Tuesday, August 02, 2022

Choose your insulin sensitivity well

People may or may not realise that I dislike meta-analysis. In the words of the great Malcolm Kendrick "One, two, skip a few, 99, one hundred". Or one of my uni lecturers, "The meta-analysis of dross is still dross". On a practical basis they just provide information overload to give a result determined by the selection criteria from which the individual results threads can be hard to extract.

So this is not one of my go-to type studies but, because it confirms my biases, I'll cite it here

which came up on a twitter feed of Tucker's.

The study looked at isocaloric replacement of 5% of carbohydrate calories with various fats or changing the number of double bonds in 5% of calories using various fatty acid substitutions under controlled conditions.

The important result of this data trawl is this, extracted here from Table 2

I think it is quite clear that particularly replacing saturated fat with PUFA (mostly linoleic acid) decreases insulin resistance. The more double bonds added, the greater the insulin resistance reduction.

That's good, right? We all want to be insulin sensitive, right?

So if I give you these HOMA scores, from a different study, which of the groups would you like to belong to?

Before you choose you might want to ask what the difference is between the groups. This is the original table from

Insulin sensitivity is increased and fat oxidation after a high-fat meal is reduced in normal-weight healthy men with strong familial predisposition to overweight

which I've mentioned previously.

OK. Choose your parents wisely.

Statistically, if both of your parents are obese, you are in a bad place for staying slim. You are very likely to be MORE insulin sensitive (p less than 0.05) than your luckier mates with skinny parents. Personally I think genes have very little to do with obesity. Learning your food habits at your parents' knee has a very much larger influence on your future waistline.

How much linoleic acid to you have to add to your diet to lower your HOMA-IR score from 1.6 (ie normal) down to 1.1 (going to end up like your overweight parents)?

I don't know for a human but for a mouse it's generally enough to increase LA from around 4% of calories to something over 6% of calories that gets the job done.

Any hypothesis of obesity has to be able to account for the above data. EBM or CIM.



raphi said...

is it:

linoleic acid => increased adipocyte fat storage => less fatty acid oxidation => glucose oxidation increases to compensate => increased glucose clearance ?

Peter said...

Yes, the rest of the paper goes on to look at lipid/glucose oxidation and for these pre-obese people then glucose oxidation predominates after a meal. The fat can't be oxidised as it is probably rapidly sequestered in to adipocytes. Or any other cell which will take it.

This is in stark contrast to established obesity where fatty acid oxidation predominates and glucose oxidation is suppressed. Because large adipocytes -> high basal lipolysis which cannot be suppressed by insulin so high glucose and fat oxidation together require adaptive insulin resistance with decreased glucose oxidation, aka correctly dealing with reductive stress...


karl said...

I've been looking at fructose again - I know it gets converted rapidly in the liver to fatty-acid - then assembled into trygly. What I'm having trouble finding is which fatty acid?

I know that excess glucose forms saturated C16(palmitic acid) - but I'm having trouble verifying that is the same case with fructose?

In the mean time - fructose is not the same as glucose when we get to the mitochondria:


I'm reminded of the studies that showed consumption of fructose-sugars before a meal increased the amount people eat. I think that is true. There are narratives about leptin - not sure it is that simple - many things are effected at the same time.

As time goes by, I see that this science is much to full of hubris - needs to be much more humble - a lot of the things 'medical science' 'knows' are really ungrounded speculation. It is as if the prime job of science, to prove itself wrong, has been forgotten. Anyway, I continue to grow MUCH less accepting of what is considered settled science than I was when I was younger.

The reality is that financial interests nudge the theories/narratives much more than the public is aware of. Financial interests nudge even honest scientists - disclosure will not cure the bias.

Looking at the history of medicine - the observation of supper low cancer rates in undeveloped people (even if they ate lots of carbs) - the concerns that arose in the 1800 of the increasing cancer rates has me working with the idea that excess fructose is a carcinogen. (I can come up with several ways to explain the effect - mitochondria dysfunction, blocking leptin, liver health ..etc.. ).

I think that we need to guard against thinking that sugar is equal to carbs. Fructose matters - does it matter as much as seed-oil? Or is it the combination that makes both so destructive?

Fructose containing sweeteners are an industry - the money always nudges the science.

In the time of Columbus, an ounce of gold would buy only 40LBs of sugar - now sugar is so cheap it is standard to add it to food to increase sales.

Peter said...

karl, fructose seems quite complicated to me!


Eric said...

