Friday, April 22, 2016

Dairy and diabetes

Mozaffarian has published this nice observational correlation between three markers of dairy consumption and subsequent onset of diabetes over the following 15 or so years.

Circulating Biomarkers of Dairy Fat and Risk of Incident Diabetes Mellitus Among US Men and Women in Two Large Prospective Cohorts

Any of the three markers is associated with a roughly halving of the incidence of diabetes. I sort of like this, living largely on bulk calories from dairy myself. I also like the size of the effect. If you consider how many people are in the process of developing diabetes in the USA alone, halving that incidence might make a significant contribution to reducing suffering.

If you eat a gram of C15:0 fat, what else comes bundled along with it? Well, in Swedish milk fat there is about a gram of C15:0 in 100g of total fat. That total fat is made up of 70% saturated fats, mostly palmitic acid, a decent dollop of stearic and myristic acids plus odds and sods of shorter chain saturates. These fats might be what reduces the diabetes risk. What makes me think that, other than my biases?

If you feed a normal Bl/6 mouse 40% of its calories as stearic acid, what happens to its blood glucose level? Taken from fig 2.3.1 part B. After 10 weeks the blood glucose of a normal mouse will be significantly lower than if it had been fed standard CIAB or 40% of an oleic acid/PUFA mix. That will be the red arrow:

The blood glucose lowering effect even occurs in db/db mice, a routine model used to vaguely represent T2 diabetes, green arrow. That's all fine and gives some sort of suggestion that it might be the saturated nature of dairy which is protective against diabetes. But why should this occur?

I'm drawn back to the perfused isolated pancreas and the insulin response to physiological levels of glucose in the presence of various fatty acids. This is the image I'm thinking of, from The Insulinotropic Potency of Fatty Acids Is Influenced Profoundly by Their Chain Length and Degree of Saturation:

Notice the marked but transient spike in insulin when glucose is raised from 3.0mmol/l to 12.5mmol/l, most obvious in the black squares representing stearic acid as the background FFA (palmitate is the black triangles). After the spike, which I think represents the first phase insulin response, there is a steady climb in insulin, equivalent to the second phase of insulin secretion. Obviously this is needed because it's an isolate pancreas prep, glucose is fixed at 12.5mmol/l in the perfusate. If the first phase insulin response does its job in real life the systemic circulation (and pancreas) would never see 12.5mmol/l of glucose. The surge of insulin would hit the liver and interact with the insulin receptor. Two things follow on from this. Most insulin would be metabolised following interaction with its receptor, so insulin would never flood the systemic circulation. Second effect is that insulin/insulin receptor activation would shut down hepatic glucose output while the Glut2 transporters continue to pretty well clear the portal vein of glucose.

So a first phase insulin response is designed to protect the systemic circulation from both hyperinsulinaemia and hyperglycaemia. That is its job.

If you want to obliterate the first phase insulin response what you need to do is to reduce reverse electron flow through complex I. Just take a peek at the open circles (oleic acid) and, even better, the closed circles (linoleic acid). For a healthy pancreas, from a healthy rat, you can eliminate the first phase insulin response to hyperglycamia just by choosing your background FFA.


Arterycloggingsaturatedfat first phase insulin response 16ng/fraction


Hearthealthypolyunsaturatedfat first phase insulin response 2ng/fraction.

Want to be fat? Use your second phase insulin response in the systemic circulation to pack fat and glucose in to adipocytes. But you must avoid the first phase response because this will keep glucose in the liver as harmless glycogen.

Try using sunflower oil or corn oil as advised by the Food Standards Agency. When you get so fat that your adipocytes start to spew unregulated FFAs, you can be a diabetic (congratulations!). You owe it all to your cardiologist. Or the FSA. Remember who to contact when you get your first diabetic amputation.


