Do Carbohydrates Turn Into Fat?

[Elron]

In fact, it is a sign that the liver is overloaded, and that the body is rapidly trying to get rid said fructose.

Why is it a sign that the liver is overloaded, and how do you know? The body is using the energy it can use most efficiently as an energy source (thus carbs).
Increased skeletal muscle mitochondrial efficiency in rats with fructose-induced alteration in glucose tolerance

Generally, if the body can meet the demands metabolically to respond to a higher energy level, then we could expect higher mitochondrial biogenesis although these come with downsides such as increased oxidative stress. So it can meet the demands, but at a cost (is it worth it?). Most people are metabolically compromised in some way, so something like pure fructose or even glucose is usually not going to be good in large quantities. I believe you could have up to 8g of fructose every hour, more so if you are active and even more if you have more muscle mass or got done working out; in which case, you could probably spike it up to 75-150g depending on your body. Given they were fasted, most of the fructose was probably converted into lactate to energize the muscle mitochondria
Fructose metabolism in humans – what isotopic tracer studies tell us

I believe fructose consumption would be useful in high fat/protein diets although that's speculation.

 

[tyw]

Why is it a sign that the liver is overloaded, and how do you know? The body is using the energy it can use most efficiently as an energy source (thus carbs).
Increased skeletal muscle mitochondrial efficiency in rats with fructose-induced alteration in glucose tolerance

Generally, if the body can meet the demands metabolically to respond to a higher energy level, then we could expect higher mitochondrial biogenesis although these come with downsides such as increased oxidative stress. So it can meet the demands, but at a cost (is it worth it?). Most people are metabolically compromised in some way, so something like pure fructose or even glucose is usually not going to be good in large quantities. I believe you could have up to 8g of fructose every hour, more so if you are active and even more if you have more muscle mass or got done working out; in which case, you could probably spike it up to 75-150g depending on your body. Given they were fasted, most of the fructose was probably converted into lactate to energize the muscle mitochondria
Fructose metabolism in humans – what isotopic tracer studies tell us

I believe fructose consumption would be useful in high fat/protein diets although that's speculation.

This is a clear overload condition given the fact that we know that oral fructose / sucrose gets directed to the liver for metabolism first, and because there is spillover to lactate production. The conditions in which lactate is produced have been described in a previous post, and this spillover is an indicator of excess input beyond what the targeted tissues could handle.

It is also clear from the comparison to an equal energetic amount of glucose, that glucose did not have nearly as much spillover to lactate as fructose did, indicating that the use of ingested glucose was closer to actual metabolic capacity of the body in that state (which was basically subjects sitting around getting their blood drawn).

If the fructose were all being used efficiently to generate ATP, then we would not see the increase in excess heat production, and we would not see the lactate spillover.

Note of course, that this was comparison of pure fructose to pure glucose. In realistic terms, people don't eat pure fructose or pure glucose (though sugar / sucrose is pretty close to fructose).

80-90% of fructose is known to be directly solely to hepatic metabolism, and not skeletal muscle. This is exactly the case which we see here. If the fructose were being directed to skeletal muscle, we would not see the sharp rise in hepatic lactate, and instead see behaviour more akin to the glucose fed group. This is also congruent with the observation that fructose requires the GLUT5 transporter for access to skeletal muscle, and that these transporters are much sparser than glucose transporters.

This is the case even in a fasted state. In an already fed state, fructose overload would likely happen even more readily.

The fructose-derived lactate can be used by skeletal muscle. This still involves the liver as a bottleneck, and if we're talking about desirability of substrate, we will have to compare fructose and its derivatives, to glucose. Glucose has much easier access to skeletal muscle compared to fructose, much more control (insulin and GLUT and what not), and much more ATP yield when compared to lactate.

The case of spreading small amount of fructose through the day is definitely more manageable, and as stated before, there is probably not much issue with a 75g total daily intake of fructose.

-----

I generally do not extrapolate the studies done on rats with regards to fructose intake. This is because rats have:

- at least 10x the amount of fractional DNL capacity for an equal amount of carbohydrate intake (when compared to humans)

- the ability to produce PUFAs from the DNL-produced lipids, while humans generally do not (ignore 20:3-n9, since that is not a significant contributor to lipid fractions in the body).

These statement from the study you quoted are correct in the context of rats:

A significant increase in plasma NEFA, as well as in skeletal muscle TAG and ceramide, was found in fructose-fed rats compared with the controls, together with a significantly higher plasma insulin response to a glucose load, while no significant variation in plasma glucose levels was found. Significantly lower RMR values were found in fructose-fed rats starting from week 4 of the dietary treatment.

Mitochondrial energetic efficiency was assessed through the measurement of state 4 respiration in the presence of oligomycin and uncoupled respiration in the presence of FCCP, as well as through the evaluation of mitochondrial membrane potential in state 4 conditions, both in the absence and presence of physiological concentrations of palmitate.

This result is in agreement with increased skeletal muscle ceramide content, since it is well known that ceramide has been identified as a key mediator of insulin resistance via inhibition of Akt phosphorylation, and indicates that insulin action is blunted in skeletal muscle from fructose-fed rats. However, this impairment is compensated by higher plasma insulin, so that the final response of skeletal muscle cells to insulin is maintained.