Rob Lustig's talk "Sugar the bitter truth"

It explains the metabolism of fructose on the Krebs cycle and even has something about small and large LDL.

cavenewt said...

@karl: "It is as if the prime job of science, to prove itself wrong, has been forgotten."

That's the basis of so many problems today, in a nutshell. Might be good bumper sticker material…

On another subject, the only sweetener I use at all is raw local honey to make kombucha. I do let it ferment till it's not sweet at all, more beery in flavor. I figure honey has some other good ingredients that might remain after fermentation, unlike sugar. The kombucha bugs seem to like honey just as much as white sugar. But if anybody knows more about this process, I'd be interested.

karl said...

@Peter who said "..fructose seems quite complicated.."

Yes, yet there seems to be this pattern of lumping it with glucose. Fructose goes down quite different pathways.

You will see lots of mice papers on fructose - but it is important to remember that mice lie - and lab mice in particular (modified telomere length).

My grandmother on my father's side, used less than 5LB of sugar in a year - today's average is 60LB( I don't think that includes HFCS?).
@ Eric
Lustig talks about JNK1 - which is related to causing insulin resistance in the liver.

He also talks about the leptin effect which would explain the excess consumption studies I mentioned above.

I'm reminded of the baby formula shortage - wonder if it will show up as a period of healthier babies - full of fructose sugars and LA.. just not human food. (They are seeing obese 6mo old babies these days)..

What I don't know is if there is an effect on the fatty-acid produced in de novo lipogenesis - and just what it does to the mitochondria - protons? etc..

karl said...

Forgot this link:

Passthecream said...

Oh boy, another trick question ..

Richard Feinman wrote a good essay about Meta-analysis: "Meta-analysis is to analysis as meta-physics is to physics"


karl said...


Meta studies are mostly the part of the degree-mill where people can publish - get their degree without doing a real study.

You really have to look at each study alone - combining studies that are 'sort of the same' is not very useful. Might point to a place to do a real study - but that is not how they are used.

The number of papers that are meta-studies has exploded over time. Data mining finds spurious correlations.


Lustig is on the right track - not sure all his conclusions are correct. I would like to see him comment on the protons issue.. His heart is in the right place.

karl said...

I'm thinking about something Lustig said and bits I've seen in other papers. Just the taste of sweet seems to cause the release of insulin, even thinking about sweet does something similar.
Lustig thinks that changes some balance - I'm not so sure he is correct. High insulin itself seems to do damage - but We also know that insulin is constantly high in people that are overweight and/or T2D - is the insulin level a cause or effect? Arrows of causation seem to be assumed all over the place in metabolism.. we need to be more careful.

The half life of insulin is very short - 4–6 minutes and the body has other control loops that also control insulin. And it isn't insulin alone that matters - instead it is the combination of insulin and insulin sensitivity. If insulin signals without the sugar - BG would go down and other control loops would step in.

So I'm thinking the addiction is in the brain instead ( I have vivid memories of eating sugar foods when I was a child - not eating bread - but only sugar - so I suspect some fructose brain interaction. It appears that we know that the brain produces fructose from glucose -
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313070/ (why?) and there is some emerging effects of fructose on the Brain:

) .

But back to T2D - My hunch is fructose is doing some sort of damage(MT?) - possibly permanent damage - which can cause cancer - and T2D - I'm suspecting some sort of genetic damage to MT-DNA - remembering the idea that our immune system gives the signal to cells to self-destruct - and it is the MT that make it happen - if the MT are faulty - they don't do the job - and cancer growth is the result. What if damage to MT-DNA is also causing changes in insulin sensitivity?

Fructose causes a spike in trygl - and we currently think that that can block leptin - a possible explanation for over eating when exposed to fructose.

Now add in LA - which inappropriately increases insulin sensitivity - Remembering that the Liver becomes insulin resistant first, muscles second, adipocytes last - again points to the liver/fructose effect. Could it be that the liver has to be first to avoid fatty liver disease? (T2D looks like fatty liver disease - what was once something just seen from ethanol consumption - but fructose rides the same track. )

What if eating fructose and concentrated seed oils exposes us to conditions quite unlike what we evolved for?

Fructose has other effects that

cavenewt said...


"What if eating fructose and concentrated seed oils exposes us to conditions quite unlike what we evolved for?"

Pretty sure you could delete "what if" from the beginning of that sentence. Further, we could Douglas-Adamsize the end of the sentence to "...conditions almost, but not quite entirely unlike what we evolved for?"

Interesting that we can convert glucose into fructose. That would be for a reason. I'm with you on wondering why.

Passthecream said...

