Impaired glycogenesis as driver of insulin resistance?

[Fruno]

This arose from a discussion with Peter@hyperlipid. I wondered what you make of it. It’s a wild idea, but with some science behind it. It references protons but you don’t have to know the theory. In fact, it’s pretty much an alternative theory why n-6 PUFAs make us fat on a high-carb diet, independent from protons.

Jason Fung points out that the assumption is weird that muscle cells become insulin resistant while other cells (like the ones in the liver producing triglycerides out of glucose, or lipid cells storing fat and not releasing it) remain apparently perfectly insulin sensitive, and I agree. He thinks that the cells are simply full of glucose, where I disagree. (After all, a few weeks of keto do not restore insulin sensitivity, while it certainly depletes glycogen stores.) But he still has a point that something doesn’t check out here.

My personal issue with the protons theory is that the RET happens in ATP production in the mitochondria, which is round the clock while food intake is time restricted. Most food has to be stored (glucose as glycogen or fat in chylomicrons) for some time. Now why are saturated fats immediately more satiating (no pun intended) as evidenced by protons, the croissant diet and https://doi.org/10.1038/nutd.2016.1 in a meal if the effects from the mitochondria should be spread out over many hours? Why would fatty acids with high F:N ratio (as per Peters protons theory) produce local insulin resistance at fat cells (or possibly liver cells, preventing triglyceride synthesis) but not affect muscle cells, causing slower glucose uptake?

We’re missing something here. And Fungs brilliant idea that the all cells are insulin sensitive but muscle cells simply don’t accept glucose for some other reason explains a LOT, if we find a solid explaination why the cells won’t accept glucose. And here it is:We replace Fungs assumption that the cells are crammed with glucose with the assumption that glycogenesis is hampered. (Lack of glycogenesis has been conjectured to be the fundamental mechanism of insulin resistance, https://www.ncbi.nlm.nih.gov/pubmed/18220643).

Obviously we have an intra-cell homeostasis that will convert extra glucose to glycogen, and glycogen to glucose if needed. Assume that we have a thrown a wrench in the spokes here, and only very high insulin and/or significantly higher glucose concentration will force glycogenesis. The effects would be exactly the ones we see in (pre)diabetics:

• Blood glucose rises, insulin rises. Eventually the high insulin levels will activate glycogenesis anyway, but until then the liver has converted a lot of the glucose to triglycerides already (because that pathway is not blocked). Sounds familiar? Most glucose goes to fat and is not available as energy.
• Insulin is remains high after glucose clearance, glycogen stores are almost empty, muscles need glucose (insulin blocks ketone production), we go hypo and need to eat again.
• Neoglucogenesis is probably running overtime but can’t satisfy the demand, because our body is not designed to run on glucose manufactured from protein with no ketones to help out. (That would explain why neoglucogenesis runs in overdrive for many diabetics.)
• This all fits. Glucose and triglycerides do their damage in the pancreas, and eventually we’ll have diabetes.
• For diabetics, insulin shots jumpstart glycogenesis and relieve the symptoms temporarily.
• It might explain the dawn effect, where the liver pumps some extra glycogen into the bloodstream (if I understand it correctly). If glycogen stores in the cells are low, we would see a spike of glucose if the liver attempts to jumpstart our muscle cells.

Now, why would glycogenesis specifically be hampered while other cells remain insulin sensitive? Enter n-6 PUFAs. Calcium (cAMP) blocks glycogenesis, and both linoleic acid and arachidonic acid mess with calcium in our body (https://www.ncbi.nlm.nih.gov/pubmed/18718873 - I admit I’m a bit fuzzy on this one). (But you’ve got to wonder if it affects artherosclerosis and calcification.)
Plus arachidonic acid activates our immune system and increases oxidative stress (https://iubmb.onlinelibrary.wiley.com/doi/full/10.1002/iub.1428) which could mess with ROS signalling. Could this be the reason why n-6 PUFAs block glycogenesis, while oleic acid and saturated fats don’t have this effect?
PUFAs will accumulate in our bodies with time in our fat tissue as per https://www.ncbi.nlm.nih.gov/pubmed/26567191, and it gets used as building blocks for cell membranes. So our body becomes a big PUFA store with time, boom! glucose metabolism is kaputt.

