Thursday, November 26, 2020

Podcast with Dr Paul Saladino (2)

Part two is up, mostly about the glycerophosphate shuttle...


Peter

26 comments:

davemoriarty2 said...

Hi Peter,

If one is lean but has autoimmune issues, would carbs also be a no-go for them? Or is it only related to obese/not obese.

And secondly, I was wondering if you've looked into Grant Genereux's theory of Vitamin A toxicity that's been gaining some traction. I have Undif. connective tissue disease and skin problems and am torn between keto/carnivory and cutting out Vitamin A. This has been the most scary period of my life.

Thank you so much,
Dave

Peter said...

Hi Dave,

People have mentioned vit A toxicity in comments but I've not had the time to chase it, so no opinion on that one.

Overall my feeling is that auto immune diseases are primarily (but not always) gut related.

Given the slow option of vit A depletion (I'm assuming that this is a long term project) vs the almost immediate anti inflammatory effect of ketosis (NRPL3 inflammasome etc) the latter seems an easy option. Also assuming the easiest route for plants to assist their seeds through the gut of an animal is to do just enough damage to speed transit w/o killing the transport animal. That gut damage seems a good way for allowing the immune system to "see" the intestinal contents, which are foreign. Plants really do hate you. All you need is an antibody to a gut antigen to cross react with collagen and you have a collagen autoimmune disease. Leucocytes with the HLAB27 receptor "see" the pullulonase enzyme produced by klebsiella in the gut. The antibody to pullulonase cross reacts with a subtype of collagen in your spine. We call that auto immune disease ankylosing spondylitis...

Peter

davemoriarty2 said...

Thanks so much for the response.

I'm going to go keto, maybe almost carnivore, but considering keeping some plants if possible. Casein is likely out, as is starch, but maybe I can get away with some berries, eggs, butter even. Maybe a few non-nightshade vegetables. Not sure.
Things like dark chocolate and coffee just intuitively seem harder on the gut than berries and veggies like cucumber, but that's pure laymen's observation, and not science obviously.

Bob said...

Dave said, "Things like dark chocolate and coffee just intuitively seem harder on the gut than berries and veggies like cucumber..."

Hi, Dave. I realize you qualified the statement (and I'm also layman here), but I'm curious; why "intuitively"?

My experience was that my gut improved when I stopped eating so many leaves, and the later addition of dark chocolate didn't seem to have the same modest laxative effect.

davemoriarty2 said...

Bob,

I don't really have a great rationale. Chocolate is pretty bitter and hard, whereas leaves are soft, but again this is no reason for one over the other. Wheat is soft and fluffy but wreaks havoc. Leaves aren't really food though.

Galina l. said...

@davemoriarty, yes carnivere diet is the way to go for somebody who has an autoimmune condition regardless of one's weight. Dr. Csaba Tott (PKD) insists on eating organs while eating diet based mostly on animal fat and meat

Galina l. said...

As an allergic I can tell that chocolate and even most berries are no go - especially strawberries and raspberries, you can eat eggs but after 3-6 weeks of carnivore and a gut recovery

Basti said...

Hi Peter,
Whats your opinion on CoQ 10 supplements?
First question, do they really increase CoQ levels in mitochondria, and 2nd if they do, wouldn't an increase in CoQ in the mitos prevent ROS production, aka cause pathological insulin sensitivity and thus far gain?

Peter said...

Hi Basti,

I think what goes in to your mitochondria is very, very tightly controlled. If you are depleted of CoQ by blocking the synthesis pathway with a statin then I guess the mitochondria might be very glad to accept a new supply. If replete perhaps less so. It will be very tightly controlled.

There is at least one mitochondrial targeted antioxidant, SkQ1 developed by Skulachev's group, which delays ageing in all species tested, up to mice. There are no weights reported but if you look at

http://protein.bio.msu.ru/biokhimiya/contents/v73/pdf/bcm_1329.pdf

the final image at Fig 13 is of two aged mice, one on SkQ1, and it is neither obese nor old at 600-odd days. You have to bear in mind that while ROS undoubtedly control insulin signalling they also control the production of superoxide dismutase and catalase. I suspect this might be where the benefits of high saturated fat diet derived ROS might come from. Coupled with normal adipocyte physiology of course.

Peter

Marius said...