When I spent some time looking at the various pathways that fructose is meshed with I found it turning up in all sorts of surprising places which probably recapitulates our long evolutionary history from small furry blue fructivores to where we are now with many adaptations, de-adaptations, re-adaptations and so on but I think I read that as things currently stand the majority of it gets turned into palmitic acid in the digestive tracts. I think complications arise as you suggest but specifically wrt sucrose, ie fructose plus glucose, when combined with pufa. I don't think we've had time to adapt to that combination yet, its just too much.

CN a new film suggestion: Adamsize Me.

raphi said...

hey @cavenewt, i noticed your Leela from Futurama profile picture and thought I'd mention that the 4 month old kitten I just got is called Leela :)

cavenewt said...

Casting about for a reply to your post, I suddenly realized why Leela said she can't parallel park. With only one eye she has no depth perception. My estimation of her driving has just gone up.

Your Leela, even though blessed with binocular vision, unfortunately is lacking opposable thumbs, which would make parallel parking very difficult. Unless she's got the polydactyly variation that takes the form of two big thumbs, as did one of my cats.

karl said...

OK - if the liver is key (first place to get insulin resistant). Suppose the healthy liver-cell is doing fine - if it needs more glucose, it gets more insulin sensitive and vs versa.

But then, large doses of fructose is eaten - it goes down the metabolic pathway to produce fat-acid- the fat turns off insulin sensitivity - the liver tries to package up the fatty-acids and dump trigly to the blood stream - if it can't keep up you get fatty liver.

The high trygly appear to mess up appetite control by blocking leptin at the blood brain barrier.

This is not at all the same as what happens with starch(all glucose) consumption.

So lets say someone eats an excess of fructose for 10 years - once they gain weight, insulin is going to be chronically high. Bad things start happening.

But what if packing the liver with fat causes damage so that the system can never correct, even if the diet is corrected?

The exposure of fructose in mitochondria is thought to cause oxidative stress - which might explain the cancer risk that I think fructose likely causes.

This same stress might well damage parts of the control look.

Addiction - I'm wondering if the seeking of sugar foods is innate or a learned response?

This seems interesting:

karl said...

Just changed my mind on artificial sweeteners..

The first studies showed a release of insulin from the taste that I figured didn't matter, but there is a study, three groups - one with artificial drinks, one with milk, one with water. The water group did the best - but the milk group did MUCH better than the ones with the sweetened drinks. I would still say that artificial sweeteners are better for you than sugar - but still messing with your insulin system - something to be avoided - not a fix for the addiction.

So, likely the insulin release is causing more fat storage - (insulin first job is not BG levels - it controls fat storage!).

So my take is fructose is a huge problem, Sweets a second problem - and PUFA in adipose tissue causing inappropriate insulin sensitivity creates a perfect storm - and why so many are dying early.

It is important to note that life expectancy is falling in the West - All the drugs and all procedures if they were effective would be extending life. This is a self inflicted pandemic and public medicine has not just failed - they appear to be making things worse.

Giving people the idea that they can just take a pill to fix things is spreading harm.

Passthecream said...

Karl "But then, large doses of fructose is eaten - it goes down the metabolic pathway to produce fat-acid- the fat turns off insulin sensitivity"

I don't see that as being much different to just consuming the fat directly.

However this might be more relevant:

" Fructose induces gluconeogenesis and lipogenesis through a SIRT1-dependent mechanism. Consumption of a fructose-rich diet leads to insulin resistance and dyslipidemia in part due to elevated gluconeogenesis and lipogenesis. SIRT1, an NAD+-dependent protein deacetylase, can induce gluconeogenesis and lipogenesis."


A messy link but it seems to get there.

Lipogenesis, yes, but it is the right type of lipid and as per Protons gives rise to appropriate insulin resistance. Gluconeogenesis is the sleeping dragon. I think insulin resistance plus gluconeogenesis lies at the heart of metabolic syndrome. Excessive sucrose intake, giving those fructose effects plus high glucose intake as well seems like a perfect way to get there. Add to that a significant intake of pufa and you could be heading beyond metsyn towards metabolic hell.

The paper you linked is interesting, shows the huge range of possible effects related to high fructose intake. But this line from the abstract was a bit startling " Starch and sucrose metabolism in muscle was also disrupted." I didn't have time to read the diet/methods section but from that give-away I know what I'll find. I also suspect their 'multiomics' approach involving principal component analysis etc might be similar to meta-analysis. (Pca reminds me of the Eysenck debacle.)

That's an interesting possibility, a study which performs meta-analysis on itself.

