Hepatic Glucose Metabolism

After writing about the liver buffers I wanted to understand a bit more on the regulation of gluconeogenesis and buildup of the resulting glucose as glycogen in the liver. I have also written about protein being a supply-driven process with the mechanism intended to increase liver glycogen storage.

In order for that supply-driven mechanism to be true we have to have a closer look and see how gluconeogenesis (GNG), glycogenesis and glycogenolysis are controlled.

The reason why I want to have a closer look at it is because one of the fundamental conclusions, if my interpretation within the above linked articles is right, is that glucagon-driven GNG continues while insulin-driven build-up of glycogen takes place. These 2 processes have to be running side-by-side.

We will look at 3 specific elements in these pathways: phosphoenolpyruvate carboxykinase (PEPCK), glucokinase (GCK) and glucose-6-phosphatase (G6Pase).

PEPCK – There is a cytosolic version and a mitochondrial version. PEPCK diverts energy substrates away from being metabolised towards forming glucose. It is an important factor in creating new glucose from different substrates such as glycerol, amino acids and lactate.

“A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis.” https://www.ncbi.nlm.nih.gov/pubmed/24497630

GCK – Glucokinase is the enzyme that converts available glucose into glucose-6-phosphate (G6P). G6P is an intermediate step between glucose and glycogen so it can go either way, depending on which process has the upper hand.

“Liver glucokinase: An overview on the regulatory mechanisms of its activity.” https://www.ncbi.nlm.nih.gov/pubmed/21280170

G6Pase – This enzyme causes the release of glucose out of the liver. When glycogen gets broken down into glucose-6-phosphate (G6P), G6Pase will further convert it to glucose, allowing it to be released.

Although some papers link G6Pase regulation to AMPK, it could still be that it is concentration dependent such that when G6P levels rise, so will G6Pase to clear out G6P as glucose from the liver.

“GLUCONEOGENESIS AND RELATED ASPECTS OF GLYCOLYSIS”, 1983 https://www.annualreviews.org/doi/pdf/10.1146/annurev.bi.52.070183.003153

Even in this still recent 2017 paper it shows that the pathway from AMPK to G6Pase and PEPCK inhibition is still unknown. Potentially AMPK is at most just correlated?

source: https://jcs.biologists.org/content/joces/117/23/5479.full.pdf

“The AMP-activated protein kinase pathway–new players upstream and downstream.” https://www.ncbi.nlm.nih.gov/pubmed/15509864

I do not agree with the paper that a reduction in G6Pase leads to GNG. What I often see as a mistake is that GNG is equaled to hepatic glucose output. This can be true under multiple days of fasting but this is not applicable all the time showing that hepatic glucose output depends on other factors as well.

But those are details that will not make much difference for us…

What I do want to point out is that G6Pase is responsible for G6P conversion to glucose. You could say this is GNG but I want to make a distinction because there are to my view 2 different processes. 1) glycogen breakdown 2) conversion of substrates (amino acids, lactate, glycerol) into glucose. Otherwise we have to consider the breakup of starch into single glucose molecules also as GNG. The neo in gluconeogenesis means new and genesis refers to creating. Are we creating new glucose from glycogen? No

Why is this important? Because both processes are separately controlled as I intend to show with this article. But it is good to keep in mind that both GNG and glycogen breakdown can result in glucose output from the liver. Glucose output however does not say anything about which of the processes is producing the glucose. For that we need to have a broader look.


If I’m right about the mechanisms on the liver buffer and supply-driven protein GNG then these enzymes are individually and differently controlled via insulin and glucagon.

As a starter I would recommend you to watch this presentation to understand how diet affects the secretion of insulin and glucagon. Skip the first 30 minutes or so, it was a live recording with static image at the beginning.

I’ll summarize with a screenshot from the video below.

  1. When eating protein, GIP is released from the intestines. When the amino acids reach the alpha cell, together with GIP they stimulate glucagon release.
  2. When eating glucose, GIP is released from the intestines. When the glucose reaches the beta cell, together with GIP they stimulate insulin release.
  3. When eating protein and glucose, GIP is released from the intestines. When the amino acids reach the alpha cell, together with GIP they stimulate glucagon release. When the glucose and glucagon together with GIP reaches the beta cell, it will be stimulated to release more insulin than when only stimulated by GIP and glucose.
  4. When GIP is not secreted for example due to IV feeding then glucagon and insulin will be stimulated only a little bit.

So in a simplistic way: dietary protein ups glucagon secretion, dietary glucose ups insulin secretion, dietary protein and glucose ups glucagon secretion and double up insulin secretion.

OK, with the above in mind let’s now have a look at how these hormones influence PEPCK, GCK and G6Pase.

Both PEPCK and G6Pase are stated to be downregulated under strong insulin secretion (which also negatively regulates glucagon secretion) but what I specifically want to know is what happens under high glucagon and moderately elevated insulin which is more close to the low carb diet situation. My theory is that PEPCK at most will be weakly inhibited so that GNG still continues and G6Pase strongly inhibited so that glycogen buildup remains very active. So active GNG with active glycogenesis leading to liver glycogen increase.

the spike of postprandial insulin secretion will rapidly inhibit glucagon secretion and expression of PEPCK and G6Pase to reduce hepatic glucose output, as well as stimulate expression of glucokinase to promote storage of ingested food as glycogen.

PEPCK (creating new glucose) – The first paper referenced tells us that PEPCK is stimulated by glucagon but is dominantly inhibited by insulin.

“Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulation.” https://www.ncbi.nlm.nih.gov/pubmed/16375695

On a low carb diet, we don’t have such a strong insulin response and as a consequence glucagon is not inhibited.

