Gluconeogenesis responsiveness




Been looking for an answer to this question for a while, but unsuccessful so far.

Imagine you are a hunter gatherer deep into ketosis, all glycogen stores depleted long ago. Now you roam the plains and suddenly have to run from the tiger. Will you have a chance?

So, how fast can gluconeogenesis provide the glucose your muscles suddenly require? Is it a response time of seconds, milliseconds? Will it be able to provide enough? You need glucose at all?

I guess there is something interesting here because using Darwin I might get the impression not much chance for humans to evolve if the tiger always wins in these situations :))

Anyone has a pointer to a source that looks at this topic?

(Michael - When reality fails to meet expectations, the problem is not reality.) #2

We are here so the tiger did not always win the chase. Thus the premise is incorrect.

  1. Ketogenic endurance athletes show no difference glycogen concentration at rest or during exercise. Jeff Volek’s group in 2015 showed no differences in glycogen content at rest or post-exercise when compared to high-carb athletes. Fat oxidation was higher in the LC athletes, who were also producing about 3 times more ketones than the HC athletes. If glycogen really mattered, there wouldn’t be a difference between the groups in ketones, or the glycogen of the LC athletes would be lower. Strike one.

  2. Leptin is just as important (if not more important) in the induction of ketogenesis. Hold on to your seat for this one, folks. This study blew me away]. Perry et al., (2018) Leptin Mediates a Glucose-Fatty Acid Cycle to Maintain Glucose Homeostasis in Starvation .

  3. To my knowledge, the only evidence to support the glycogen depletion theory is correlative . There’s simply no evidence to suggest that glycogen depletion is absolutely necessary to induce ketogenesis.

(Michael - When reality fails to meet expectations, the problem is not reality.) #3

For those who didn’t click the link in my previous post, here’s the study cited (Perry et al). Rat study so usual caveats apply.



The transition from the fed to the fasted state necessitates a shift from carbohydrate to fat metabolism that is thought to be mostly orchestrated by reductions in plasma insulin concentrations. Here, we show in awake rats that insulinopenia per se does not cause this transition but that both hypoleptinemia and insulinopenia are necessary. Furthermore, we show that hypoleptinemia mediates a glucose-fatty acid cycle through activation of the hypothalamic-pituitary-adrenal axis, resulting in increased white adipose tissue (WAT) lipolysis rates and increased hepatic acetyl-coenzyme A (CoA) content, which are essential to maintain gluconeogenesis during starvation. We also show that in prolonged starvation, substrate limitation due to reduced rates of glucose-alanine cycling lowers rates of hepatic mitochondrial anaplerosis, oxidation, and gluco-neogenesis. Taken together, these data identify aleptin-mediated glucose-fatty acid cycle that integrates responses of the muscle, WAT, and liver to promote a shift from carbohydrate to fat oxidation and maintain glucose homeostasis during starvation.


Ah, okay, that is interesting on its own! That means for the running needed you might not even need glucose or at least you still have some in reserve. And if I understand that right you dont have to wait for your glycogen stores to be zeroed for fat metabolism to begin. Really cool!

But it what about the core question? How responsive is gluconeogenesis? Can it start ad hoc or does it need time to ramp up and how much can it deliver?

(Michael - When reality fails to meet expectations, the problem is not reality.) #5

In my continuous glucose monitor experiment I determined that while in ketosis, gluconeogenesis maintains a normal level of blood glucose. In my case that was generally in the mid-low part of the normal range.

So if glycogen is required by muscles to function properly, and I think it is so required, then I conclude that glycogen is being synthesized as required. As noted above: “Jeff Volek’s group in 2015 showed no differences in glycogen content at rest or post-exercise when compared to high-carb athletes”. So it’s not the case that glycogen is depleted and then requires some period of time to replenish. It’s maintained within a normal range of values.

If you’re no longer in ketosis, of course, gluconeogenesis stops. There’s no need to waste energy synthesizing glucose when you’re eating it.

(bulkbiker) #6

When you are fat fuelled you don’t use GNG… you are already using ketones for energy and fat for fuel.
GNG simply provides the “required” glucose to keep the tiny amount we need running through our veins.


GNG is a demand driven process that will just provide enough glucose to keep certain things running that want it. It can’t provide you bursts of it, if it could people who eat keto wouldn’t have a disadvantage vs carbs when it comes to very glycolitic things. I’d say it may be that tigers change of a good meal that day.

(Bacon enough and time) #8

The liver stores glycogen, as well as the muscles, so there is a store ready for use when needed (liver glycogen, unlike muscle glycogen, can be shared). The liver’s store of glycogen is then replenished from gluconeogenesis. As well as those cells that require glucose, because they cannot handle ketones or fatty acids, glucose is needed for explosive muscle performance; fatty acids are used for endurance performance.

When I joined these forums, it was believed that glycogen stores were permanently low on a ketogenic diet, but Volek et al. have since shown that by two years of fat adaptation, glycogen stores in fat-adapted athletes are indistinguishable from those in carb-burning athletes. So the return to proper glycogen levels takes longer than fat-adaptation, but less than two years.