The higher you get, the fewer.

Eric said...

Totally off topic, but maybe worth a post by Peter?


This particular study seems to have shown a dramatic protection against Covid infection in type 1 diabetics who are more prone to infections (why? higher average glucose level?). The NYT article does not say when (i.e. during Delta, Omicron, etc.?) those infections did not happen or whether the participants ever received a Covid vaccine.

Other studies (using other strains of tbc bacteria) did not show such a strong effect or at all.

Still, it seems puzzling that a random attenuated bacterium should give you substantial immunity against viruses.

Eric said...


"So, likely the insulin release is causing more fat storage - (insulin first job is not BG levels - it controls fat storage!).

So my take is fructose is a huge problem, Sweets a second problem - and PUFA in adipose tissue causing inappropriate insulin sensitivity creates a perfect storm - and why so many are dying ear"

I'm mostly with you but I don't see how insulin would trigger an insulin response - unless it gets converted to glucose, that is.

cavenewt said...

A little OT, on the history of Austrian vegetarians.


cavenewt said...

This is nutrition-adjacent. Here's an interview transcript with our not-favorite Dr. David Katz, which has some surprisingly thoughtful observations about the pandemic; the interview is early, April 2020, before we really knew what to expect.

But the reason I am offering this is for the very last question and his answer, which is about the obesity pandemic and how people tend to not notice slow motion dangers, versus the acute pandemic of coronavirus and how we're freaking out about it.

He goes into more depth about some of that earlier on in the interview, which you might find interesting, but at least read the last question and answer.

The entire series "perspectives on the pandemic" seems worthwhile; they interviewed one of my personal favorites, Dr. John Ioannidis, more than once. Episode 1 was with him and it has been pulled from YouTube.


karl said...

Just started reading Nick Lanes new book:

'Transformer: The Deep Chemistry of Life and Death'

It is about the Krebs cycle - mitochondria - aging - origin of life etc.

For me - as an old biology nerd - it is excellent - a treat.. I think Lane is the best science writer of our time - and that he is writing about this topic puts it off the charts.

I started reading the intro - sort of a rehash about how biology works - nothing new for me - but worth reading if only because Lane writes so damned well.

I've read all of his other books - the first one I read was 'Oxygen: the molecule that changed the world' - thought it would be a good one to read as I went to sleep - boring enough to induce sleep - totally surprised that it was a 'page-turner' - couldn't put it down - didn't sleep well until I finished it.

Fuctose is NOT the same as eating fats - it produces FFA in the liver - causes NAFL - high-fat/low-carb diets don't do that. It appears that only some of the FFA gets packaged up as trygly and excreted. - But - while there are more papers out about fructose, too many of them are poor quality - it is as if there is an invisible-hand that keeps academia from doing good science. We need some good papers focused on the effects of fructose on the MT - some reasons why cancer-cell lines grow so well in fructose media.. Way more questions than answers.

karl said...

FFA is not the same as eating fat. Fats don't cause NAFLD

Thinking about fructose - I was concerned that feeding sugar to humming birds might do them harm - looks like they manage where humans fail:


High Fructose diets are for humming birds - not for humans.

Krissie said...

Karl and Passthecream, Cavenewt said:

Interesting that we can convert glucose into fructose. That would be for a reason. I'm with you on wondering why.

If you (all) haven't listed to both Dr. Richard Johnson's interviews with Peter Attia, he is the researcher who has a sound theory to answer this question. His team also discovered the full pathway of fructose metabolism fairly recently - he is fantastic to listen to, but his main method of communication is papers - he publishes prolifically.

He talks about when human ancestors left hot Africa - the only survivors were the ones who had fructose stores that allowed them to make it through scarce cold weather. Also, there is a tribe in South America who don't metabolise fructose and they have zero T2diabetes no matter how much sugar they eat.

Thank you, Peter, for continuing to blog!!
Once in a while I think about the post where you fed youe veg to the chickens and it still makes me laugh out loud.

Captain Sunset said...

Where'd he go? Who? Him!

Monica said...

It's been more than 3 months, Peter, are you okay? And how about everyone else? This blog used to be very active....

Monica said...

Hi Peter,
It's been a very long time since you posted; are you okay?

Monica said...

Hi Peter,
It's been a long time; are you okay?

Monica said...

Hi Peter,
It's been a long time; are you okay?

Richard B said...

Sad to see the posting rate dropping off on your brilliant channel Peter. I guess it's almost job done. I have been reading you avidly for over a decade now, still love to see what you have to say.