerance.  I don't know, the more I learn about insulin and its myriad functions in the body aside from glucose trafficking, the more I believe having it flowing and signaling properly is the optimal state.  
  • If you struggle with blood pressure control, NEFA appears to interfere with insulin's vasodilatory effects and this may be the problem.
  • Listen to your body.
It seems to me that while eating a high fat diet will not cause diabetes in those not predisposed, a ketogenic diet has been shown to hasten the progression of diabetes in a genetic diabetic rat model.  I don't think this result should be dismissed lightly especially since we have no real human cultures to study in this regard.  And, after all, though diabetes tends to have a heavy genetic component, it has been known to happen to folks with no family history of the disease.  I, personally, have no concerns over VLC/VHF (though I prefer a leaner version of the diet) in the context of a reducing diet.  Why?  Because the elevated NEFA are also being utilized for energy.  

But the health risks of obesity seem quite closely tied to the degree of insulin resistance the obese state creates.  I'm not entirely sure that a normal weight person consuming a high fat diet doesn't run the risk of being one of those metabolically obese thin people, with most of the inherent risks of IR (IR is a CVD risk factor independently of IGT/diabetes) to go with.  Just my opinion.


Paul Jaminet said…
Hi CarbSane,

Thanks for engaging me on this.

I should clarify that in saying "carb intake suppresses NEFA clearance from the blood and enhances glucotoxicity" I'm thinking in the context of a person with pre-diabetes/diabetes (which I'd previously said is the context in which glucotoxicity occurs). In this case insulin resistance is a factor, adipose cells aren't readily taking up fats, and I would expect suppression of beta-oxidation and competition from glucose to dominate the insulin signaling aspect. But I would be glad to be corrected if I am wrong.

I don't believe I said that a high-fat diet can never be problematic except when accompanied by hyperglycemia. There are many kinds of pathology, diabetes is only one. Rather what I do affirm is that for healthy people a high-fat diet will not produce a harmful lipotoxicity. I think in metabolic pathologies it's still mostly an open question what the optimal long-term diet is.

That said, it's not obvious that low-carb diets (therefore, presumably, high-fat) have performed badly in diabetes. Short-term they seem to do quite well.

I'm glad you think our PHD is a good diet. If I'm understanding you correctly you are proposing that our diet avoids lipotoxicity because the starches trigger insulin that keeps NEFA down, and it's the lack of insulin that makes VLC dangerous. If so, that's a novel and interesting view.
Just thought I'd pass along this new study whether it's relevant to this blog post or not:

How fatty diets cause diabetes.

And the study here (if you want to pay)
Sanjeev said…
Christopher Robbins wrote ...
Just thought I'd pass along this new study whether it's relevant to this blog post or not
ooohhhhh ... the dominoes just keep falling. (Even though it's a mouse study. it just confirms the earlier study "curing" diabetes with a crash diet that causes some fat loss. )

Thanks so much.
Kindke said…
Im curious if theres any studies looking at serum NEFA + pancreatic fat immediately before and immediately after Roux-en-Y gastric bypass surgey as this crowd seem to be cured of thier type 2 diabetes overnight.

Does the Roux-en-Y surgery instantly correct high serum NEFA + lowers pancreatic fat?
Sanjeev said…
Taking this together with the earlier University of Saskatchewan mouse study on methylglyoxal (which has no supportive/indicative human studies), first the pancreas gets damaged, leading to high circulating glucose, leading to high methylglyoxal.

I hope these leads pan out, instead of petering out as so much in the past has.

By this scheme dietary starch doesn't do much damage.

And massive fructose plus massive PUFA damages the liver, but as related to diabetes & obesity, not hugely significant.
psychic24 said…
So if i'm understanding this correctly, this invalidates the title of one of Dr. Harris's previous posts: Carbohydrates:No dietary requirement...

I'm only saying this because from the gist of it you're saying that if you are going to do VLC, you must stay VLC forever. Or you need a moderate carb intake always to prevent peripheral IR and the increased NEFA release you get when eating a high fat diet...

Am I on the right track?

