Monday, September 15, 2008

Physiological insulin resistance: The wild type mice

I've just got an afternoon to blog so I thought I'd put up something new before the daunting task of going through comments which have built up with the surf/work/weekend session that has (very pleasantly) limited net time.

I wanted to go through the data from the mice in this paper.

It's a Nature paper so I'm not sure how I got the full text, but there it is on the hard drive! The brown fat ablated mice are interesting enough for a post in their own right eventually, so it's the control groups that I'm looking at today. Ortmann does discuss the macronutrient preferences of mice, strain being one factor, and she does discuss in particular the role of early exposure to grains in future food choices, no surprises in what happens there! But any sensible mouse which has not been permanently broken by early exposure to lab chow loves fat. How much fat? Well, you have to let the mice choose for themselves. No lab chow for these mice. They got three separate food blocks, one lard/coconut oil, one casein and one of that sucrose/cornstarch poison so beloved of rodent researchers. Here's the composition of the blocks:

What did the mice choose? Here's the cumulative food intake from 4 weeks to 17 weeks of age. Look at the column WT (ignore the UCP-DTA column for today), these are wild type (WT) mice without any genetic engineering. They're lab mice.

Okay.... casein. It seems mice eat enough protein to grow, about 12% of their calories. How about that scrummie sugared cornstarch? I was thinking they might not have touched this junk with a barge pole, but those clever mice ate just under 6% of their calories from sucrose/starch. Very close to what I eat! And the rest? FAT!

These macronutrient ratios are pretty close to those of the Optimal Diet. It is a genuine high fat diet. There is nothing Western or Cafeteria about it. It's JK all the way.

The lab chow is unspecified but was probably Purina 5008, low fat, high starch, minimal sucrose. A bit Ornish like...

So what happened to the mice?

As you can see the free choice mice (WT 3CD, black triangles) grew indistinguishably from mice on lab chow (WT SD, black circles) re bodyweight.

Now look at energy intake, again it's only the WT SD black circles of the lab chow normal mice we are comparing to the WT 3CD black triangles of the normal type mice eating to the Optimal Diet (by choice).

Would you rather eat 90kj/d or 70kj/d to maintain your growth rate under unlimited food conditions?

Finally it's pretty obvious that eating all that saturated fat will make you instantly insulin resistant and diabetic. Well, interestingly, the fasting glucose is actually higher in the high fat eating mice.

The hatched bar is the high fat eating mice, again its the WT groups we're looking at.

Aha, the AHA was right all along. No! Insulin sensitivity is the same in high fat or lab chow mice. Each mouse was injected with insulin and their fall in blood glucose in response to this tracked. The bigger the fall, the more sensitive you are to insulin. Don't play this at home, an OGTT is much safer!

Again it's the black triangles eating to the OD. Although there is no statistical testing of the difference from the black circle lab chowers, the glucose fall in response to exogenous insulin is GREATER in the high fat group and eyeballing the Standard Error bars suggests that the difference is probably significant.

So does a high fat diet cause insulin resistance? Only in so far as there is a higher fasting glucose level in this group, of which I'm an honorary member. In terms of shifting glucose when I need to, it's effortless. But if I'm shifting free fatty acids because I'm exercising without having eaten I can still use NEFA to fuel muscle, have that muscle reject glucose and so leave that glucose for my brain, if I'm using it at the time that is...



donny said...

So it increases insulin resistance only in the absence of actual elevated insulin? Oh no.

Stephan Guyenet said...


So if I'm understanding this correctly, the mice eating OD are consuming considerably more calories than the lab chow mice? Why do you think that is? It seems at odds with what you see in humans.

I think it's interesting that these mice prefer fat to carbohydrate. Apparently, wild Mus musculus aren't nearly as vegetarian as lab mice. In some places they get most of their calories from bugs and other animal sources. Grubs are very fatty. So maybe fat is not so foreign to them.

Peter said...


Oh yes. Otherwise we'd be hyperglycaemic on high fat diets and the ADA and AHA would be correct, which would be a logical absurdity.


Peter said...