This increase in mitochondrial mass could be a compensatory mechanism to the increased fatty acid supply due to higher plasma NEFA levels found here, since it has been shown that raising plasma NEFA levels induces increased mitochondrial biogenesis in skeletal muscle

However, the compensatory increase in mitochondrial mass probably failed to buffer NEFA oversupply, due to the increased mitochondrial coupling found in rats fed a fructose-rich diet, since in this condition, less amount of fuels are oxidised to obtain the same amount of ATP.

The oxidative status of skeletal muscle mitochondria was also assessed and, in fructose-fed rats, signs of oxidative damage were found, together with the decreased activity of SOD, one of the enzymatic components of the antioxidant defence system.​

It is likely the fructose-induced fat accumulation in skeletal muscle that caused this effect in mice.

In humans, not designed for high PUFA use, we only see such skeletal muscle lipid accumulation in metabolically deranged states -- Diabetes

SIDENOTE: the only other situation with high levels of intramuscular triglycerides is with the use of certain PEDs. The "hard and grainy" look in muscles achieved by PED-enhanced humans is thought to be partly due to this accumulation of intramuscular triglycerides. In non-PED-using humans, getting to a lean state inevitably reduces this intramuscular triglyceride content, leading to them looking "stringy and flat".​

Rats are uniquely evolved to use lots of PUFA on their mitochondrial membranes, to have a very "eager" metabolism. I discussed this here -- PUFA, Birds, and Genetics

The case of a high fructose-fed rat can almost be synonymous with a high PUFA-fed rat, due to the amount of DNL that they can undergo. Again, this makes the context very different from a fructose fed human.

Still, the fructose fed rats suffered from metabolic issues, reduced metabolic rate, excess superoxide production, etc .....

​

----

In the context of heavily carbohydrate reduced diets, fructose may uniquely be able to keep liver glycogen levels at fed-state levels. Whether or not this leads to better outcomes of dietary tolerance is probably going to depend on the individual.

I can see it going either way, with some people having the ability to use fatty acids in all other tissue, while the liver remains happy (no alarm bells), and in other people, having an inability to make ketones in the liver, and slowly fizzling out with brain fog and what not while being caught in the no man's land between carbohydrate and fat metabolism.

....

 

[Elron]

In the context of heavily carbohydrate reduced diets, fructose may uniquely be able to keep liver glycogen levels at fed-state levels. Whether or not this leads to better outcomes of dietary tolerance is probably going to depend on the individual.

I can see it going either way, with some people having the ability to use fatty acids in all other tissue, while the liver remains happy (no alarm bells), and in other people, having an inability to make ketones in the liver, and slowly fizzling out with brain fog and what not while being caught in the no man's land between carbohydrate and fat metabolism.

Yes, I feel like fructose is bad with most people because they are not metabolically efficient. Not to mention, fructose studies doesn't correct for the disturbed micronutrient adjustment they would be getting from real food. Did you take a look at fructose to lactate in the human isotropic studies? A large amount of fructose is converted into lactate in humans, so I'm still not sure if your line of reasoning is correct seeing as you didn't address that conversion. You did say 80-90% of fructose is used yet up to 25% of fructose can be turned into lactate in humans. These humans were exercising, and I'm not sure how that would address the conversion or even how fructose is converted into lactate. ATP generation produces heat, so I'm not sure how people being hotter (most likely from mitochondria uncoupling) is necessarily a bad thing or indicates that there was lactate 'spillover' which is almost an absurd term, given how you're quantifying it.

 

[Dan W]

Thanks for your thought-provoking posts as usual, @tyw. I'm impressed at the rate you tackle people's questions, so I'm going to toss another straw on the camel's back and see what happens:

Personally, I've done the adaptation both ways, have spent prolonged periods in the past on ketosis as well as other schemes, and it seems like I've never lost the ability to metabolise either fatty acids or glucose for fuel when either is given. That is to say, I can reliably drop into ketosis within a day (morning BHOB >0.5mM), and then go back to eating carbohydrates just fine. Call it "metabolic flexibility" or whatever, but I'm not really bothered too much with these 2 macronutrients.

Do you have suggestions on ways to improve that "flexibility"? On days I take a break from my standard low-fat diet to have high calorie "cheat" meals (with the extra calories generally from fat), I notice rapid heart rate, feelings of dissociation, and low-ish blood sugar. It's particularly bad early in the day, which seems like a clue.

 

[tyw]

Yes, I feel like fructose is bad with most people because they are not metabolically efficient. Not to mention, fructose studies doesn't correct for the disturbed micronutrient adjustment they would be getting from real food. Did you take a look at fructose to lactate in the human isotropic studies? A large amount of fructose is converted into lactate in humans, so I'm still not sure if your line of reasoning is correct seeing as you didn't address that conversion. You did say 80-90% of fructose is used yet up to 25% of fructose can be turned into lactate in humans. These humans were exercising, and I'm not sure how that would address the conversion or even how fructose is converted into lactate. ATP generation produces heat, so I'm not sure how people being hotter (most likely from mitochondria uncoupling) is necessarily a bad thing or indicates that there was lactate 'spillover' which is almost an absurd term, given how you're quantifying it.