Also I was wondering why exactly athletes do not experience the diacylglycerol and ceramides would seem that just because an individual is not burning off their fats in the same fashion that an athlete does, the relative intake of a more sedentary individual would be burned similarly to the relative intake of a more active
Mirrorball said…
Evelyn and others, I can upload the new study's full article if anyone is interested.
CarbSane said…
If you mean Christopher Robbins' article, yes! However it's easier. You can attach on the discussion board or do the Scribd thing I think you did last time.

I spent some time on other stuff today so I'll be answering comments here sometime tomorrow or Tuesday. Tomorrow is a busy day.
Mirrorball said…
This comment has been removed by the author.
perishedcore said…
Also a neat-o keen interactive eposter courtesy of Nature Medicine on metabolism and metabolic syndrome...

LeonRover said…
It is a pity that one has to pay for the scientific meat (fat?) in this study.

The summary states that the molecular events reported were "induced by elevated levels of free fatty acids OR (my caps) by administration of a high-fat diet".

So is the "fat" in the NEFA or in the "eating" of the fat, or both?

Abstract and summary editors very often go "beyond the data". One wonders whether that is the case here.

Health and Medical Epidemiologists should take an Hippo(hypo?)cratic Oath:

I swear to present the Data, all the Data and nothing but the Data. S'welp me, Gawd.
CarbSane said…
Hi Paul, I was about to agree on the NEFA in that we were talking two different things, but on second thought I'm not sure. Carb definitely increases NEFA clearance into adipose tissue which is presumably not what you're referring go if I understand correctly. You're talking clearance into peripheral clearance presumably mostly the largest "sink" skeletal muscle? Transport across cell membranes is driven by diffusion and does not require a transporter AFAIK. This makes sense to me that the cells cannot refuse a NEFA delivery. Inside carb suppresses FA oxidation and vice versa. Carb is supposed to take preference, but it seems when FA is very high the cells are forced to use them first. When this happens glycogen stores fill and the cell can say "no" to more glucose by downregulating GLUT's --> peripheral IR.

I've got a blog post on a FA transport paper in the works.

Does switching a normal person to an energy balanced high fat very low carb diet pose any risk? I don't know for sure, but it seems less than optimal to me.

That said, it's not obvious that low-carb diets (therefore, presumably, high-fat) have performed badly in diabetes. Short-term they seem to do quite well.

They seem to. What troubles me is that there are now three pathways with a rather high *cure* rate -- as in normal glucose tolerance/insulin secretion & signaling -- GBP, Crash Diet & early insulin therapy -- while improvements, even with VLC for somewhat extended periods (6mo in Westman study) seem to level off as time goes by and weight loss slows/stops.

I would love to hear anecdotal evidence from a person who cured their diabetes with VLC and was eventually able to return to a "normal" diet (not the SAD!) demonstrating good glucose tolerance. Better yet a followup study. But most who do LC tend to stick with it (or at least try) to control hyperglycemia. It seems to me that fatty acids can be somewhat toxic in their own right. I'm not in a position to say definitively even to myself, and probably never will. That's where I play "Risk" with myself.

A sticking point with me for this is that folks can rattle off a long list of cultures comprised of billions of humans who thrive virtually disease free on high carb diets. On the other side? We have the Inuit and that faction of the paleo crowd who believes humans were carnivores and foraged for other things that were fiberfull and starch-deplete. When I balance the known and unknown, I do tend towards a lower fat diet. I'm not sure we were "intended" to run on ketones or fatty acids. And even if we were, it sure seems groups of humans have become so highly adapted to their traditional diets (and thrive on them) to where that seems more optimal.

I think it's almost as hard, perhaps harder, for the lipophiles to give up their beloved fat than for the carbaholics to give up their carbs.

