Very Low Carb and Insulin Resistance
In response to my recent post -- Can low carb cause central adiposity? -- James Krieger posted a link to a recent study indicating I may well be on to something. So I thought I would post this study separately (I don't have access to the full text on this one).
Longitudinal effects of a very low-carbohydrate (VLC) and a calorie-matched high-carbohydrate (HC) weight reduction diet were compared in dietary obese Sprague-Dawley rats exhibiting impaired glucose tolerance and insulin resistance. Obese rats were divided into weight-matched groups:
(i) VLC rats consumed an energy-restricted 5% carbohydrate, 60% fat diet for 8 weeks,
(ii) HC rats consumed an isocaloric 60% carbohydrate, 15% fat diet, and
(iii) HF rats consumed a high-fat diet ad libitum.
HC and VLC rats showed similar reductions in body fat and hepatic lipid at the midpoint of the weight-reduction program, indicating effects due to energy deficit. At the end point, however, HC rats showed greater reductions in total and percent body fat, hepatic lipid and intramuscular lipid than did VLC rats, suggesting that diet composition induced changes in the relative efficiencies of the HC and VLC diets over time.
Yes ... this is a rat study with all the issues inherent in trying to extrapolate to humans, but let's not forget Dr. Eades' favorite c57bl6-mouse that he says provides evidence for the so-called metabolic advantage of low carb diets. In that study, the growth rate of ketogenic diet fed mice was stunted to that of the calorie restricted diet vs. three other diets. I'll try to remember to update with a citation, but in one longterm study on epileptic children treated with a ketogenic diet, their growth percentiles (height AIR) declined following treatment. But I'll leave a dissembling of this study and the conclusions Eades draws from it for another day.
It is important to note that these were not genetically obese rats, but rather were made obese through diet and then put on weight loss diets. In this study, the VLC and HC rats lost the same for a period of time but the metabolisms of the VLC rats apparently became more efficient indicating an adaptation. Anecdotally, most low carbers seem to plateau out well above their goal weight. The various long term studies of LC diets seem to follow a similar trajectory of rapid initial losses followed by regain that would be consistent with the findings of this study. My own metabolism is in the tank as I do seem to become very efficient during long strings of low carbing. It would be an interesting study to recruit a number of long term weight loss success stories and compare the metabolisms of VLC'ers to LF'ers.
Back to the study:
HC rats showed marked improvement in glucose tolerance at the midpoint and end point, whereas VLC rats showed no improvement.
This ties in with what I've been saying now in many posts regarding "curing" diabetes with low carb diets. Whatever the glycemic issues of the VLC rats before diet and weight loss, the underlying metabolic impairment persists.
Impaired glucose tolerance in VLC rats at the end point was due to insulin resistance and an attenuated insulin secretory response.
So, again, a VLC diet may not only mask symptoms of IR and impaired insulin production, but could potentially sustain the underlying issues and/or further complicate matters by reducing the insulin response.
Glucose tolerance in energy-restricted rats correlated negatively with hepatic and intramuscular lipid levels, but not visceral or total fat mass. These findings demonstrate that adaptations to diet composition eventually enabled HC rats to lose more body fat than VLC rats even though energy intakes were equal, and suggest that the elevated levels of hepatic and intramuscular lipid associated with VLC diets might predispose to insulin resistance and impaired glucose tolerance despite weight loss.
This paragraph reads a little vaguely to me b/c they lump the VLC & HC groups into one when they talk about the energy-restricted rats. It sounds like they are saying that VLC rats had higher hepatic (liver) fat and intramuscular lipid (IMCL) compared to the HC rats and this correlated with impaired glucose tolerance/IR. But visceral and total fat mass was not associated with IGT so it wasn't just the lesser VAT/SCAT fat loss of the VLC group that was responsible for the observed IGT and IR in these rats.
So, yes, this is a rat study. But it is adding to concerns over long term low carbing.