Well, in general, the more metabolic capacity a person has in their liver specifically, the less likely that. I distinguish the concepts of "capacity" from "efficiency" from "metabolic rate", since it is liver capacity and metabolic rate specifically that determines fructose tolerance.

When discussing conditions of input vs use, we are first interested in ability to accept inputs (capacity), and the ability to use those inputs (metabolic rate). The ability to convert that input to useful by-products like ATP -- efficiency -- is a secondary concern in the context of fructose overload.

For example, someone with fatty liver disease is known to have decreased liver glycogen storage capacity, and their tolerance to fructose is low. Conversely, a person who just ran for 1 hour, and has depleted some of their liver glycogen, can probably take a 50g bolus of fructose just fine, and not be overloaded. Hence I use the words "overload" or "spillover" to refer to a situation where supply exceeds both capacity and metabolic rate. Something then needs to be done about that overload.

80-90% of ingested fructose gets pushed to the liver. If a person can metabolise all that fructose to pyruvate to acetyl-CoA and NADH (via oxidative phosphorylation), then no lactate is produced.

Any production of lactate means that pyruvate from glycolysis or fructolysis is not being pushed towards Oxidative Phosphorylation, and is instead, pyruvate is converted to lactate for whatever reason. The conditions in which we get lactate from pyruvate is when there isn't enough oxygen, or there is too much pyruvate (or both).

SIDNOTE: I ignore the case of pyruvate-catabolic enzymes being broken. That is yet again a separate case, but we shall compare a fully function metabolic chain for this discussion wrt fructose vs glucose.​

The fact that in some contexts, a significant amount of a large enough fructose bolus is converted to lactate, indicates that either one of these lactate-favourable conditions is present. This is still dependent on the amount of fructose, and the capacity of the individual, so I will not say that fructose always leads to this lactate production in all people.

As you mention, the case of pure fructose is not realistic. Can we say that a person is going to be metabolically overloaded at the liver after eating nothing but 2 scoops of ice cream, and say 50g of sucrose / 25g fructose, while walking around during their vacation? Probably not by much, especially since factors like gastric emptying of a mixed-macro food will slow absorption of any sugars in that ice cream anyway, with that fructose being absorbed over quite a few hours.

However, there is also a tendency to overestimate how much extra liver capacity exercise confers. It is not much, and I have previous mentioned somewhere (with evidence) that more trained individuals tend to use less liver glycogen. This is to say, a bolus of 75g of rapidly absorbed fructose (which is the usual testing conditions) is likely to overload the liver of even a person who has just exercised for an hour. The caveats regarding rapid absorption meals vs real food still applies here.

Also, ATP generation via oxidative phosphorylation should not produce much excess heat. Uncoupling of electron chain transport from ATP production does create lots of heat, and of course, the use of ATP towards kinetic processes produces heat.

The liver-specific heat production in the 75g fructose fed group is likely a combined effect of some metabolic uncoupling, and increased liver activity (NOTE: "activity" doesn't mean oxidative phosphorylation, and it is clear that the lactate dominant pathway skips ox-phos). Is this excess activity a good thing for the liver? Probably not.

The key idea was that we have incoming energetic substrate supply exceeding capacity for use. Lactate production is simply a side effect of insufficient capacity to metabolise pyruvate via oxidative phosphorylation. For fructose, this seems to be bottlenecked by liver capacity. The same will occur with glucose of course, such that capacity of all glucose metabolising tissues is exceeded. It just happens to be the case that glucose capacity and metabolic rate is going to be greater than fructose.

----

Do you have suggestions on ways to improve that "flexibility"? On days I take a break from my standard low-fat diet to have high calorie "cheat" meals (with the extra calories generally from fat), I notice rapid heart rate, feelings of dissociation, and low-ish blood sugar. It's particularly bad early in the day, which seems like a clue.

Well, note that I personally put my "junk" intake during hypocaloric days. The theory was to basically have a caloric deficit buffer to prevent any accumulation of excess.

Realistically, this depends on the foodstuff, especially since Saturated fat can take days to fully metabolise. But then again, I'm not concerned about saturated fat accumulation from a metabolic regulatory perspective. I'm more concerned with stuff like excess PUFAs and sugars being completely oxidised (which does usually happen within 24hrs or less in either case), which is going to be much easier with an overall hypocaloric intake for the particular period where junk is consumed.

Personally, total energy intake vs expenditure was the biggest factor in being able to deal with junk intake. The energy expenditure side can be tackled too of course -- more activity during such days, and if you believe in caffeine, that too can help.

We can talk about circadian timing of intake, addition of digestive aids, exercise-induced pre-depletion of glycogen stores, various other supplements, etc .... but honestly, I just put myself into a caloric deficit, which by definition is a state biased toward use of fatty acids (ie: body fat), and then then resume regular high carb eating the day after.