I do essentially PHD these days but b/c I don't eat all that much, my fat intake is not that high in absolute numbers. It works well for maintenance. Enjoyable too, and I've been having a blast exploring various foods in the Asian market.
CarbSane said…
Hi Leon: Here's how I read a study. Scan the abstract to see if there's anything of interest. Skip to the results section. Then go back and read the intro if there is one, then the discussion, then the conclusions. Keeps investigator bias from entering my interpretation as best as possible this way.
CarbSane said…
Hi Kindke: The crash diet took around 8 weeks. Reports for GBP often speak of days so I think something else is in play and I strongly suspect (and there's a lot of lit on this) GLP-1 is that soumething. GLP-1 not only stimulates insulin secretion but facilitates glucose uptake on its own. Crash diet reduces dietary carb significantly and creates large caloric deficit but doesn't "fix" gut --> takes a while to restore. Insulin therapy doesn't create caloric deficit but removes gluco and lipo parts of toxicity by driving down NEFA and restoring normoglycemia. Takes a while but beta cells restore. GBP sort of a mix between the two? Same result a little faster.
CarbSane said…
Welcome psychic! I think you make a good case. There may be no requirement (as in there is no "essential carb"), but if you look at it this way -- that you can only eat so much protein and you have to get your energy from somewhere -- carbs may well be essential for optimal metabolism if high fat diets can(?) be detrimental.

As to athletes and DAG/ceramides, it's been a while since I read the papers but here goes: The hypothesis used to be that IMTG caused IR, but the athlete's paradox was that trained endurance athletes had comparable IMTG levels to obese women in one study. The women had excess stores from over-nutrition, the athletes had adapted to have extra stores on hand locally. Makes sense. They then looked at DAG and ceramide and find these do correlate quite well with IR. The way I see it the first step of "fat burning" is taking off the first fatty acid leaving a DAG. Don't burn all the FA's and some DAG build up. The athlete is probably adapted to using FA's as needed and burns them more cleanly with fewer fragments of partial metabolism to hang around. The obese person isn't adapted at all and still burns fat at a slow rate so they build up.

The "relative intake" is perhaps similar in terms of NEFA delivery to the cells.
CarbSane said…
Thanks for that paper suggestion CR and the paper itself MB!
Thomas said…
@Carbsane-It seems that when we are talking about the dangers of high fat (or high anything) we are referring to a diet that provides maintenance or above in calories, correct? It would seem that much of the dangers of any diet with extreme macronutrient ratios (not including extreme protein reduction I guess) reduces when calories are below maintenance. This makes calorie reduction the #1 important factor in any diet IMO.
CarbSane said…
Yes Thomas. I have some lingering fears that the very high NEFA in fasting on a hypocaloric VLC diet may contribute to complications (whether it's orthostatic hypotension, hypoglycemia, arrhythmia, whatever ...) but since I didn't really experience my own symptoms this time (I attribute that to the cheats that were periodic "carb ups" just on no particular schedule, and perhaps my higher protein lower fat version of VLC) I'm no longer worried about this short term personally. However, if ever experienced again, I would eat some carb.

In deficit, the elevated NEFA do not lead to buildup in the cells b/c they are burnt off. This is why LC works so well for IR when it does but I see diminishing returns on that in maintenance.
Archibald said…

"It does seemingly have much impact on metabolic rate but rather regulates which fuel the cells are 'burning' for energy at any given time."

Is this a "don't that becomes a do" as per your recent Eades the "Shai'ster" post? Anyway, I'm pointing it out just for the record 'cause I'm sure that most would read the sentence as intended owing to the word "rather".

Melchior Meijer said…
CarbSane, everything you dig up is extremely compelling and one would instantly become a fat phobic. Based on this post it seems very logical to conclude that a high fat diet might cause beta cell dysfunction, especially in sedentary people who are on their way to develop features of the metabolic syndrome.

Then what do we do with this small real life RCT? The group with the lowest fat intake developed almost twice as much diabetes after four years as the group with the highest fat intake. It was an ad lib experiment, so my bet is that the high fat group took in considerably less energy than the high lower fat group (haven't checked that though). This study seems to indicate that in the real world, and in humans, the higher fat induced calorie restriction overrides the possible negative effects of the extra fat.
Melchior Meijer said…
Hmm, I overlooked the observation that all three groups kept the same weight... There goes my calorie restriction argument.
CarbSane said…
@Archie: Yep! Good catch. Thanks! Fixed :-)
Melchior Meijer said…
In this trial in type 2 diabetics LDL tends to go down on low carb high fat, which, if I understand your science right, would reflect lower NEFA, not higer, right?
CarbSane said…
Yes, at least I would suspect so. I would note this is hardly a VLC diet according to current "standards" ... 30 +/- 10% and 137 +/- 41 grams. The study where NEFA were elevated was weight loss, and this appears (?) to be weight stable?