Hi Stephan,

Yes, lots more calories. I guess the explanations might lie in brown adipose tissue, which lab rodents do life long, or with them being hyperactive adolescents on a high fat diet, less so on lab chow. Or you get back to Gunther's interest in whether you can eat 3500kcal/d on high fat diets if they are low carb. Possibly so.

Re the lab rats/mice being vegetarian, maybe they are avid vegetarians when the alternative is starvation! If Ancel Keys decided what went in to that food hopper... Given the choice I've seen a number of studies which come out with a fat preference, though not quite to the OD ratios these mice did.

BTW when put at risk of diabetes by ablation of their BAT they went ZERO carb and avoided diabetes. Mice are not so dumb, given the choice.


Stephan Guyenet said...

Interesting. I just saw a paper showing that brown fat descends from muscle lineage rather than adipose. Humans can uncouple in muscle, so we might not be that different even though we don't have much brown fat as adults.

gunther gatherer said...

Yes, this confirms our Fat Challenge quite well. I'm not eating around 3000-3500 kcal a day, and as long as I keep carbs low, I don't see any weight regain. I don't work out.

But I want to add that I need to feel hunger sometimes for this to work. As in go without food for several hours or stop eating at around 7 or 8:00 pm. I have a feeling you need to give the body time to eat the adipose tissue you've trained it to eat.

At least I've thrown away calorie counting. Who knew I could be as smart as a mouse...

gunther gatherer said...

The above should read "I'm NOW eating around 3000-3500 kcal a day..."

gunther gatherer said...

Peter, I have some questions about fermentation as a way to make pasteurised dairy digestible again.

I've noticed when I eat normal cream, I seem to develop some puffiness, trouble sleeping and a general recurrance of my old health problems (general inflammation-related). But when I return to fermented cheeses and sour cream, etc., these problems go away.

What are your thoughts on pasteurisation and what it does to the proteins and enzymes in milk?
When you occasionally eat non-fermented cream, do you notice any similar adverse reactions?

Weston Price also notes the recurring fermentation process in native foods, which seem to enhance health and vitality. But if pasteurisation changes protein shape and renders milk undigestible or worse, changes protein shapes so that they can freeload through the gut wall, does fermentation revert this?

Any good articles you can point me too in this regard? Thanks, G

ItsTheWooo said...

The mice on the high fat were just a hair heavier than the other mice on the chow; not significant but it does make me wonder why. Probably that is healthy tissue.

The mice had to eat more most likely because the fat was coconut oil, which is known to encourage weight loss.

Things would probably be different if they used a very high omega 6 oil, like corn. This would produces inflammation and IR, and I suspect dietary preferences as well as total intake and weight trends would have been a LOT different (probably a lot like fatty americans...)

gunther gatherer said...

Hi Peter, you said the following in your "Casein and Gluten and Gastric pH" blog entry:

"I think there is a case to be made for both the pasteurisation of liquid milk and the drying of powdered milk altering the shape of the protein structure of casein to render the 1-28 amino acid sequence protected from digestion in the stomach. This is absolute speculation, there's no data to support this. Except the world is full of anecdotes about people tolerating raw milk but not pasteurised milk. I'm also willing to speculate that bacteria used to ferment milk to yogurt or kefir may cleave this amino acid sequence, making fermented dairy products far less problematical, even if they are derived from pasteurised milk."

This subject is fascinating me.

Why would pasteurisation render the protein structure undigestible? And if heating amino acids in milk renders them useless to us, wouldn't the same hold true for cooking meat?

Can you also describe how fermentation or bacteria would bring milk amino acids back into shape so that they could be broken down by pepsin in the stomach?


Peter said...

Hi Gunther,

On the pasteurisation front it is very much speculation. The process undoubted will alter protein shape. The question really is whether this will protect the undesirable 1-28 aa sequence which is used to open tight junctions and yet still allow the tight junction opening effect. I'm just looking for an explanation of how both you and I tolerate fermented dairy better than unfermented industrial dairy... I don't think the protein structure ever gets back to any sort of normal shape, more likely the breakdown is in to more handlable size chunks, ditto cooked meat. Just guessing. I think ultimately the casein will get fully broken down in the SI, also ditto meat. The main difference being that meat is not designed to open tight junctions for functional reasons in milk glands. At which stage it fully breaks down seems less important.