Oh, picked up this quote about dairy and heart disease from Tom Naughton's blog:

"Rather than suggesting that the saturated fats in dairy products are harmless, Aslibekyan and co-author Ana Baylin, an adjunct assistant professor of community health at Brown, hypothesize that other nutrients in dairy products are protective against heart disease, for all but perhaps the highest dairy consumption quintile in their study. The potentially beneficial nutrients include calcium, vitamin D, potassium, magnesium and conjugated linoleic acid (CLA)".

The authors are completely wrong in the interpretation of their own data. On every front. Saturated fats are NOT harmless. Shout it from the roof tops. THEY ARE PROTECTIVE.

"calcium, vitamin D, potassium, magnesium and conjugated linoleic acid (CLA)"?

Bollocks. Ask the mice on stearic acid.


Gretchen said...

There are myths about diabetes just as there are myths about saturated fat, and this is one:

"Remember who to contact when you get your first diabetic amputation."

As William Polansky says, "Well controlled diabetes causes nothing."

rq said...

What about MUFA, such as the 30% oleic acid found in butter? How does MUFA affect insulin at the ETC, is it more like stearate or more like PUFA? Peter, would you hazard a guess? I guess all the coconut oil lovers out would also like to know :)

Neha Hooda said...
This comment has been removed by a blog administrator.
Peter said...

Neha, sorry to delete your comment but it does look like the sort of advertising I usually delete immediately. The gear actually looks quite good but the text of the comment is too much like spam for me to leave it!

Gretchen yes, but still there are questions about what we have done to the mitochondria to keep needing to avoid carbs in T2DM. T1DM folks with Bernsteinian control have no underlying mitochondrial pathology and do very well long term...

rq MUFA are the physiological flip side to palmitate/stearate. A ratio, as in so many things, is probably important. But no-one eats pure palmitate or oleate. Or has a liver which would allow this to persist if they managed to do it.


Gretchen said...

Peter, I agree we need to know more about mitochondria. T1DM folks with Bernsteinian control are on very low carb diets, so I'm mystified about your statement that T2 need to avoid carbs, implying that T1 do not.

My point was that although some people with T2 go blind and lose their feet (microvascular complications), most don't. The problem is not microvascular as much as macrovascular complications, heart disease. How do mitochondria impact that?

Mitochondria evolved from bacteria, and I keep wondering if we could somehow use that fact to our benefit.

Peter said...

Gretchen, I feel the need to avoid carbs for T1s in Dr B's protocol is the difference between exogenous injected insulin and pancreatic portal vein secreted insulin. The basic mitochondrial function at the time of acute onset is probably completely normal. For a T2, with years of hyperglycaemia/hyperinsulinamia behind them, their mitochondria are long damaged. Of course, avoiding glycolysis per se is a Good Thing, even for a T1 freshly diagnosed or a normal person, for that matter. That's another set of posts to come, depending on which ideas I get around to...


Kevin FST said...

Here's hoping you get round to glycolysis sooner rather than later. I would be especially interested in your ideas about mechanism for >mitochondrial dysfunction>glycolysis.

Passthecream said...

That's a killer graph ... literally!

NY said...

How does physiologic IR fit into all this mechanism? Which worsens glucose control.

Peter said...

NY, this post started as a huge tome (!!!) on the role of stearate/palmitate on insulin secretion (retained), insulin signalling, insulin resistance and how the three integrated. It just ended up as the Protons thread, yet again...


karl said...

I imagine them saying - "We must protect the narrative..but perhaps we can just tip-toe away.. "

"All truth passes through three stages.
First, it is ridiculed.
Second, it is violently opposed.
Third, it is accepted as being self-evident."
Arthur Schopenhauer

I think we are somewhere near the end of violently opposed.. this recent paper:

. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73)

Seems to be a start of a possible paradigm shift. In a few years, I suspect that the medical community will start saying that LA increases CAD. Later, they will say it was obvious. It might even be entertaining to watch them walk backwards..

So how to definitively show the difference between SatFats and LA? There is a problem in that by some measures LA has a half-life in adipose tissue of 600-days - how long a study will it take to test this?