Interestingly, the carbs consumed were from: "rice and noodles made from wheat or buckwheat, and also from potatoes, fruits, bread and confectioneries." Where's Fred Hahn the LC Kindergarten Cop when you need him to point out how this is NOT a low carb diet! Just funnin' Melchior :-) They sure weren't doing it "right" with approx 20% protein and 44% fat.

This demonstrates, however, that diabetics can see improvements in biomarkers with a modest restriction of carbohydrate. Does this fix the underlying pathology? I'm thinking not, and that if they return to an isocaloric high carb diet they will see that HbA1c shoot right back up. Therefore, I disagree with this statement:
"The effectiveness of the diet may be comparable to that of insulin therapy". In light of the recent study demonstrating insulin therapy early on effectively cured diabetes. Still, these were more severe cases but none were on insulin therapy.
Melchior Meijer said…
OK, I agree.

Any idea what happened in the first study, where people who ate more fat developed less diabetes than the people who ate more fat (see copy pasted abstract)?

And maybe you have missed it, but how is it possible that a NEFA inducing endeavor like a 500 kcal/day diet restores beta cell function, if NEFA is what kills us? How could a severe ketogenic diet basically reverse diabetic kidney damage? Is high NEFA uniquely damaging to beta cells?

Just a futile attempt to play Miss Marple:

- Very low calorie/fasting restores beta cell function
- Gastric bypass restores beta cell function
- Cutting out visceral fat restores beta cell function
- Insulin therapy restores beta cell function
- Paralyzing pancreatic nerves restores beta cell function
- Correcting hypercortisolemia restores beta cell function

Is there a common culprit?

***OBJECTIVE To test the effects of two Mediterranean diet (MedDiet) interventions versus a low-fat diet on incidence of diabetes.

RESEARCH DESIGN AND METHODS This was a three-arm randomized trial in 418 nondiabetic subjects aged 55–80 years recruited in one center (PREDIMED-Reus, northeastern Spain) of the Prevención con Dieta Mediterránea [PREDIMED] study, a large nutrition intervention trial for primary cardiovascular prevention in individuals at high cardiovascular risk. Participants were randomly assigned to education on a low-fat diet (control group) or to one of two MedDiets, supplemented with either free virgin olive oil (1 liter/week) or nuts (30 g/day). Diets were ad libitum, and no advice on physical activity was given. The main outcome was diabetes incidence diagnosed by the 2009 American Diabetes Association criteria.

RESULTS After a median follow-up of 4.0 years, diabetes incidence was 10.1% (95% CI 5.1–15.1), 11.0% (5.9–16.1), and 17.9% (11.4–24.4) in the MedDiet with olive oil group, the MedDiet with nuts group, and the control group, respectively. Multivariable adjusted hazard ratios of diabetes were 0.49 (0.25–0.97) and 0.48 (0.24–0.96) in the MedDiet supplemented with olive oil and nuts groups, respectively, compared with the control group. When the two MedDiet groups were pooled and compared with the control group, diabetes incidence was reduced by 52% (27–86). In all study arms, increased adherence to the MedDiet was inversely associated with diabetes incidence. Diabetes risk reduction occurred in the absence of significant changes in body weight or physical activity.

CONCLUSIONS MedDiets without calorie restriction seem to be effective in the prevention of diabetes in subjects at high cardiovascular risk.***
Melchior Meijer said…
"And maybe you have missed it..."

Sorry, that should be "And maybe I have missed it...(maybe you have already addressed it)"
Stephan Guyenet said…
This is a great summary of your ideas (also shared by a number of senior scientists of course). Very compelling.
Mel said…
Hi,CarbSane,i would like to see the references of this interesting information please.
CarbSane said…
This post is 18 months old. I'm sorry but my memory has its limits as to which papers I was reading at the time I was referring to. If you could be more specific as to which part you are interested in, perhaps I be of more assistance. My current research interests are looking into beta cell dysfunction.