I cannot say that this sort of strategy works for other people. I've basically spent a lot of time now getting used to an intermittent fasting pattern of eating (jumped on the LeanGains bandwagon back in 2008, and have continued since), which makes it easy to just fast until a big meal, put in a little of extra walking, have a 2000kcal cheat meal, and wake up the next morning back to normal. The opposite effect could occur, where fasting leads to hyper-consumption of food, and all the metabolic derangement that occurs. YMMV

Also, I've been a proponent of taking advantage of circadian rhythms in substrate consumption. Carbohydrate clearance is generally better during daylight hours, and thus that is when I eat my carbs, while keeping the night time state free of carbohydrate intake. This probably helps to maintain the ability to use both fuels adequately.

SIDENOTE: the exception is with the obese, where the difference between day time and night time adipose tissue insulin sensitivity is not that great. I even remember seeing a study showing the highest adipose insulin sensitivity at 12pm in obese people. High adipose insulin sensitivity just means more energetic substrate to fat tissue, instead of the more metabolically active all-other-tissues (which is where you want carbohydrate intake to go to)​

.....

 

[Dan W]

Thank you @tyw, that's helpful.

I have previous mentioned somewhere (with evidence) that more trained individuals tend to use less liver glycogen.

I think it's this post.

 

[Elron]

However, there is also a tendency to overestimate how much extra liver capacity exercise confers. It is not much, and I have previous mentioned somewhere (with evidence) that more trained individuals tend to use less liver glycogen. This is to say, a bolus of 75g of rapidly absorbed fructose (which is the usual testing conditions) is likely to overload the liver of even a person who has just exercised for an hour. The caveats regarding rapid absorption meals vs real food still applies here.

Extra liver capacity for runners/endurance athletes, which you posted about, I'd imagine would actually be less glycogen storage because there body is mainly adapted to burning fat during exercise, and thus most likely is chronically adapted to burn more fats than the average person. The body stores glycogen preferentially besides in times of higher Vo2 outputs. I imagine if you looked at olympic athletes' livers such as those doing olympic lifting, it would be a different story or at least in muscles, I'm not sure if the liver itself can adapt to store more of anything but gene expression could be involved to adapt to the stress imposed.

 

[ATP]

@tyw Thank you for all your input, it is very informative. You have made me completely re-evaluate Peat's work on fructose.

 

[tyw]

Extra liver capacity for runners/endurance athletes, which you posted about, I'd imagine would actually be less glycogen storage because there body is mainly adapted to burning fat during exercise, and thus most likely is chronically adapted to burn more fats than the average person. The body stores glycogen preferentially besides in times of higher Vo2 outputs. I imagine if you looked at olympic athletes' livers such as those doing olympic lifting, it would be a different story or at least in muscles, I'm not sure if the liver itself can adapt to store more of anything but gene expression could be involved to adapt to the stress imposed.

I never said anything about athletes having more liver glycogen. I emphasised that there was no difference -- Natural Bodybuilding Competition With RP's-style Diet:

I don't really see any particular difference regarding glucose and fructose needs between endurance athletes and regular people, except in total volume of glucose. Fructose may scale up a little with longer bouts of exercise, but honestly, it probably doesn't make too much of a difference.

NOTE: usage of liver glycogen stores in the face of exercise is reduced in trained individuals:
- Liver glycogen metabolism during and after prolonged endurance-type exercise
- Effect of endurance training on hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men. - PubMed - NCBI

Very substantially so -- on the order of 25% less (5.3 mg/kg/min in trained vs 6.9 mg/kg/min in untrained). Let's say, you metabolise 6 mg/kg/min of liver glycogen during exercise, and that you are 70kg, and go for a 90 min training run (enough for a training response). That's 6 * 70 * 90 = 37,800mg of liver glycogen. One does not need lots of extra fructose to replenish that amount of liver glycogen. Glucose loading will do just as well, unless of course, you need to do another run that same day (which begs the question, "why is training so inefficient?")

Of course, most fructose is probably going to do the least harm to people who are exercising so much .... and therefore, it probably isn't worth it to focus on optimising fructose intake -- just eat enough carbohydrate from whole food sources and be done with it.​

High exercising populations may have higher fructose metabolism rates, solely by virtue of higher overall energy expenditures. Total liver glycogen is at best just over 100g, regardless of training status. All the more reason why I say that hepatic fructose overload can happen to any person.

....

 

[Elron]

I never said anything about athletes having more liver glycogen. I emphasised that there was no difference -- Natural Bodybuilding Competition With RP's-style Diet:

I don't really see any particular difference regarding glucose and fructose needs between endurance athletes and regular people, except in total volume of glucose. Fructose may scale up a little with longer bouts of exercise, but honestly, it probably doesn't make too much of a difference.