BUT! I think there is a way (NMR) to see the LA content of ones body fat - important as it is an objective measure (quite different than diet surveys). If we look at correlations with different disease processes - say CAD, obesity, PN(Peripheral Neuropathy), thyroid, depression/anxiety what will we find? My hunch is heads will spin.


There appears to be some papers the show a T4->T3 conversion effect from LA exposure.. :
LA Thyroid connection

Not to get lost in some high level stuff - but I remember somewhere that T3 effects the power of norepinephrine - and the sympathetic nervous system releases norepinephrine to effect adipose tissue. (Of course no one really knows if this effect is of a magnitude that makes it important etc etc.. )

But if we look at the inputs to adipose tissue - insulin, type of fatty-acid, auto-leptin control, etc - where in the world do autonomic nerves fit in? They are there for some reason? If we just stick with a single adipocyte don't we have to account for the effect of the nerves?

Zachary said...

Hey Peter,

Last time I wrote a comment here it was about my local university doing a "high fat study" (laughs) using tv dinners.

I was thrilled to find out you gave it a mention in a following post some months later after i'd forgot to check back in for a while. It really made me smile as this is easily my favorite place on the Internet.

This might sound a little gushy, but your collection of musings and especially your wonderful citations around have certainly changed my life in a very significant way. Now that I've learned more, I can't see myself changing my ways again. I'm much better now at analyzing research papers and I find myself now really enjoying looking them over even though i'm no scientist. This blog itself and where it's led my curiosity has been very educational.

It's a bit alienating sometimes, this way of eating, because it's so radical to people now. I'm slowly learning just to keep my mouth shut and be content with what it's done for me. I eat lots of fatty nutritious food with my dog and he also benefits from it. At this point we are practically sharing every meal together. Even my own family, despite seeing my health greatly improve, still is in denial. I get told "oh, you're just young" a lot.

It's a good good thing though. I am very thankful for this blog and what you have shared here.

Bob said...

"It's a bit alienating sometimes, this way of eating...I'm slowly learning just to keep my mouth shut..."

Hi, Zachary,

I very much relate to your comment and more of it than just the paragraph I quoted. There's no "like" button on this blog, but I certainly like and can relate to what you said.

My daughter works as a respiratory therapist. When I went low-carb seven years ago, she was infuriated. I couldn't discuss this way of eating with her at all. She figured I'd read "something on the internet" (thank you, Gary Taubes), and figured I'd sooner or later switch back to low fat. Not gonna happen.

Not, of course, that she would show any curiosity regarding what I read on the internet. I'd love to show her this blog. It's mind-blowing in a way few blogs on any subject are. And the cast of characters it attracts -- Karl, George Henderson, Stan (Heretic), Bill Lakagos, Wooo, Ash Simmonds, Tucker Goodrich, Gretchen, raphi, etc.. -- add so much to the discussion.

It's the closed-mindedness of most of the medical community, and the public which patronizes it, which is most disappointing. I think it will take this and maybe another generation to die off before generalized sanity will return to nutrition research, and the low fat way will be viewed as quaint medical history, on par with bleeding George Washington or challenging Edward Jenner.

Larcana said...

Thanks for another great post! I'm in the trenches... as a physician that eats very low carb/high fat and I am always reading labels for gluten due to Celiac Disease. But I get a lot of funny looks from my colleagues when they watch me eat at a drug rep dinner. They are still drinking the HFCS Kool-aid.
I try, with my patients, to change their diets so they can heal. BTW, I work in wound care and hyperbaric medicine and MAYBE the incidence of amputation is not that high but peripheral neuropathy is rampant, retinopathy and tooth loss as well.
So, quality of life suffers regardless of wound statistics.
LaurenRomeo, MD MS

cavenewt said...

Hey, what do you guys make of this study, and its several statements about recent research showing that saturated fat causes leaky gut?

"Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia"

Peter said...