Thoughts?

[Keto6468]

I’m not a scientist but your explanation sounds convincing.
So eat in a ketogenic fashion, and avoid PUFAs.

[ctviggen]

After all, a few weeks of keto do not restore insulin sensitivity, while it certainly depletes glycogen stores.

Actually, keto does do that:

https://insight.jci.org/articles/view/128308

That one is not related to insulin sensitivity, but others are. In fact, keto is GREAT for reducing the main sources of insulin resistances, fatty liver and fatty pancreas.

[ctviggen]

It might explain the dawn effect, where the liver pumps some extra glycogen into the bloodstream (if I understand it correctly).

I think it works differently. The liver is always pumping out glucose (at least if we’re in ketosis) at some level. The body becomes more insulin resistant in the morning, meaning the glucose level rises. (Though some define this as insulin sensitivity, which doesn’t make sense to me.)

[Fruno]

After all, a few weeks of keto do not restore insulin sensitivity, while it certainly depletes glycogen stores.

Actually, keto does do that:

https://insight.jci.org/articles/view/128308

That one is not related to insulin sensitivity, but others are. In fact, keto is GREAT for reducing the main sources of insulin resistances, fatty liver and fatty pancreas.

No, keto eliminates only some symptoms but not insulin response. The insulin response (Kraft pattern) and the fasting insulin (or HOMA-IR) may take years to normalize. But it certainly depends on how far one was gone.

[Fruno]

I think it works differently. The liver is always pumping out glucose (at least if we’re in ketosis) at some level. The body becomes more insulin resistant in the morning, meaning the glucose level rises.

Um, do we have any biochemical reasoning for this assumed insulin resistance? Sounds to me as if this is just a conclusion from the fact that we see higher glucose levels, which would be circular reasoning in this case. After all the whole thing is based on the assumption that insulin works, that is, glucose can enter the cells. It’s just that it’s not converted to glycogen so the cells won’t store glucose.

Note that all that I have described assumes that we’re not in ketosis, but on a high carb diet.

After all, a few weeks of keto do not restore insulin sensitivity, while it certainly depletes glycogen stores.

Actually, keto does do that:

All the results from that study fit my theory, actually. Metabolic syndrome is caused by hyperinsulinemia, eating low carb cuts down insulin, issue solved. What’s not changed quickly is the insulin reaction to carbs, if we reintroduce carbs. Along with that goes fasting insulin and HOMA-IR.

Unfortunately we don’t have a ton of data on this one. Maybe I can find a study that includes the relevant data in the supplements (HOMA-IR not only before and after the intervention, but also at intermediate points), but the issue is: We have to separate the effects of keto from the long-term insulin response. If we go keto, insulin (and often fasting glucose) goes down quickly and so is HOMA-IR. But fasting insulin and HOMA-IR don’t return to normal levels (0.6-ish), and it may take years of keto and fasting/OMAD to normalize it. My HOMA-IR was 1.7 after several months of strict keto, last time I measured. And we have no clue what happens to the Kraft patterns, because this would require the patient to “carb up” (go to a medium-carb diet for a week or so) and then have insulin response to a glucose drink measuered. I don’t think this has ever been done. But if HOMA is significantly elevated, I’d expect Kraft patterns to be abnormal too.

And the assumption that PUFAs are responsible for hyperinsulinemia (both fasting insulin and postprandial insulin) corresponds very nicely to that. If we go keto and stop eating n-6 PUFAs, it will certainly take a very long time until their concentration in body fat drops, aided of course by weight loss. And this could exactly be the reason why common knowledge is “as long as you’re losing weight your blood values will be wonky”: As long as we’re losing weight we’ll burn a lot of n-6 PUFAs stored in our lipid cells. For someone who’s seriously obese, of course it will be years until we see a stabilization.