Hi Peter,
a bit of topic (but maybe not really). I have a question regarding life and cancer.
My thinking has come to where I consider early life to be something like a concentrated, fast flowing current of molecules and energy. Self sustaining and self correcting patterns emerge over time and populate the land of possible biochemistry. The main difference between single celled organisms and multi celled organisms then seems to be the emergence of a tight control of energy throughput which allows for cooperation instead of competition. I envision it something like a dam, holding back and regulating the entry of available energy into individual cells as needed. Your proton-thread seems to spell out the the biochemical heart of the matter.
In the case of cancer this regulation system and therefore the basis of what is in effect non-proliferation for the benefit of others and ultimately the same cell since it still depends on the other cells seems to have broken down. Like water rushing through a broken dam, energy throughput is no longer restrained with all the proliferative consequences this brings with it.
I would like to hear your thoughts on the validity of this thinking.
Thank you,
Marius

Luke said...

Hi Peter, i dont quite understand what seems to be a key part in the protons concept:
why is it fat tissue which is preferentially targeted by insulin resistance created by sat FA? There are cells of way faster metabolism that burn through way more fat (eg the heart) and thus should become IR sooner..  in fact i would say almost all lean tissue burn more fat than adipocytes do.. 
The theory goes, that adipocytes become IR first so you dont lose kcal into adipocytes thus more are remaining for the lean tissue to feast on it... right?..
But wouldnt you expect the opposite to be true? The cells burning the most fat, aka the lean tissue becoming IR first thus reducing their uptake of energy leaving more for the adipocytes..?
Whats my mistake in logic here?
Im confused

Johannes said...

i just finished listening to the podcast and found something kind of confusing:
First you explain that inhibition of mtG3Pdh DECREASES insulin signaling and for example you explain why this might also be the reason metformin can be used for cancer.

But then you show that mtG3Pdh knockout mice (which is basically total inhibition) die of hypoglycemia because they are not able to generate insulin resistance. Thus, this shows that mtG3Pdh inhibition has INCREASED insulin signaling!! (due to the inability to generate IR).
The same was shown in the other study with the rodents on metforming. Those on metformin had lowered blood glucose after insulin injection... again, you explained, due to the inability to generate insulin resistance (aka INCREASED insulin signaling)

So now i am confused .. what does inhibition of mtG3Pdh do? Increase or decrease insulin signaling?

Peter said...

HI Johannes,

Not sure quite where to add this in, it occurred to me later: fatal hypoglycaemia with metformin is a serious risk when using exogenous injected insulin (or oral sulpha drugs). Endogenous insulin is reduced by both reduced pancreatic secretion and also reduced secondary to lower hepatic glucose output. Interestingly metformin has almost zero or actual zero effect on the blood glucose levels of non-insulin resistant individuals. The combination of actions appears to target pathological insulin resistance. Anyway, here’s this mornings initial thoughts:

Metformin is a very tricky drug. I consider it to reduce the peak generation of ROS which are produced secondary to insulin’s activation of the PDH complex which activates the glycerophosphate shuttle. That ought to allow more insulin signalling and more fat storage, much as the PUFA do.

Metformin also shares the ability to suppress the output of insulin from the pancreas (which is ROS facilitated), also a feature shared with PUFA. Which ought to produce hyperglycaemia.

But this is offset by a direct reduction in glucose output from the liver due to decreased gluconeogenesis from glycerol and lactate. This is not ROS dependent, merely driven by the redox status change of the hepatocytes due to blunted mtG-3Pdh action. This is not a feature of PUFA.

So metformin combines a failure to develop insulin resistance under the peak insulin conditions (the fed RER stays high in humans), at peak exposure time, with a decreased absolute supply of insulin per se. The lack of increased glucose output reduces the requirement for an increase in insulin secretion. Overall cells experience less insulin signalling exposure, much as the partial insulin gene knockout mice from Jim Johnsons lab.

Under fasting conditions reducing insulin signalling via blockade of the glycerophosphate shuttle facilitates fatty acid release from triglycerides and lowers the fasting RER. It doesn’t matter if the triglycerides come from within muscle cells or adipocytes, the RER drops.

While metformin is debatable as a performance enhancing drug in people, in rodents with knockout of either cytoplasmic or mitochondrial glycerol-3-phosphate dehydrogenase there is enhanced endurance exercise ability. In humans under metformin there is reported some enhancement of pushbike sprinting ability under acute exposure but clearly sprinting requires glycolysis to lactate, not insulin signalling. Lack of a clear cut performance enhancement under chronic metformin tends to push me towards accepting that really might be some mild blockade of complex I under clinical dose rate exposure. Maybe.

Peter

Peter said...

Hi Luke,

Under fat oxidation all tissues become insulin resistant and saturated fat produces this effect to a greater extent than PUFA. Whole body, but not necessarily adipocytes. Adipocytes do become pathologically insulin resistant per se, ignoring fatty acid exposure, but that's a whole other post about a paper I have lying around.