NOTE: usage of liver glycogen stores in the face of exercise is reduced in trained individuals:
- Liver glycogen metabolism during and after prolonged endurance-type exercise
- Effect of endurance training on hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men. - PubMed - NCBI

Very substantially so -- on the order of 25% less (5.3 mg/kg/min in trained vs 6.9 mg/kg/min in untrained). Let's say, you metabolise 6 mg/kg/min of liver glycogen during exercise, and that you are 70kg, and go for a 90 min training run (enough for a training response). That's 6 * 70 * 90 = 37,800mg of liver glycogen. One does not need lots of extra fructose to replenish that amount of liver glycogen. Glucose loading will do just as well, unless of course, you need to do another run that same day (which begs the question, "why is training so inefficient?")

Of course, most fructose is probably going to do the least harm to people who are exercising so much .... and therefore, it probably isn't worth it to focus on optimising fructose intake -- just eat enough carbohydrate from whole food sources and be done with it.​

High exercising populations may have higher fructose metabolism rates, solely by virtue of higher overall energy expenditures. Total liver glycogen is at best just over 100g, regardless of training status. All the more reason why I say that hepatic fructose overload can happen to any person.

....

Humans can actually have up to 150g of liver glycogen. Runners will have metabolic adaptions and sparingly use glycogen stores while untrained indivinduals will not have an adapted Vo2 max and thus must create atp more rapidly from carbohydrates in order to meet energy demands

 

[Wagner83]

Rice will have some small degree of other minerals and vitamins, some protein, is arguably more palatable, has a more controlled GI response, can be paired better with other foods, etc ...

In general, whole foods over isolates for energetic needs. There are plenty of starch sources out there beyond rice. See which is suitable.

Pure Glucose IMO should be used only as a primary source of fuel in the situations where it is needed, eg: athletic scenarios, bedridden and unable to tolerate solid food, etc ...

If all starch sources are not tolerable, then one should question whether or not they should be eating as much carbohydrates as they think they need, and experiment with different macronutrients. I still stand by the recommendation to start at high carb, very low fat, and then add fat until a suitable situation is reached, or the opposite -- very low carb, high fat, add carbs until suitable.

Finally, it is not uncommon for someone to:
- not do well with plain potatoes (ie: no fat)
- but be fine with potatoes with some olive oil or duck fat (ie: more unsaturated fats)
- and do poorly with potatoes plus butter (ie: more saturated fats)
- do poorly with more than 30g of fat with the potatoes, but be fine with just a tablespoon (15g) of fat (enough to slow gastric empty by a little)

Or have any permutation of the 4 given scenarios, or not ever tolerate potatoes at all.

....

Thanks for the the answer and the tips. You seem to view the balance of macronutrients (rather than any particular foods besides saturated and polyunsaturated fats) as one of the key to avoiding energy crash and recommend people to experiment with it. Timing of each being an other important factor to consider.
Speaking of the starch sources, do you see particular issues with most grains/whole grains ?

 

[tyw]

Humans can actually have up to 150g of liver glycogen. Runners will have metabolic adaptions and sparingly use glycogen stores while untrained indivinduals will not have an adapted Vo2 max and thus must create atp more rapidly from carbohydrates in order to meet energy demands

Agree that untrained individuals will experience lactate threshold at lower percentage of VO2 max. However, proper programming should respect that limitation, and base training sessions on an intensity metric that best approximates lactate levels -- Methods of Endurance Training: Summing Up Part 1 : Bodyrecomposition

Human liver glycogen levels will vary. See attached PDF of article for details -- http://www.tandfonline.com/doi/abs/10.3109/00365517309084355

Basal Glycogen levels were a mean of 300 +- 30.5 mmol glucosyl units per kg wet liver tissue.

After an overnight fast following a period of normal mixed diet, the whole material (n = 19) showed a wide range of glycogen content from 87to 420 mmol glucosyl units per kg wet liver tissue with a mean of 270.9 +- 24.67 S.E.M (14.3-69.3 g glycogen per kg wet liver tissue, mean 44.7).

Refeeding with a carbohydrate-rich diet gave a rapid increase of the liver glycogen to supernormal values, 424–624 mmol glucosyl units per kg wet liver tissue.​

Note how an overnight fast barely affected liver glycogen levels -- 10% drop on average.

The refeeding protocol here was high carb low fat for several days -- a state of caloric excess that led to liver glycogen super-compensation.

I will assume a 1.5kg liver, based on measurements in males -- Normal organ weights in men: part II-the brain, lungs, liver, spleen, and kidneys. - PubMed - NCBI

Assuming the average of 3-glycosyl groups to a single glycosyl unit, we get a molecular mass of 162 Da.

Then, to convert the above values to grams:

Basal Mean: 300 / 1000 * 162 * 1.5 = 72.9 grams
Overnight fast mean: 270 / 1000 * 162 * 1.5 = 65.8 grams
24hr Starvation Low: 24 / 1000 * 162 * 1.5 = 5.8 grams
24hr Starvation High: 55 / 1000 * 162 * 1.5 = 13.3 grams
Super-compensation low: 424 / 1000 * 162 * 1.5 = 103.0 grams
Super-compensation high: 624 / 1000 * 162 * 1.5 = 151.6 grams​

Those are averages of course, and you will see in the study how one of the female subjects managed to only go from a basal value of 230 mmol/glucosyl units per kg to a super-compensated 336 units (336 / 230 = 1.46), while another female subject went from a basal 213 units to a super-compensated 624 units (624 / 213 = 2.93), and how all the male subjects maxed out around 520-550 units.