Comments
Paleolithic diet researcher Loren Cordain might suggest that the reduced growth of children on ketogenic diets is not a bad thing. Read Section 9.1 of this paper:
http://www.thepaleodiet.com/articles/Hyperinsulinemic%20Diseases%20Final.pdf
I would be interested in the comments of you and James on this paper, which traces a lot of health issues to elevated insulin. I know you are sceptical of claims along these lines.
The problem is people equivocate hyperinsulinemia secondary to insulin resistance (which the paper you mention discusses) with insulin surges caused by high carbohydrate intake. They are not the same thing.
Hyperinsulinemia secondary to insulin resistance certainly can contribute to disease processes...there is no doubt about that. But that does not mean that, because I eat a high carbohydrate diet, that I'm going to get these diseases. Insulin surges due to meals, and chronic hyperinsulinemia due to insulin resistance, are completely different things.
I would also add to James' comment that people routinely confuse the insulin resistance of starvation or low carbohydrate eating with the insulin resistance of type 2 diabetes.
Obviously simply taking a young, fit, healthy athlete and depriving him of all food, or just all carbohydrate components of food, he will become insulin resistant. This is essential to preserve his blood glucose for brain function.
http://www.ncbi.nlm.nih.gov/pubmed/16627573
The development of insulin resistance in the presence of ample carbohydrate is clearly a very different problem and part of a pathological process.
The study you mention mixes obesity with its associated insulin resistance with carbohydrate availability at the starting point with subsequent diet protocols which involve increased insulin sensitivity to make maximum use of the HC diet supplied or insulin resistance related to carbohydrate restriction in the VLC group. Obviously fat burning does not require a sensitivity to insulin.
I would very much like to read the full text to see what can be teased out about what was actually happening to the rats. If I send you my email address is there any chance of a copy?
Peter
@Jeremy: I'll read that link in detail when I get a chance, but would simply say at this time that I agree with what James is saying. IMO it is erroneous to conflate appropriate post prandial insulin responses to a high carb load with high basal insulin and the increased post prandial responses in the obese and insulin resistant. I believe I have posted about pancreatic receptors sensitive directly to NEFA and this would be a plausible mechanism by which adipose tissue increases insulin. I don't believe it is insulin that does damage directly.
@Peter. Email me! I've come across a rather large body of material in the past few days on this topic and will blog on it in the coming days. The problems with IR extend far beyond glycemic control. Probably the most critical role of insulin is its inhibitory action on lipolysis in adipose tissue. This controls NEFA levels that are responsible for a number of deleterious things analagous to the glycosylation damage seen with elevated blood glucose. This might not be an issue for a lean active person regularly consuming a VLC diet, but this person should rarely if ever consume carbohydrate.
The other thing I'm interested in is VLC for a person who has already developed IR or T2. If diet progresses the disease to where the person can no longer produce insulin, we know this isn't a healthy state!
I would agree completely about the role of insulin in that it's core function is the inhibition lipolysis.
It does this at levels which don't even touch glucose uptake. If we accept this then even minor elevations of insulin will shut down fatty acid supply before increasing glucose flux in to cells. In fact you could argue that it is the decrease in FFAs which allows GLUT4 transporters to be put on to the cell surface. As in intracellular diglycerides etc.
So hyperglycaemia should never be accompanied by elevated FFAs. If the system functions correctly FFAs release should shut down to allow normoglycaemia without even thinking about hyperglycaemia.
I've not had chance to read the blog extensively but have you looked at HIF in adipocytes and mitochondrial function in adipocytes? I've no time at the moment and these are my key areas of interest in why adipocytes should spill FFAs in the presence of both glucose and insulin.
I have a view of the second core function of insulin as the suppression of hepatic glucose output. If this fails around the same time as adipocytes start spilling FFAs then a person who has been gaining weight steadily converts to a type 2 diabetic. Obesity does not seem to be necessary. The "thin but metabolically obese" concept...