I’m not saying that this is the one and only truth. In fact this theory started out as a “think of 7 different theories before breakfast” exercise, where I wouldn’t expect anything to come out of that. However, after thinking it through a bit more I’m still very surprised how many observations fall line up with that theory (observations that can’t be explained with the CIM alone), and so far I have yet to find something that contradicts my theory.

That one is not related to insulin sensitivity, but others are. In fact, keto is GREAT for reducing the main sources of insulin resistances, fatty liver and fatty pancreas.

Again, show me the causality. Both are associated with IR, but why would they cause it, on a biochemical level? I think both are consequences of hyperinsulinemia (which causes high triglycerides), which is exactly the reverse causality.

And again, my theory is that we’re not insulin resistant at all. This may sound technical, but think of it like this: A muscle cell is a bag that stores glycogen and has a lock, insulin is the key, and glucose is whatever goes in the bag. Insulin resistance assumes that the key does not work, even though the bag has room. My theory assumes that the key is just fine but the bag has no room for glucose.

[atomicspacebunny]

Thoughts?

PUFA’s in natural Whole Foods will do no harm what so ever, it is when you apply lots of heat to it, then make foods with it and put in bottles is when it starts missing electrons?

The PUFA hysteria is way over-rated?

No matter what you eat, it will have PUFA’s, the better question is; are your PUFA’s heated, rancid, oxidized i.e. missing electrons it once had before you eat it?

I could get all my dietary fat on a ketogenic diet with bottled PUFA’s, partially hydrogenated or fully hydrogenated fat sterols and still be keto and lose body fat, people have been doing it for years on a ketogenic diet, so that kind of kills all that unnecessary PUFA hysteria and ridiculous theories that have no place in reality…lol

It is when you add lots of sugar to all of the above that causes the real problem?

When you have people waving there arms in the air and running around in little circles in hysteria proclaiming “OMG it’s the PUFA’s;” that could lead to malnutrition because they will start eliminating foods that have essential nutrients and PUFA’s are one of them?

[Fruno]

I could get all my dietary fat on a ketogenic diet with bottled PUFA’s, partially hydrogenated or fully hydrogenated fat sterols and still be keto and lose body fat, people have been doing it for years on a ketogenic diet, so that kind of kills all that unnecessary PUFA hysteria and ridiculous theories that have no place in reality…lol

Because weight loss is the one and only criteria for a healthy diet, right. Might be more healthy too fast forever, then?

Knock yourself out with n-6 PUFAs. For some dumb reason I feel that I should point out that it has been done with rats, who were fed a ketogenic diet very high in linoleic acid, resulting in a much higher rate of cancer (and the inevitable headline “keto causes cancer” because this was keto, right?).

When you have people waving there arms in the air and running around in little circles in hysteria proclaiming “OMG it’s the PUFA’s;”

Clearly there has been no change in n-6 fatty acid consumption. I guess this is fake news then.

[atomicspacebunny]

Some how the low sugar ketogenic diet has been transformed into a “…don’t eat that type of fat diet…?“ bottom line it is still a long chained fatty acid and does not matter.

Give me any substance on earth and I will show you it causes cancer in a lab animal when you feed it supra-physiological high doses of any substance that has been highly concentrated? Just add lots of sugar (carbohydrates) to that mouse chow along with it and mouse gets cancer?

Strangely enough Vitamin C can kill cancer in supra-physiologic or highly-concentrated doses because the cancer thinks it’s sugar, but vitamin C is an oxidant to cancer cells and creates apoptosis cell death of the cancer cell without killing you?

Structurally Vitamin C and sugar share the same molecular bonds with slight differences, so I guess the human body thinks sugar is vitamin C? Cancer also thinks Vitamin C is sugar?