For me the main response to unfermented cream is the occasional acne spot. Exactly how this might be mediated is wide open to speculation!


JohnN said...

The Pasteurization process denatures the protein in milk. Some of which when consumed by the bacteria that ferment the cream will be refolded by the bacteria's heat shock protein (HSP) - reconstituted, essentially.
There are other benefits: more free amino acids broken down by the microbes (lysine, methionine, etc.), conversion of lactose to lactic acid which is readily used by the heart (if you're active), vitamins and other enzymes produced from the bacteria actions.

gunther gatherer said...

Hi Peter. This was in the Journal of Dairy Science and pertains to our discussion of protein shapes and nutrient content in fermented dairy.

Please let me know what you think.
Regards, G

gunther gatherer said...

Here's another one. Yes, I know it's a dairy industry study, but the results, if there are any, don't seem to favour them one way or the other...

gunther gatherer said...

This last one concludes that "proteolysis during fermentation may lead to the formation of novel peptides during gastrointestinal ingestion."

Fermentation breaks the 28 chain so it doesn't go through the gut wall and/or creates a new way to digest the milk amino acids??

Pass the yogurt.

Brad Reid said...


I wonder what your thoughts would be regarding Micellar Casein protein powders, available here in the U.S.A. for an "arm and a leg." Essentially, and as best as I can tell, Micellar Casein is protein powder derived from "undenatured" milk sources, that is, milk not exposed to heat, ultraviolet light, chemicals, etc.

At least one observer has suggested that a well-known protein powder peddler used Micellar Casein as sort of a magic ingredient early on to establish the efficacy of its protein, then owing to its high cost, after the protein developed an extensive following, dropped it from their formula. Which one? MetRx.

I know the majority of folks on this site have less enthusiasm for the muscle-building qualities of diet and focus more on other nutritional aspects, but I wonder what any of your thoughts would be regarding Micellar Casein, presumably not pasteurized as that would imply heat treatment, and its viability as a protein source for a high fat diet.

Cheers! Brad R.

ItsTheWooo said...

If unfermented cream brings acne as well as weight / hunger problems, I would look to growth hormones, insulin-stimulating proteins which are naturally found in milk, and *especially* in factory-farmed milk. For me, acne is the #1 sign I am overdoing carbohydrates (have not had carb-related acne in months since I never go overboard with carbs anymore).

Fermenting probably destroys these proteins (casein?), thereby making the cream endocrinologically benign. Result? An end to acne, as well as inappropriate insulin release, but plenty of yummy cream to enjoy.

Unknown said...

New book listed @ Amazon:

Trick And Treat - how 'healthy eating' is making us ill (Paperback)
BY Barry Grives

Few people have 'old age' as a cause of death on their death certificate.Today, we die of cancer, heart attacks, strokes, osteoporosis, diabetes…And we accept these conditions as normal causes of death.They aren't - and neither is the ill-health, pain and discomfort that make our later years a misery.

In this controversial, evidence-based account of how and why the health-care establishment has got the concept of 'healthy eating' so wrong, Barry Groves shows us how to take charge of our own health and lives, in contravention of what the health-care industry would have us believe and do.

Part I: How 'Healthy Eating' Is Making Us Ill
1. Medical Corruption
2. What's Behind The Screen$?
3. How We Got To Where We Are
4. Learning From History
5. Fats: From Tonic to Toxic
6. The Seeds of Ill Health
7. Climb Off The Bran Wagon
8. Why 'Five Portions'?
9. The Phoney War On Salt
10. Soy, Fluoride and the Thyroid
11. Our Irrational Fear of Sunlight
12. Exercise Care
13. Homo Carnivorous
14. The Metabolic Syndrome And Glycaemic Index
15. Unhealthy Dogma Means Unhealthy Diet
16. So What Should We Eat?
17. Why Low Carb Diets Must Be High Fat, Not High Protein
18. You Are What Your Grandparents Ate
19. Prevention is Better

Part II: New Diet, New Diseases
20. ' Healthy Eating' is Fattening
21. The Diabetes Time Bomb
22. Diseases of the Heart and Blood Vessels
23. The Dangers of Low Blood Cholesterol
24. Cancer:Disease of Civilization
25. Gut Reaction
26. Deficiency Diseases
27. Diet and the Brain
28. Multiple Sclerosis
29. ' Healthy Eating' Shows
30. And Finally . . .