(Ethan) #9

I lift weights when fasted for days—clear ketosis. After a workout, my glucose my register 30-40 points higher than when I started (up to 120). Clearly, GNG works


We can’t use only fat for strenuous exercise…

(Michael - When reality fails to meet expectations, the problem is not reality.) #11


I am quite sure my glycogen stores aren’t depleted in that situation :slight_smile: I’ve read about these things and what else would make me not having the old water weight changes when I go out of and into ketosis? My weight tends to be super stable. I always had the same weight for ages and I always lost 4 lbs when I went into ketosis and gained 4 when I came out. Every time I checked and it was probably dozens. Some years passed, I guess I saw +/-2 at some point but I rarely checked then… And now my weight is the same every morning (with very rare and tiny changes now and then, my old 4 lbs was huge!), no matter my carb intake. I don’t always weigh myself and rarely excercise very much but with my usual moderate or sometimes zero acitivity, my weight is super stable (too stable, what am I, a robot? I don’t think my scale can’t show some other weight :D).
When I will have bigger muscles, I will be able to say more reliably that they look the same on/off keto, maybe someone else…?


Thanks for all the thoughts so far - fun to read!

In my little brain there was always this number 9 - 9 calories in a gramm of fat, 4 in a gramm of glucose. Then I thought hmm, using fat seems preferable which makes those who can do lots of stuff with fat more likely to survive (Darwin again) then the organism depending all on glucose. Now, if the body does the majority of storage in fat it is safe to assume that it will be originally optimized to use this fat. Until we make ourselves carb adapted and lose fat adaption. And again optimisation kicks in: if a process is not “needed” - burning fat - its resources will be reassigned to somewhere else. Things actually change. And if you go without food for a while your body will use glycogen stores assuming that there will be more carbs again in the near future. And it cant use fat anyways, so it needs that fuel.

Once you become fat adapted again there is no need for the body to tap into your glycogen stores all the time - it makes sense to use as much fat as possible for anything because of the hundreds of thousands of years we actually took to optimize these processes based on the 9 advantage.

Thats why I was pondering this responsiveness question. Because if things are as described it should not be a lack of glucose that delivers you to the tiger after all :slight_smile: The genepool with that defect should have been eaten long time ago :)))

Anyways, I gain the picture that once you are fat adapted your body keeps the glycogen stores for absolute emergencies and recharges them continuously if the chance arrises. GNG does not need to be fast (it still might be though!) because it works with a buffer.

BTW, I am also tending towards that after a meal fat metabolism does not kick in suddenly only after insulin drops under a certain value of x - in a fat adapted body the transition to me seems continouus but not linear. If you do not run down your stores anymore you might go into using fat again only a few hours after a insulin kicking meal. Ketosis not yet, but using fat already. Does getting into ketosis speed up, too?

(Butter Withaspoon) #14

The athletes in the Volek and Phinney study exercised for 3 hours at 60% (or 65?) or VO2 max. This intensity is low enough that muscle glycogen of the fat adapted athletes was not depleted. Running from a tiger is a shorter and much faster effort! The muscle glycogen would supply some of the energy in this emerging all fuel valves open sort of situation. If the athlete eats no carbs at all the glycogen stores should be repleted over the next 24 hours via gluconeogenesis.

For fat adapted athletes eating low carb, training twice a day becomes an issue if at least one session is moderate or high intensity.

This is from listening to the many musings of one of the athletes from that study. It’s early days, there’s still a lot of conjecture, but it’s all so interesting!

(bulkbiker) #15

Tell that to the keto marathon runners.

(Bacon enough and time) #16

It was Yalow and Berson, who invented the radioassay technique for measuring serum insulin, who demonstrated that if insulin is above a certain level in the blood, fatty acids cannot leave the tissue they are in. Insulin above a certain level inhibits the breakdown of triglycerides (lipolysis), and triglycerides are too large to pass through cell walls. Insulin has to drop below a certain level before triglycerides can be broken down and the individual fatty acids can pass through the cell wall for transport to muscle cells to be metabolised.

(Michael - When reality fails to meet expectations, the problem is not reality.) #17

Sort of one of the major points of staying in ketosis consistently rather then in/out. :innocent:

(Bob M) #18

I think this is why some (many?) more-athletic people who do low carb may also get higher morning blood sugar, and possibly HbA1c, though I’m not convinced A1c is a great indicator for low carb. (I’d like to seem more data from CGMs in conjunction with HbA1c and perhaps other values.)

I have noted, when I was wearing my CGM, that if I exercised in the morning, then worked on a project requiring a lot of physical labor, my blood sugar went up during/after exercise, but then stayed high all day. I got my lowest daily blood sugar when I did no exercise that day and sat in my chair all day (though I do have a standing desk). It could be 10+ (US) points difference (so, about 1 European point).

(Bacon enough and time) #19

HbA1C and C-peptide are markers for insulin resistance. People on keto who experience adaptative glucose sparing have normal HbA1C and C-peptide, even though their serum glucose is a bit higher.

(Butter Withaspoon) #20

So I suppose it’s Glycogenolysis that supplies sudden increased glucose demand, using muscle and liver glycogen, and Glucogenesis that refills theses stores over the next 24 to 48 hours.

The other glucose source that can be overlooked is the glycerol backbone of the triglyceride. This source is a good reason for being very well adapted to utilising fat, and having a higher metabolic rate - more glucose available from glycerol. Kind of cool if you’re doing endurance activity!

I love thinking about this stuff and I don’t have anyone in the real world who is interested :open_book: :books:
Thank you nerds!