In terms of liver glycogen capacity, we are looking first and foremost at a qualitative change -- ie: Whether or not the liver is Empty, or Fed and adequate, or Overloaded.

It is not about how much the liver can hold, but how much it should hold to signal to the rest of the body that there is enough nutrients around. The super-compensated state is one that signals excess, which is not desirable in a chronic sense. For specific athletic performance, it can be beneficial, but as a chronic state, it is likely harmful.

The adequate state only ranges from about 50-100g total liver glycogen. The mean value above is why some people claim that "the liver normally holds only about 50g of glycogen".

In the normal case, people who are eating a non-ketogenic diet are going to be dropping to the overnight fast men at the star of each day. The amount needed for replenishment to the adequate state is tens of grams at most. Even if we make more generous liver size measurements, with say a very large 2.5kg liver, the difference between the basal mean and overnight fast is (300 - 270.9) / 1000 * 162 * 2.5 = 11.78 grams.

This is likely why we see a uniform lactate increase in all studies using a relatively small fructose bolus (anywhere from 25-75g) after an overnight fast in normal populations.

It is this normal state that is more relevant to people, and not the super-compensated state.

Thanks for the the answer and the tips. You seem to view the balance of macronutrients (rather than any particular foods besides saturated and polyunsaturated fats) as one of the key to avoiding energy crash and recommend people to experiment with it. Timing of each being an other important factor to consider.
Speaking of the starch sources, do you see particular issues with most grains/whole grains ?

A lot of people can't seem to do well with grains. Gluten is still an issue for those who are sensitive to it. Corn animo acids are sometimes problematic. One can look at all the Paleo movement precautions regarding all these supposed harmful compounds, discard the alarmism, and simply test each foodstuff from the perspective of professional paranoia.

And yes, macronutritional balance is always the goal. Some people are balanced at a 85% carbohydrate intake, others at a 50 gram a day carbohydrate intake, and possibly everything else in between.

I do not view a particular macronutrient as superior to another in terms of "metabolic worth". Both carbohydrates and fatty acids can provide lots of ATP, with any low level metric of either being insignificant compared to the higher level mechanics that overall macronutrient intake can affect.

That is to say, low-level metrics like ATP yield per unit O2, or ATP yield per unit Carbon, differ by maybe 5-10% depending on which carbohydrate and fatty acid sources you compare it to. Whereas higher level function like fatty acid mobilisation rates, insulin sensitivity (which pushes nutrients into the cell for use), expression of glucose transporters, fatty acid shuttling, and maybe even muscle fiber type distribution (and their different propensities toward fatty acid or carbohydrate use), etc .... all can have huge variations.

The innate differences in insulin sensitivity alone, which easily exceeds a 100% variance amongst individuals, can affect how readily carbohydrate sources can be used.

I just get back to, "figure out what works" .... and try to create heuristics to triangulate acceptable macronutrient ranges for a particular individual.

....

 

[Travis]

ATP is an interesting molecule. Gilber Ling's website is back up, and he discounts the concept of the high-energy phosphate bond.

In the three sets of experiments and computations, by far the largest sources of the (maximum) available energy to the surviving muscle cells came from the decline and presumed consumption of energy in ATP and creatine phosphate (CrP). Not long afterward, the revolutionary findings of Podolsky and Morales ( J. Biol. Chem. vol. 218, p.945, 1956) and of George and Rutman (Progr. Biophys. and Biophys. Chem. Vol 10, p.1, 1960) showed unequivocally that there is no high-energy-phosphate-bond energy to speak of. Or put it differently, the concept of high-energy phosphate bond was a mistake. By taking this new knowledge into consideration, the energy required would no longer be only 15 to 30 times but from 600 to 1200 times greater than the energy available--- even though the earlier lower set of figures of 15 to 30 times were already more than enough to disprove the membrane-pump theory.

Three independent disproofs of the membrane-pump theory

He instead views the function of ATP as a cardinal adsorbant, which adsorbs onto the cardinal sites of proteins altering their electric distribution (polarity) which can cause all sorts of effects such as changing caroxyl (Glu, Asp) preference between K⁺ and Na⁺.

ATP is the final end-product of the food materials we consume. At one time, biochemists thought ATP is unusual in that it contains a great deal of energy in special phosphate bonds. This idea turned out to be wrong. In time it became established that while ATP does not carry so-called high-energy phosphate bonds, ATP has powerful affinity for the protein it interacts with, thereby affirming the unique role of this compound as the queen of cardinal adsorbents in maintaining the resting living state and in shifting between alternate states. If one stops eating, ATP spent cannot be replenished. And without ATP, the cells die. And with that, the individual dies.

Nonetheless, the concepts of the membrane pump and the high-energy phosphate bond persist. I find Ling's work convincing.

 

[Mito]

A lot of people can't seem to do well with grains. Gluten is still an issue for those who are sensitive to it.