About the Author
Barry Groves, who lives with his wife, Monica, in the Oxfordshire Cotswolds, can rightfully claim to be Britain's leading exponent of the low-carb way of life as he has lived on, researched, lectured and written about it for well over 40 years.

He and Monica were overweight from 1957 to 1962, when he discovered the low-carb regime for weight loss. It worked; they haven't been overweight since.This started his questioning of conventional diets.As a consequence he took up full-time research into the relationship between diet and 'diseases of civilisation' such as obesity, diabetes, heart disease and cancer. As a result of his researches, he realised that the perceived wisdoms, both of low-calorie dieting for weight loss and 'healthy eating' for the control of heart disease, were seriously flawed.

Now an award winning international author with a doctorate in nutritional science, Barry has written both popular and more technical books which have been published in countries as far apart as Argentina and Russia, as well as all English-speaking countries. He currently divides his time between researching, lecturing and writing books about the management and prevention of obesity, diabetes and associated conditions.

Peter said...

Hi Brad (and ItsTheWoo),

Can't really comment as this is the first I've heard of it. The whole subject of nutrition and metabolism is so huge you can only delve in to certain bits... My gut feeling is that I always drift back to whole foods I guess. But then my preferred physique is one which would allow me to blend in to a well nourished HG society... But there again milk is designed to convert little calves to big calves so I can see why it might work for bodybuilding.

This comes back to ItsTheWoo's suggestion about insulin mimetic/release stimulants in milk, they're certainly there. And the body building gurus are well aware of the role of insulin as a muscle builder.

Before refrigeration and trains relatively few people would have access to fresh milk and humans do seem to have a long tradition of culturing it. Back when I could get "house cow" milk I used to just leave it a room temperature overnight and let it self culture. It was good.

Hi Sverlyn,

I'd heard Barry Groves had a new book on the way, didn't realise it was so close to publication!


mess talker said...

At the optimal polish deli in chicago, they sell "settled" goats milk. Fresh from the farm and fermented. Oh, so good. Makes me think that this is what yogurt used to be.

gunther gatherer said...


Here's an update on the Fat Challenge: it seems obvious, but there is a limit to how much you can eat of it without feeling totally over-full and disgusting. I tried to eat loads more fat calories after reaching 65kg, and failed because it made me into a lifeless slug. The exercise seemed pointless, since I was never going to live like that anyway, so I gave it up.

I can't really tell you the outcome. The problem is that you can't tell if you gained weight or not when you've got 3 times more food in your stomach. In any case, I didn't feel fatter and my clothes fit the same after ten days trying to gain weight by upping fat.

Bruce made a comment in another blog entry of yours that has really proven to be true: taking chocolate out of my daily diet resulted in MUCH less hunger and I felt much fuller much longer after eating. Any reason why this could be? I also find coffee, even decaf, makes me hungry afterwards too.

Has anyone else tried taking the 85% chocolate out to see how they feel?


Mark said...

Yeah, Gunther.

I have taken chocolate in and out of the diet, mainly for economic reasons. Used to buy this Polish Wawel chocolate for 1.50 Canadian for 90% cocoa, but they lowered the cocoa butter concentration and upped the cocoa powder, so more protein, less fat. So not economic reason, but fat content. Now I have moved and am purchasing Lindt chocolates at an outlet mall 10 for 12.00 USD, which the whole family is in joy over.

Anyway, yeah, chocolate does make me hungrier. Or maybe I am hungrier and therefore eat chocolate because I have not enough to eat. Not sure on the cause there lol.