[Fruno]

Some how the low sugar ketogenic diet has been transformed into a “…don’t eat that type of fat diet…?“ bottom line it is still a long chained fatty acid and does not matter.

This subforum is called “Show me the science”. Perhaps you’d like to give some kind of evidence that n-6 PUFAs are healthy. Pretty much every keto-supporting doctor I know cautions against n-6 PUFAs. I have given some links supporting that. Some doctors use the word poison, and I happen to agree.

Apart from that… Charcoal, potassium nitrate and sulfur form black gunpowder. Would you conclude that charcoal is evil and the other two are good, because eliminating charcoal will make the mixture non-explosive?

I happen to believe that it’s necessary to understand how a disease progresses, why we have symptoms. Sugar/carbs alone can’t explain why we saw a sharp increase in obesity and diabetes since the late 70s.

[atomicspacebunny]

So you think that PUFA’s are the root of all evil?

Do you have any idea what kind of variables you are talking about to narrow something down to a omega 6 without taking into consideration the millions of other factors?

Again I could take any substance on earth and describe how that is really the cause and the root of all evil and make it look bad so I can sell you my new book? When there 100 other books that will contradict it? Not only that, it is so unbelievably easy to manipulate research and study variables that you end up with endless contradictory paradoxes to keep the observer confused and on top of that you have placebo and little boys and girls in adult bodies wearing lab coats who are still playing with there script kiddi chemistry sets who think they are scientists. And additionally most of these idiots who think they are scientists cannot even duplicate there own research and then your going to show me there pseudo-science papers that tell me omega 6’s are bad for you, I think NOT!

[Fruno]

So you think that PUFA’s are the root of all evil?

Of course not. I never said that.
What I said is that too much n-6 PUFAs will make you sick. Obviously there are plenty of other ways to get sick, including (but not limited to) too much carbs/sugar, even though this takes slightly longer than swallowing cyanide
And obviously n-6 PUFAs are essential, but they (as most other nutrients) have a U-shaped optimal curve, so the dosage makes the toxins.

The thing is, we ate a lot of carbs and didn’t get (as) fat in the 60s. We ate just as much sugar in 1980 as we do today. There are plenty of examples where civilizations on high-carb diets were typically lean and healthy (see “french paradox”, the Kitavans, or some japanese cultures before they introduced crappy food there). So, it’s not only carbs. You can eat high carb and not get sick, even though these examples are few and mostly historic. What is it, then? And if it’s not only carbs, can it make us sick even if we go low carb? Why were the french people around 1970 so lean that it’s hard to even find numbers for obesity, while the people in Kuwait today eat almost the same mix of macros (including sugar!) and are among the most obese and diabetic people in the world? The difference of course is that the french ate butter and cheese, while vegetable oils dominate in Kuwait.

One popular exercise is to point out what healthy cultures (like the ones considered in the blue zones) didn’t eat (because what they actually ate was very, very different and no one can make out a pattern). Taubes/Lustig point out that they don’t eat sugar. Gundry says they don’t eat lectins. They certainly didn’t eat emulsifiers and artificial flavors, but they didn’t eat a lot of n-6 PUFAs either (because they all eat traditional diets that don’t contain oils from any grains). So why would you focus on the sugar (alone) and not on the other ones?

My personal opinion is that n-6 PUFAs are bad if consumed in large quantities even if you go keto. And that n-6 PUFAs and high carb together are very, very toxic for us, way more than just high carb or high n-6 PUFA alone. We might not have an diabetes/obesity epidemic today if we would stick to butter instead of soy and corn oil.

BTW, if you look for them, you’ll find plenty of studies that conclude that ketogenic or low carb diets are unhealthy. If you dig deeper and see what exactly they fed to the subjects (animals and/or humans) on these diets, you’ll find that – if they are really low carb (idiot like Guyenet or Katz cite studies where 40% carbs is considered “low carb”) and the endpoints weren’t bs targets like artificially low cholesterol – they were invariably high in “heart healthy” n-6 PUFAs.