Do you have an opinion on if blood testing such as Cyrex Labs Array 3 or 4 (Array 3 | Wheat/Gluten Proteome Reactivity and Autoimmunity™) is useful to objectively identify gluten sensitivity? In other words, if injesting gluten may eventually cause damage (even if there are no immediately identifiable symptoms)?

 

[tyw]

Do you have an opinion on if blood testing such as Cyrex Labs Array 3 or 4 (Array 3 | Wheat/Gluten Proteome Reactivity and Autoimmunity™) is useful to objectively identify gluten sensitivity? In other words, if injesting gluten may eventually cause damage (even if there are no immediately identifiable symptoms)?

Probably accurate to some degree, in the sense that it can detect gluten and gliadin and other-supposed-harmful-compound immunoglobulins in serum, and thus indicative of a prior immune reaction to said compounds.

Does it mean that a person is still going to react the same way to those compounds today? Not always, and it depends on how well a person's gut has healed, and their risk tolerance and philosophy toward food.

Personally, I've never had the test done. I've have prior issues with wheat when I was sicker -- gave immediate nausea upon consumption. I do not have issues with wheat today. If I have to eat some gluten out of social obligation or just for fun, I probably wouldn't worry about it today. I'd buy bread and random gluten containing snacks today. Still far from a majority of my calories, but it is present, with no significant issues. eg: nothing like my reactivity toward dairy, which I still cannot tolerate well to this day.

Each individual will have to assess themselves.

.....

 

[Mito]

nothing like my reactivity toward dairy, which I still cannot tolerate well to this day.

Do you think it is the lactose or casein that causes your reaction to dairy? I wonder how you would test for lactose or casein on Cyrex's Array 4?

 

[tyw]

Do you think it is the lactose or casein that causes your reaction to dairy? I wonder how you would test for lactose or casein on Cyrex's Array 4?

Both, those tolerance to lactose is better than to casein. Have tested basically every permutation of dairy at this point, from most ruminant sources, in various forms of isolation (eg: isolated micellar casein vs cheese), various forms of processing, etc ...... none really agree with me, though isolated Whey isolate is the least problematic.

Not like I experience any major issues nowadays that I am healthier. More like the sudden 1kg stomach bloat after consuming significant dairy, which then 2-4 days to dissipate while being very annoying.

I have no idea how the Cyrex tests would pan out for me. My stance on such testing has always been that if you can afford it, and it is convenient, and there are no side effects from the test, then get as much data as possible. I don't bother with such testing because of the limited utility and high cost.

In this case, an immunoglobulin test is simply testing for elevated levels of particular compounds (antibodies/ immunoglobulins) used for pathogen recognition. It only says:

You have produced an immunoglobulin that we think is used to recognise this particular component (eg: of wheat) as a pathogen, which is then used to mark the pathogen for clearance by other immune system functions.​

Such tests will tell you nothing about T-cell function for example. It will also not tell you if "auto-immune" reaction will occur, not will it tell you how quickly the body will attempt to react to antigen recognition of the tested compounds. All the test says is that "your body has recognised X as a pathogen in the past (and maybe in the present as well)".

This fits the wildly varying observations in the real world, both of people whom had prior problems with say gluten, and now are fine, and those who do not test for the known antigens, and yet feel horrible with gluten.

I would rather just experiment in the real world and find out for myself. Such experiments have led to the conclusion that dairy of any form is bad for me.

However, I should again highlight what I wrote in response to Dan Wich's comments here -- Do Carbohydrates Turn Into Fat? No . I have consistently observed better tolerance to and recovery from exposure to intolerances (like dairy) when I concurrently restrict overall food intake.

.....

 

[tyw]

Sidenote Regarding ATP

@Travis It is only by use of Gilbert Ling's proposed mechanics, that I have managed to understand many aspects of biology. I have read all his works, and am personally convinced that his mechanics are correct. They underlie my explanations for inflammation (A General Definition for Inflammation) , and helped me fully understand William F. Koch's carbonyl chemistry mechanics.

NOTE: Koch kept talking about the "Functional Carbonyl Groups" of a cell. Ling gave a full explanation for what they were, how they function, and wha sort of contexts they function in.​

The idea of high energy phosphate bonds powering the processes of the cell is wrong. It is EZ water / multi-layered polarized water -- formed via the ATP-induced unfolding of proteins and exposure of hydrophilic CO and NH groups -- that serves as the medium for charge transport. Of course, heat (infrared) absorption and emission will happen in areas with such EZ water, and tissue activity will bring with it heart production.

....

 

[Travis]

Cool. I'm glad that you agree with Ling. I have read hist first book The Association Induction Hypothesis: A physical theory of the living state. I have a first edition hardcover.

It makes perfect sense. Gilbert Ling makes the membrane pump look like s crazy idea a child would come up with. I have always hated mechanistic analogies in biology. Have you heard about Huxley's cross-bridge theory of muscle contraction? LOL!