BTW, I am weighing in at 148 pounds or so, and can hit up to 155 on a high fat diet and not feel sluggish. I am very low body-fat %-wise, and have a small frame. I think the reason Peter may not put on much weight on his calories is lack of protein to put on muscle mass? Obviously no proof for this, but suspect instead calories are going into metabolism. I eat virtually the same as Peter, except I'm eating less calories than he does. My carb content is same, if not lower, and my protein content is higher maybe by double is the major difference between my diet and his.

Peter, you get cold much?

Think when you go surfing, it's cold as all hell and you can hack it. I don't handle cold well. I wonder if you have an amped metabolism from the calories that results in overheating, and that's where your calories are going to.


emil henry said...

Hi guys.

Excellent discussion you are having on dairy.

I've found my ideal morning drink, quite low in caffeine: butter tea. Just make strong tea (I use organic Ayurverdic chai, which is 35 % black tea by weight), then add butter (I add maybe 4-5 tablespoons of cultured organic butter per half pint). Then blend or shake it until the butter stops separating. For added goodness, blend or shake it a lot to create a large layer of foam (I use a stick blender for this end). Delicious. They tend to drink a lot of it in Tibet. I guess you can add some (fermented) cream as well.

Praise the lard!

ItsTheWooo said...

Hunger from chocolate is probably just the carb content... plus, chocolate is tasty and that could stimulate feeding centers in the brain; there is a link between beta endorphin release and insulin release. Chocolate stimulates beta endorphin. Coffee does as well, which is why people tend to feel calm and satisfied after a coffee (it's not the dopamine, it's the endorphin).

According to the link above, opioid-mediated feeding plays a big role in "emotional eating". Any eating that is done after stress: fasting, starving, or non-food stress produces a big opioid response to food, which in turn causes insulin release.

Predictable and monotonous feeding disengages the opioid system, which may have something to do with the theory that eating bland food regularly is slimming (e.g. shangrila diet). For a lot of women who hate protein and low carb foods, perhaps the diet works for this reason too (because the low carb food, for them, is monotonous and predictable whereas their usual feeding habits are to eat unpredictably and of very enjoyable food). I can't help but notice a lot of dieters have an innate fear of enjoyable flavorful food (e.g. splenda and chocolate) and I wonder if it is because their weight gain and eating is more mediated by the opioid induced insulin secretion?

marco said...

Dark chocolate (72% or 85%) makes my 2 y.o. daughter SNEEZE.
Very immediate reaction.

Whenever she has a little piece of chocolate she sneezes.
Even with the purest type.

Higher the cocoa in the chocolate, more immediate and stronger the reaction.

I read about a lot of people suffering from this on the web.

Allergy to theobromine?
Sort of "photic sneeze reflex"?

Anyone else has this problem?

Has Squiggs ever had this reaction, Peter?

Lauren said...

I have a question Peter. Since you have a scientific background and can look at scientific studies with a trained eye, will you please see what you can find regarding agave nectar (Agave Tequilana/Azul Tequilana)? It seems to be the "it" sweetener right now in the U.S. with vegans and those seeking a low-glycemic "natural" alternative to white sugar and honey. What's your take on agave's physiological impact? What about the high concentration of fructose in agave, and its long term effects on the human body? I've found only one study on PubMed talking about it.

Thanks for any info!

Anna said...


Good for you for inquiring about the latest darling of the "natural" sweetener world, agave syrup. I find the high % of fructose in agave syrup/nectar alarming and worthy of caution, to say the least (wikipedia says some brands are as much 92% fructose!). I like to think of agave syrup as an even faster method of producing human foie gras (fatty liver) than HFCS.. hee-hee.

Peter said...

Hi Lauren,

Have to agree with Anna, Agave syrup makes HFCS look like a health food!

Despite possible minor exceptions fructose is fructose is fructose, and it's bad...


Peter said...

Hi Gunther,

No time to read the dairy links yet but on the list...

Re chocolate I rather like the idea that any appetite increase comes from the inhibition of the break down of endocanabinoids.

May not be the correct answer but I like it!

Re allergy to chocolate Marco, no, no problems from Squiggs on that front. More problems with impetigo which seems to be triggered by salicylates, blackberries and raspberries (his favourites) seem to be a trigger...