I've gotten past caring what people think. I will order extra butter for my steak and no chips please. I would also agree that the more medically qualified a person is the more anti LC they tend to be. Not always, just mostly. Anyone who has survived medical school will be well aware that telling your prof in a viva anything other than what he wants to hear will result in re-sitting in the Autumn. By the time medics qualify they've given the correct answer so often they tend to believe it. Why bother checking? I occasionally wonder how folks like my wife and I got through vet school with the ability to think intact.

cavenewt, my response is "shrug". The implication is that endotoxin is a Bad Thing. That is a very open question. I'd be more excited if a massively high fat diet with minimal carbs was pro-inflammatory. Last time I checked my crp it was bottom of the scale...


George Henderson said...

@ Peter,

we are on the same page re: this first-phase insulin stuff, but I didn't know about the stearate (seems consistent with chocolate epidemiology BTW). The nicotinic-acid prepped rats show that the SFA/UFA balance determines phase 1/2; and of course a very low fat diet will give a sound SFA/UFA balance too.
All those paleo H-G diets with lots of UFA but a high 3/6 ratio can't be bad, but it seems tricky reverse engineering those with modern foods.
From most human feeding studies I get the idea that it takes a long time for excess UFA to deteriorate glycemic control. But we have a long time and no-one thinks that T2DM develops overnight (except in the fructose-drenched soft-drink ketosis model maybe). So it's easy for researchers to be deluded by the UFA = good paradigm into interpreting early changes as positive ones. Come back in 20 years time, maybe not so cool.

raphi said...

@Peter @GeorgeHenderson,

Last time i checked my CRP it was 0.7

What about the insulinogenic properties of dairy? Even the pasture-raised full-fat raw delicious kind, do we mind? I'm guessing not since it seems to arise from the particular mix of amino acids and not its carb content. Apparently glucagon is released alongside the insulin (in contrast to when insulin spikes are mainly carb-derived), which is a good thing apparently.

Do you think dairy's insulinogenic property is a valid concern for people finding weight loss difficult on LCHF?

Peter said...

George. Good, it's nice to have a similar outlook.

raphi, my feeling is that it's in the amount. I'm currently looking to get total protein below 60g/d. So most of my daily is cream... I've long thought that AA inputs to the TCA at oxaloacetate might be the blunting mechanism on ketosis but I've not tried to follow through whether this would suppress weight loss.


Peter said...

dairy, not daily! Damned autocorrect!

raphi said...


Gotcha, quantity - the insulin response might thus have more to do with the AA bolus, as dairy products are calorically dense.

The AA input into TCA is of particular interest to me currently as im designing my MSc thesis experiment on supposedly oxidative cancer cell lines...Im trying to parse how much of of mitochondrial contribution to total ATP turnover is from true OxPhos vs mitochondrial fermentation. There are big energy gaps to account for in the research as well as the 'missing oxygen' piece.

So there's what you mentioned 1) Asparagine & Aspartate entering @ oxaloacetate.....then there's also 2) Phenylalanine & Tyrosine entering @ Fumarate..... then 3) Isoleucine, Methionine, Threonine & Valine entering @ Succinyl-CoA.... & lastly 4) Glutamate => (derived from Glutamine, Arginine, Histidine or Proline) entering @ alpha-ketoglutarate.

One premise of the Mitochondrial Theory of cancer is that mitochondria are functioning differently that some might describe them as broken: the inputs aren't turned into ATP because of 1) uncoupling (& proton leak?) and 2) amino acid fermentation rather than OxPhos.

Yet when rotenone & other mitochondrial inhibitors are used to lower oxygen use, the cells produce very little ATP compared to before. The authors then conclude "yep, cancer cells have perfectly fine, respiring mitochondria".

I'm not so confident given that mitochondrial inhibitors hurt multiple complexes which could affect other non-respiring activities going on...what says you? What do you think I should look at to figure out the yes-respiring / no-respiring question?

Peter said...

A bit of thinking to do there raphi!


Passthecream said...