However, what happens in adipocytes normally and what happens in the rest of the body is not simple. If you go to here:

https://high-fat-nutrition.blogspot.com/2017/02/protons-obesity-and-diabetes.html

and some more relevant stuff here

https://high-fat-nutrition.blogspot.com/2011/10/adipostat-ballon.html

you should get the idea.

The differential even applies even under ketogenic conditions where calories are artificially adjusted to maintain an unchanged bodyweight (though this may well not be what would occur in real life). Once you start to adjust calorie intake to manipulate bodyweight/fat mass (even if that means forcing no change) you are immediately out of the signalling processes which determine long term body weight/composition. But in an experiment you clearly try to control your variables, the two ideas at hard to accommodate in experimental design. I found this paper interesting along those lines.

https://academic.oup.com/jcem/article/89/4/1641/2844241

Notice insulin is higher in the saturated fat period. But you have to ask what is happening signalling-wise. More difficult to answer that one.

As a slight aside, measuring insulin sensitivity is a nightmare. If you go to the gold standard of a hyperinsulinaemic euglycaemic clamp, obviously the insulin/glucose administration will, within minutes, profoundly affect the lipid oxidation status of your (perhaps previously ketogenic) subject(s). And measuring insulin signalling status in the peak absorptive phase, after a meal, looks to be clinically impracticable. That would need you to be looking at activation of signalling pathways well down stream of insulin receptor activation...

Peter

Peter said...

Hi Marius

Well, all life seems to be a dissipative phenomenon. Energy flow is undoubtedly core. And undoubtedly cancer can be viewed as a failure to regulate energy dissipation... It always amazes me that this dissipative structure can be frozen but will restore itself on thawing. I guess the energy gradients are still there, preserved.

Peter

Unknown said...

I posted the below question on YouTube comments, but think this is a better place to post!

####

Still wrapping my head around this all, after listening to multiple podcasts! I had a question, that might tie more things together for me.

Does blood glucose levels, or glycogen/ATP levels give people the "feeling" of energy? I would initially think someone with insulin resistance, who has elevated glucose levels/spikes, would have a rush of energy and therefore burn more through Neat (Non-exercise activity thermogenesis). But in reality, do they not actually feel the excess energy because of insulin resistance in their muscle cells? Their glycogen / ATP aren't being topped of properly because of latent palmitic acid in the blood stream which makes them feel tired and unmotivated to move?

Peter said...

Whoa now, that's a very complex question!

First, given ad lib food access LA causes pathological insulin sensitivity to sequester calories in to adipocytes. So energy is lost and hunger rises (or satiety is delayed while eating) and adipocytes expand. This is an energy DEFICIT situation and insulin, glucose and fatty acids are low, except more calories are eaten to make up for this deficit, ie you make yourself functional by eating to compensate for the loss in to the fat. Energy levels stay normal-ish.

Insulin resistance is a whole other kettle of fish. Here there is a failure to keep fatty acids within over distended adipocytes. They leak in to the bloodstream and provide EXCESS calories. There is a need to shut down caloric ingress in to cells because the cells have lots of fuel supply. Palmitic acid is an excellent, superb, almost infinite fuel supply, IF you have mitochondria.

Obese people are strong. They may have trouble running etc in the same way as I would have if, being a 63ish kilo person, I was to run/climb while carrying 140kg of lead in a backpack, to be on a par with a 200kg person. But, I agree, they do seem to find running/climbing hard.

Perceived energy availability and the willingness to run etc are even harder to pin down that satiety/hunger. How much is mitochondrial loss through over riding the normal insulin resistance by eating carbohydrate to pathological hyperglycaemia, leading to pathological ROS generation and mitochondrial destruction, is a fascinating rabbit hole. Part of ketoadaptation might well be the time needed to replace those lost mitochondria...

Fascinating thought train.

Peter

Unknown said...

Thanks Peter,
Your answer (though not exactly what I was trying to ask) I think helped me reframe your theory in my head.

I was thinking of consumption of LA as a one time event, that the body will eventually find a way to achieve homeostasis through the leakage of excess energy to other tissue. But I really should be looking at a persons diet as a semi-consistent stream which has signaling properties along with the mass flow rate. I went to school for engineering so what you and fireinabottle talk about bring me back to my not-so-found Thermodynamics classes, and the laws of conservation of energy!

I think it is fairly accepted to say that the body is always counter balancing short term and long term survive-ability; and our modern food production and refining of food, has tilted things too far towards fat storage because of cheaper and easier calories. But, your ROS theory really explains why the general public is fighting a uphill battle when eating a standard western diet that screams to their body "times are tough, get fat".