A follow on to James' comment, I think humans seem to function pretty well between VLC and about 70% of calories from carbs. Somewhere above 70% progressive rise in blood pressure occurs with age and is well established by 90% of calories from carbs (from the Bantu studies) is eaten. At a carb intake of around 3% there is also a progressive increase in BP with age. I've not tripped over study finding a cut off for how low you can go in carbs before the CV effects seen in the Greenland Eskimo kicks in. It seems reasonable to suggest a carb intake between quite low and around 70% seems fine in undamaged humans eating real food.
Once we become pathologically insulin resistant (whatever that means exactly) then we can still process fat perfectly well and carbohydrate restriction becomes beneficial to side step insulin resistance. Only a glucometer tells us how broken we are.
The concept of "curing" insulin resistance means restoring normal liver function and normal adipocyte function. Plus sorting out a mess of down stream shrapnel damage in the autonomic nervous system and within the pancreas itself. All seem highly unlikely to me. A cure means you can eat pizza with normoglycaemia. Err, no.
Carb Sane: Again, sorry if I'm teaching egg sucking, but I'll email you Zierler and Rabinowitz' 1964 paper on intra-arterial insulin infusions in human volunteers and lipolysis inhibition....
Peter
http://carbsanity.blogspot.com/2010/08/critical-visceral-adipose-tissue-theory.html
There's some info there as to why adipocytes start to spill FFA's in addition to explaining the "metabolically obese" thin folks. I keep coming across conflicting information as to the number of fat cells (most indications are that the numbers are fixed by adulthood, so maybe further differentiation is mostly turnover?). But I don't think the release is any great mystery once the cells get "stuffed". Dietary fat is cleared from the blood stream by chylomicron activation of acylation stimulating protein (ASP - I have a few posts categorized under this). While not a classic equilibrium reaction, the sequestration of FFA's liberated by lipolysis at the adipocyte membrane to adipocyte trigs is influenced by a gradient. A key word to research on regarding this would be "sick fat" or "adiposopathy".
I've also posted how VLC increases NEFA release after a high fat meal: http://carbsanity.blogspot.com/2010/05/acute-exposure-to-long-chain-fatty.html
Humans seem to do better at the "moderate end of the extremes" if that makes any sense but not so much in the middle. Our appetite signalling and metabolic controls seem ill equipped to handle any significant carb + fat load simultaneously. But I would point out that the examples of high fat VLC cultures, e.g. Inuit, are (a) VERY high in omega 3 consumption, and (b) living in harsh cold climates where fatty acid cycling and oxidation is necessarily elevated to maintain body temperature. I contend that neither is the case for most consumers of high fat VLC diets.
A perfect liver would probably allow any mix of fuels away from the ultra extremes but few of us on Western diets have a perfect liver........ Just my impression.
Peter
That said, the SAD of the 1970's certainly contained its fair share of mixed fuel meals but the obesity rate was low and I doubt we all had perfect livers back then either! I think that we are just exposed to more (convenient) calorie dense fat+carb foods, not to mention the various caloric drink crazes. When one looks at the calorie contents of a muffin, a small order of fries (let alone a large), or one latte at Starbucks, it is easy to see how we "passively overeat" and gain weight.
Most people eat more calories than they think or think they need more calories than they do. Either or both ....
A lot of that portion size inflation is, IMO, driven by the fact that as a society we purchase more foods in single serving portioned form. So you go to buy a A or B, and instinctively if A's bagels are a bit bigger, we see value. Then B notices A is doing better business so they make their bagels bigger, and so on ... Now you can't go to a bagel shop and get what used to be a normal sized bagel. My husband and I were not light eaters to get to the size we did. Yet on the occasions we do take out, we share one entree and often still have left overs! Yet as I pass tables on the way to the takeout counter, I see an awful lot of fully cleaned plates.
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