Raphi, not exactly what you're looking for but a few links to papers in that general area that I've stumbled over lately:

Passthecream said...

Raphi, not exactly what you're looking for but a few links to papers in that general area that I've stumbled over lately:

raphi said...


Thanks, I'm having a look at them now.

raphi said...


all great links. they contain many avenues i want to go down but cant, given the constraints of the 'simple' in vitro experiment im designing.

You seem to take 'old school' (aka proper) science to heart, so i'll ask you:

what is the simplest way to convince you cancer cells are or aren't using their mitochondria normally (aka respiring)?

Passthecream said...

Raphi, metabolism isn't my area unfortunately just a badly educated enthusiasm, but if i were to hazzard a guess I'd suggest the response of a cell culture under very tightly controlled conditions to forced steps in the various substrates taken one at a time, measuring the anticipated outputs. Straightaway that tells you that I'd prefer it if there was some sort of biological oscilloscope and signal generator available. I dont know if step-functions per se are explicitly used in biology much, probably implicitly only, but at the edge there is all sorts of interesting information. Oh and you'd compare the response of your culture to a supposedly healthy one.

I recall in the last chapter or tho of Powrer sex suicide etc, Nick Lane mentions a technique he developed to test mitochondrial health of organs pre-transplant. Might be worth a look.

I cant remember if any of those links I pasted mentioned citrate but that's another interesting line to follow in this area as an inhibitor of phosphofructokinase.


Passthecream said...

Ps monochromatic light (defocused lasers, leds) and absorbance spectra constitute another interesting and cheap bunch of techniques for probing cells.

raphi said...


Right, I'm trying to find the simplest & robust 'substrate => product' assay done in control & cancer cells in both normoxic & hypoxic conditions, with a 1-substrate change at a time (the 1 variable isolation shtick already discussed in the comments of previous posts).

I've started reading Nick Lane's "Vital Question" (better late than never, right??).

If yo want to suggest anything more please do by email, I'm raphi.inter[at]


Rattus said...

Tim Ferriss podcast with Dom D'Agostino. Dom talked about how his LDL went quite high when he ate 500,1000 surplus dairy calories a day. When he cut the dairy [sour cream/cream] intake in half and used coconut cream instead, his LDL went back down. Thoughts?

Peter said...

And lowering LDLc is good???????


Rattus said...

"Heavy cream, sour cream and butter in large amount increased my LDL (and LDL-p). Simply replacing the heavy cream with coconut cream and cutting my sour cream consumption in half (to 2 servings/day) caused the LDL to go back down."

I have 0 knowledge about the implications of having high LDL, but he viewed it as a bad sign. I'm assuming that you view his concern as unfounded, and that this is another example of dogma vs newer insights.

Also, since we are talking about dairy, I think my problems stemmed from whole dairy products [milk, cheese w. high lactose] raising insulin, and fermented dairy containing histamine. Sour cream = can't breathe. Normal cream = no probs.

Peter said...

Yes, people have their individual reactions to various foods. But I'm interested in the time point when the lipid hypothesis converted from complete bollocks, i.e. the 1950s, to something believable. I must have blinked!


Rattus said...

I just thought the dairy-insulin thing was interesting in the context of this post, as many people report trouble with sustaining weight loss when consuming full dairy on a keto diet. So, while the high sat. fat content might be generally beneficial, milk/cheese/yogurt might not be wholly beneficial in themselves on a HF-LC diet. So I think its important to distinguish between full dairy vs things like heavy cream/sour cream/double cream/cream cheese.

The podcast itself is interesting. He talks about taking 1g metformin/day, and pretty much all blood-markers improving except for testosterone, which dropped on metformin and returned to normal levels once he stopped taking it. He also talks a lot about exogenous ketone use, and studies he has done on rats using exogenous ketones to prevent seizures, etc. I'm sure all of this is old news. Kinda surprising that someone seemingly at the forefront of keto research would maintain an archaic view on LDL.