If you do have a genuine allergy problem you would have to think way beyond just the theobromine to the host of other compounds in a plant derived food... Chocolate contains amines and certainly histamine triggers sneezing. There might be more about this on Emma's blog and it's links to the failsafe diet about amine/salicylate sensitivity.


Peter said...

Hi Mark,

No, I don't feel the cold much, it was a bit of a standing joke back when I lived on the East coast where the wind is lazy (goes through you, not round you!). Back on carbs I was surfing cold waves but tended to get very, very cold and take some time to thaw afterwards. Used to get exhausted too, with no "pull" in the arms to get out through the break after an hour or so. Things are easier and warmer on NEFA.


water said...

I think there can be a histamine reaction from dairy also.

I just found this study after a major flare-up. I'm not on Failsafe, but beginning to suspect I could benefit from fewer amines at the very least.

(PMID: 18007585)

J Invest Dermatol. 2008 May;128(5):1280-5. Epub 2007 Nov 15.

Identification of histamine receptors and reduction of squalene levels by an antihistamine in sebocytes.

Peter said...

Hi Water,

Yes, amines might well be important for those who's acne doesn't go on LC alone. My skin is good enough that going Failsafe is too much like hard work! Depends where you are starting from I guess...


Unknown said...


I wonder if you're familiar w/ Rob Faigins " Natural Hormonal Enhancement " ?

He combines low card days w/ carbo load days- the advantage being in the carb loading an increase in T3, an increase in the anabolic effect of insulin and a reduction in sex-hormone-binding globulin. He also states that periodic carb loading can enhance testosterone production @ the testicular level.


Gyan said...

A paper with interesting epidemology.
Does Total cholesterol increases with
lack of vitamin-D?

Coronary risk factors in Northern India

American Heart Journal,vol 79, 181-187 (1970 )

Donald N. Wysham M.D Kuldip C. Kohli M.B., B.S.and Sandra Mulholland
Department of Medicine, Christian Medical College, Ludhiana, Punjab, India.

Received 19 May 1969.


A study was made of 175 sedentary male lawyers and bank employees between 40 and 60 years of age in Punjab, previous termIndia,next term to observe the relationship of diet, body build, and directed daily exercise to serum cholesterol levels. Dietary analysis was made from interviews. The consumption of previous termsaturated fatnext term was found to be moderately high (30 per cent of calories), and of cholesterol low (mean 126 mg. per day). Of dietary factors, only cholesterol was positively correlated to a significant degree with serum cholesterol. The effect of dietary cholesterol was small, with 3 mg. per cent change in serum cholesterol per 100 mg. of change in dietary cholesterol. Relative body weight appeared to have more influence than dietary factors on serum cholesterol. Short periods of daily exercise had no significant effect on serum cholesterol levels. Dietary sugar was found to be negatively correlated with serum cholesterol.

Ed Clements said...

Hi Peter. I find your blog very interesting but am still on the fence on many issues.
We know that fructose above say about4-6g /day is bad. But what about FOS such as is found in artichokes asparagus, chicory, yacon etc. These are all traditional vegetables and wikipedia says (search inulin) that many traditional diets contain in excess of 20g / day of inulin? According to many sites, Duncan Crow's site on curing candida in particular, it is said the long chain FOS cannot be used by -ve bowel bacteria and 1 study on his site shows that feeding of 15g inulin/ day makes bifidobacteria predominant in the colon. Plus, it has been shown that FOS is a component of breast milk. What is your take on this? As I say I am undecided.

williebr said...


In the last paragraph of this post, were you saying that on a very high fat diet your lean tissue becomes insulin resistant so free-up glucose for your brain?

If so, is that very good for optimizing body comp? You would want your lean tissue/muscle to be insulin sensitive right?

Peter said...

Hi williebr,

Yes, and not really. I run my muscles on FFAs so I have no need for them to be insulin sensitive. I do not do physical culture and absolutely do not have the physique of Anthony Colpo. Nor would I would want it.

I can catch waves in my kayak as well as my mates running on carbs. That's good enough for me.


skepticle said...

I love this post! Saw a recent article about Ornish reversing aging with vegetarianism and yoga, and I just couldn't resist having a laugh by searching the blog for 'Ornish' =)