Peter said...

Hmmm, I would still view it in reverse. A modern diet shunts consumed calories in to adipocytes. Those calories are no longer available. You simply have to eat extra because, by getting fat, you are functionally hypocaloric. Your brain looks at what is in the arterial blood, what leptin tells it and probably has neural input from all cells, hepatocytes and adipocytes included. But if the blood supply to the hypothalamus is hypocaloric this will over ride all other markers of energy status.

If you designed a drug which removed calories from the blood and sequestered them in adipocytes while having absolutely no flavour at all, it would make you fat. You would have to over eat to account for the lost calories.

The drug is linoleic acid.

Peter

Unknown said...

Makes sense, that's my understanding too but maybe I'm just not communicating it as concisely as you!

Thankful for you sharing, I've been incorporating your concepts into me and my growing families' diets. Switched from pork to beef bacon, to omega3 eggs and reducing our total amount. Still not sure what to do about our occasional seafood consumption (fresh/smoked salmon, canned tuna/sardines, sashimi, and shrimp). I'll eat anything for health, but I gotta make things tasty and provide variety for my breastfeeding wife and my two year old.

Passthecream said...

Peter: "The drug is linoleic acid."

You've written about fructose in various ways --- I don't want to go the full Lustig but I have a strong feeling that it has a similar drug-like effect to LA. I consume minimal LA but still find that I gain weight easily if I eat much fruit or sucrose.

Peter said...

Pass, fructose is very, very interesting. It seems quite possible that the fructose:uric acid system might be deliberately designed to cause weight gain, as reviewed here

https://pubmed.ncbi.nlm.nih.gov/31621967/

Obviously weight gain is a marked survival advantage if you are heading in to drought or winter. Twiggy wouldn't have lasted long if the cariboo migration was delayed for a month for some reason and the dried meat was running low. Bit temperocentric, as always but...

Peter

Passthecream said...

Twiggy, could eat twigs?
Hard to explain Twiggy to younger people.


Thanks for the link to that paper. That's amazing. It ties up a whole lot of loose ends for me.

It's Apricot season here atm and we have a tree covered in the damn things which is hard to walk past without sampling. That's very sweet neolithic fare and apricots also have the highest levels of sorbitol IRC.

Unknown said...

Peter/Pass,
What is your take on dextrose syrups/powders? I have been bouncing around between using brown rice syrup or raw honey as a dessert. They obviously aren't health foods, but a few spoonfuls of raw honey helped break my ice cream/dairy cravings. (Big deal for me since it seems dairy protein causes an inflammatory response in my joints).

My current scheme is using a little rice syrup, which is all glucose and probably has a ridiculously high glycemic index (GI), during the day, especially if I plan to exercise. And if I crave sugar at night, I'll eat some raw honey, since I assume my liver will burn the glycogen/visceral fat by the time I eat my breakfast.

Is the brown rice syrup's high GI going to have any detrimental long term affects? Or is it no different than eating a serving of white rice, which I have with many of my meals.

Peter said...

Too many unknowns really. Sucrose in lab diets for rodents doesn't seem to be a problem provided the LA content is kept low...

Peter

Passthecream said...

It certainly varies from person to person!

Putting consideration of pufa to one side - avoid!!!, I think Peter's blog from a couple of years ago about Minger and carbosis vs ketosis is informative here. If you're on a high fat/meaty diet I think any great amount of carbs is going to be problematic and vice versa. Should be one thing or the other but how much is too much? I try to keep to the Lutz limit ( 'Life without bread') of 72g carb per day much lower than that --- doesn't work for me, it's always a balancing act but nowadays I try to only have plain types of starches like a bit if rice or potato or etc.

After my recent brief flirtation with fresh fruit and following some physical stress on my foot from kicking a ball with grandchildren I'm paying the price with a small burst of gout for the first time in a couple of years. I don't usually eat much fruit so it looks like the connection between fructose and uric acid is pretty strong for me just as that review paper discusses, and blood pressure also I think.


It's a bad idea to have a lot of salt if you're consuming much fructose so that covers the SAD pretty well: high salt, high fructose eg in sugar and fruit juice and soft drinks and everywhere, topped off with heart-healthy-polyunsaturated-vegetable-oils.


Gout is erratic btw - it usually breaks out some time after uric acid has been high and classic gout is in the second joint of the big toe, a site at the coolest extremeties which is also highly stressed and prone to injury therefore inflammation. It can be made worse by dropping the urate levels too quickly eg during weight loss and fasting.

Books have been written about it ...