I'll just put this up as a brief post, there is a lot of background to it.
We all know that long chain fully saturated fatty acids yield approximately twice as much NADH as FADH2 giving an FADH2:NADH ratio just under 0.5 and that this high rate of FADH2 input at the CoQ couple facilitates superoxide generation by reverse electron transport through complex I.
Equally, we know that glucose oxidation, with five times the generation of NADH as FADH2, gives us a ratio of 0.2 and minimal reverse electron transport
We also know that, in order to balance the cytosolic NAD+:NADH ratio that NADH must be converted back to NAD+ to allow glycolysis to continue. This can be done using the malate-aspartate shuttle, conversion of pyruvate to lactate (both of which are redox neutral) or by using the glycerophosphate shuttle.
The latter is far from redox-neutral from the FADH2 input perspective. A cytoplasmic NADH is converted to an FADH2 within mtG3Pdh. This inputs at the CoQ couple. As far as the mitochondria are concerned that cytoplasmic NADH never existed. It behaves exactly as an FADH2. So, while the glycerophosphate shuttle is active, glucose presents to the mitochondria as two FADH2 and four NADH, giving us a nice, rather neat, FADH2:NADH ratio of 0.5. Slightly higher than palmitate or stearate.
I consider the glycerophosphate shuttle as generating essential ROS for insulin signalling. Small amounts of ROS generation facilitates insulin signalling. Large amounts inhibit it. Glucose, even hyperglycaemia, dose not generate ROS by the RET route. Adding insulin does do so because as the pyruvate dehydrogenase complex becomes more active then so the glycoerophosphate shuttle also becomes more active. The FADH2:NADH from glucose rises from 0.2 towards 0.5 and ROS increase to generate (given enough activation of the PDH complex) insulin resistance.
Insulin induced insulin resistance.
Peter
12 comments:
So, eat a lot of rice?
I understand from this that glucose with a certain level of insulin creates ROS as well. Is this then the way high carb communities have their metabolic way? From data of indigenous people it make sense to be healthy and lean as long as you avoid linoleic acid, no matter high or low carb.
I think linoleic acid is central to obesity but fructose can produce insulin resistance w/o obesity. Of course, with the correct tweaks you can design a fructose fed model without obesity or hyperinsulinaemia too... But both the PDH complex and glycerophosphate shuttle look to be doing much the same as stearic acid in terms of normal physiology to limit adipocyte size.
Peter
You should write a book, with translations for the layman too.
Ndns
Sorry, wouldn't let me edit.
Hi Peter,
Great blog. Been following Paul Saladino and Michael Eades who follow your blog. Was wondering what you would have to say about food combining in particular separating fats and carbs. Perhaps the solution is eating both but just not on the same meal/day.
My intuition tells me the insulin would act as shuttles for the fats. Shuttling in stearic acid sounds like a good idea or even epa and dha under a sat fat diet to replace the LA we've stored over many years.
Having to eat outside socially LA foods by "not eating the bun" may work to not shuttle those LA in. And if "the bun: is unavoidable would supplementing with epa or dha or stearic acid cause competition for fat storage and have a net positive effect?
On another note, I'm not sure if it is right to say we are replacing the LA in our fat with better fats such as stearic acid or n-3, but assuming one is in that process, and LA is being oxidized in the mitochondria causing insulin sensitivity, it seems like a catch 22 for those trying to lose weight. As the adipocites are insulin sensitive because of the beta oxidation of the LA then consuming anything would prevent fat loss as it would be stored.
Which leads me to think I can either eat only carbs and protein and no fats. As I think carbs won't turn to fat through denovolipogenensis unless my calorie intake is absurd. Or two, I fast and not eat until all LA is burned off.
I'm still trying to wrap my head around a lot of these concepts so I apologize if I didn't make any sense.
In the 4th paragraph I am talking solely about LA that already exists in our fat. Not dietary.
Trying to lose fat* (stubborn fat in particular, not just weight)
Unrelated:
https://jamanetwork.com/journals/jamacardiology/fullarticle/2768916
Wonder what they fed them while in hospital?
Eric, worse still, what did their cardiologist bully them in to eating over the previous decades?
Peter
Hi Unknown, sorry for the delay but your comment does not come down to a one line answer…
Food combining, over the years, has become more and more biochemically acceptable to me. The word being food. Food, real food, does not contain substantial PUFA so there should be no problem with calorie “loss” in to adipocytes, ie weight gain. Given a high PUFA sourced food such as nuts the weight gain in temperate climates pre winter would absolutely be a Good Thing. Being lean and ripped gets you no brownie points when the bison heard tracks through somebody else’s patch of ground that winter.
I’ve not looked at VLC omega 3s in enough detail to comment on whether they provide benefit short term, though in your heart mitochondrial membranes when you turn 100 years old, they won’t.
I also think you might find that certain amino acids provide reduced electron transferring flavoprotein as part of their catabolism which might well affect fat loss, if that is a target.
Ultimately having adipocytes loaded with LA is probably pathology in its own right. Kid nowadays are born that way and the outlook for them fully reversing it seems poor to me. I think the chances of a five year old with type 2 diabetes making it to be a centenarian are remote.
Peter
That's ok. I've got all the time in the internet. Thank you for taking the time to answer my questions.
In this context "Food, real food, does not contain substantial PUFA so there should be no problem with calorie “loss” in to adipocytes, ie weight gain." Then, would the RET from the burning of endogenous LA from WAT (fat burning but from stored LA ) cause local insulin sensitivity, causing even real food to be stored in adipose tissue? I guess what I am having trouble with is LA already in your fat (fat we have accumulated for years from all the soybean and LA oils) vs. Dietary LA. If we halt the latter, the former would still play a role. We still have to get rid of the LA in the our fat cells. But doing so causes fat cell sensitivity as per RET. So even real food would be stored as fat? That's why I was wondering if burning off the LA through fasting first would avoid that metabolic catch 22.
Insulin doesn't cause insulin resistance. Insulin cause cell to flood with energy substrates, this causes generation of H2O2 generation. H2O2 inhibits phosphatases and kinases phosphorylate insulin receptor and IRS.
So insulin doesn't cause insulin resistance, but accumulation of energy substrates causes insulin resistance.
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