I just read one of Ling's articles yesterday. A Historically Significant Study that at Once Disproves the Membrane (Pump) Theory and Confirms that Nano-protoplasm Is the Ultimate Physical Basis of Life — Yet so Simple and Low-cost that it Could Easily Be Repeated in Many High School Biology Classrooms Worldwide

Good stuff. The Na⁺/K⁺ ATPase cell membrane pump is probably the biggest unicorn in biology. I still see it in books that I read and I just shake my head.

I was wondering what implications this might have for X-ray crystallography. If ATP-free and water-free proteins are diffracted, then their structure can only represent the denatured state. The proposed catalytic sites of enzymes could be totally wrong.

Maybe I'll read another Gilbert Ling book someday. I think you might enjoy reading this: How protein chemists learned about the hydrophobic factor

Protein chemistry is very interesting. Also interesting is Pauling's original alpha helix article: THE STRUCTURE OF PROTEINS: TWO HYDROGEN-BONDED HELICAL CONFIGURATIONS OF THE POLYPEPTIDE CHAIN

 

[tyw]

Cool. I'm glad that you agree with Ling. I have read hist first book The Association Induction Hypothesis: A physical theory of the living state. I have a first edition hardcover.

It makes perfect sense. Gilbert Ling makes the membrane pump look like s crazy idea a child would come up with. I have always hated mechanistic analogies in biology. Have you heard about Huxley's cross-bridge theory of muscle contraction? LOL!

I just read one of Ling's articles yesterday. A Historically Significant Study that at Once Disproves the Membrane (Pump) Theory and Confirms that Nano-protoplasm Is the Ultimate Physical Basis of Life — Yet so Simple and Low-cost that it Could Easily Be Repeated in Many High School Biology Classrooms Worldwide

Good stuff. The Na⁺/K⁺ ATPase cell membrane pump is probably the biggest unicorn in biology. I still see it in books that I read and I just shake my head.

I was wondering what implications this might have for X-ray crystallography. If ATP-free and water-free proteins are diffracted, then their structure can only represent the denatured state. The proposed catalytic sites of enzymes could be totally wrong.

Maybe I'll read another Gilbert Ling book someday. I think you might enjoy reading this: How protein chemists learned about the hydrophobic factor

Protein chemistry is very interesting. Also interesting is Pauling's original alpha helix article: THE STRUCTURE OF PROTEINS: TWO HYDROGEN-BONDED HELICAL CONFIGURATIONS OF THE POLYPEPTIDE CHAIN

Regarding Huxley cross bridges, I shall quote Harold Hillman -- A Serious Indictment of Modern Cell Biology and Neurobiology | Dr Harold Hillman

Thick and thin muscle filaments, and cross bridges between them, are the structural components, which form the basis of the sliding filament hypothesis of muscle contraction.(Huxley and Hanson, 1959).

It is an absolutely beautiful hypothesis, but there are some problems:

(a) the filaments are too uniformly distant apart in sections. They should appear in a range of distances apart depending upon the angle of section;

(b) it is extremely difficult to find oblique sections of muscle in electron micrographs; one usually sees either perfect transverse or perfect longitudinal sections. This would seem to be rather strange, as it is so difficult to align a muscle before it is stained and sectioned;

(c) the muscle should contract with the maximal force when it begins to contract, because the cross bridges should be maximally stretched at the beginning.

When the muscle has contracted maximally, the force exerted by the transverse component should have reached its maximum, and, therefore, the muscle fibres should narrow their waists. A contracted muscle should look thinner not fatter. The usual explanation given for this is that muscles are isovolaemic, so that a longitudinal contraction must cause a transverse expansion. Unfortunately, this failure of the muscle to contract in its middle is seen not only in the whole muscle, but also when single muscle fibres are dissected out.

It must be concluded that the myoplasm in life is a viscous fluid, which, when dehydrated, forms thick and thin filaments. A new alternative theory to the sliding filament hypothesis requires to be formulated.​

Regarding Potassium, Peter @ Hyperlipid has recently been raving about LUCA (last universal common ancestor) enzymes and K+. Example article -- Hyperlipid: From Skulachev to LUCA

The first line of that article is:

TLDR: Cells become islands of raised K+ ion concentration when energy is supplied.​

I like Peter's writing a lot, but I wish he'd also read Ling's work in detail .... That is basically what Ling has been talking about for 50 years .... in the Ling model, K+ adsorption and Na+ exclusion are fundamental mechanics during ATP-to-protein binding. Ling even generalises this via the c-value of various EWCs other than ATP, and how that affects susceptibility for either K+ or Na+ exclusion, and explains why certain membranes use different EWCs, and sodium-based mechanics instead.

What I like though, is that we have studies like that discussed in the article, which continually confirm this sort of K+/Na+ behaviour, but whereby the authors seem to have no idea of Ling's work. These independent discoveries lend credence to the observations and models presented in Ling's work.

Instead, what we see as explanations for ion-exclusion behaviour, are various "pumps" and "antiporters". Where does the energy come from? Why can't we see these large chunks of protein on the cell membrane (neither using light microscopy, nor electron microscopy)? Too much magic IMO

As a final aside, I thought Ling's writing got better as he aged. However, I like the 2001 book 'Life at the Cell and Below-Cell Level' best, mainly because it was very complete.

.....