What we do notice in the paper is that insulin stimulates the expression of GCK so the buildup of glycogen is demanded under insulin.

G6Pase (break down glycogen) – Foxo1 is responsible for the transcription of G6Pase. Insulin moves Foxo1 out of the nucleus so that G6Pase cannot be created. This is done through PKB/Akt.

“The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression.” https://www.ncbi.nlm.nih.gov/pubmed/11696581

So G6Pase cannot even be produced under influence of insulin which means that turning the G6P into glucose is inhibited. This is maximizing the buildup of G6P for conversion to glycogen because GCK is enhanced.

So the question really comes down to PEPCK. By how much does insulin affect PEPCK? This is hard to establish because PEPCK is not just inhibited by insulin, it is also increasingly expressed by glucagon.

This makes in vitro studies difficult to interpret but I managed to find one where they got pretty close to what I’m looking for. Here’s one where they measured the effect of insulin and cAMP. Glucagon stimulates PEPCK through cAMP so it is our proxy for glucagon. Also note that the study was done on rat hepatocytes so human mileage may vary.

Without stimulation of PEPCK by cAMP we see a strong effect of insulin on the suppression. 1nM is 1000pM.

Next we see that under cAMP activation, the level of synthesis is still up while under suppression of insulin. This time the insulin was 5nM. A 5-fold increase versus the strong inhibition already seen under 1nM but without cAMP stimulation.

Note also the additive effect of dexamethasone, a glucocorticosteroid.

The insulin side represents 5nM which is equivalent to a serum level of 720 mIU/L. To give you an idea, on my blood panel the upper range for fasted insulin is around 25 mIU/L. 0.2nM would be 29mIU/L which is close to the upper range for fasting and 1nM would equal around 144mIU/L.

“Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. The dominant role of insulin.” https://www.jbc.org/content/259/24/15242.abstract?ijkey=3592397c6a35bc3186238101f0df40eb36a5ac9d&keytype2=tf_ipsecsha

In a study of obese people we get to see their insulin response to a diet with 15% protein, 65% carbohydrate. In the worst case it gets to around 90mIU/L. An other reason I wanted to reference this paper is because they also tested a high frequency-high protein diet (45% protein, 35% carbohydrate). It is not the same as our really low carb high protein but it gives an idea about the trend. It is hard to see from the graph but the insulin response is around 55mIU/L.

“Alteration of postprandial glucose and insulin concentrations with meal frequency and composition” https://www.ncbi.nlm.nih.gov/pubmed/25231499

What this means is that even though insulin has an inhibiting effect on PEPCK, the level of insulin that needs to be reached to have a dramatic effect is quite high.

The level of insulin rise that we can expect on a high protein low carb diet is not sufficient to have a severe oppressive effect. According to our in vitro study,

PEPCK is also further controlled by glucose but for this glucose levels have to rise. I will ignore this part because glucose is generally well controlled under low carb. Even when protein is converted to glucose thanks to diverting the glucose to glycogen.

“The Repression of Hormone-activated PEPCK Gene Expression by Glucose Is Insulin-independent but Requires Glucose Metabolism” https://www.jbc.org/content/273/37/24145.full

In this chinese study they tested a high fat, high carb and high protein meal and response. You can ignore the red line as these were obese. The idea is to have a look at the insulin sensitive people (blue line) and see what happens to their glucose and insulin.

Fig 1
image sourced: https://www.ncbi.nlm.nih.gov/pubmed/29385178

As you can see in this study, the high protein meal has the best glycemic control. People would think that it is because the resulting amino acids are only converted to glucose on a demand basis. But if that would be true, there would be no reason to react with the highest insulin response compared to the other meals. The 2500% increase would mean that a fasting insulin level of 9mIU/L would go up to 225mIU/L. Such high increase is to be expected because the meals were liquid drinks which cause rapid absorption.

Did you watch the video on incretin a bit further up? Then you understand that as the amino acids start to stimulate glucagon, glucose levels are ramping up. GIP in the circulation together with glucagon and a rise in glucose will start to stimulate insulin production. So even protein, in isolation from glucose (carbohydrates) will also trigger insulin together with the insulin-stimulating amino acids.


If you read my article on insulin resistance then you will also understand that under a low carb high protein, the type of insulin resistance is the one that is still responsive to insulin. This is a good thing as you’ll see below.

With this deeper dive into the regulating mechanisms I’m now firmly convinced that dietary protein are partially converted to glucose and stored in the liver under a supply-driven mechanism.

The dietary glucagon-stimulating amino acids raise PEPCK so glucose production goes up. Normally that would also result in a higher glycolysis but in order to control blood glucose, insulin goes up (also in part stimulated by some of the amino acids from the dietary protein). Insulin has a much stronger counter-regulatory effect on glycolysis and a strong up-regulating effect on GCK effectively stopping the breakdown of glycogen and increasing the buildup of glycogen.

The modest rise in insulin (on a very low carb and certainly on zero carb diet) is not sufficient to counter the effect of glucagon on PEPCK so that any substrate, including glucogenic amino acids, are converted to glucose at a higher rate.

Some of the amino acids will end up in the cells, stimulating protein synthesis via mTOR so obviously not all of them get converted to glucose. It is simply a matter of substrate availability aka supply.

There is nothing wrong with this supply-driven conversion of amino acids to glucose. It likely helped our ancestors to survive as it protected them from muscle catabolism.

This is even more so important for lean individuals if they are unable to obtain sufficient fat to generate ketones. The ketones (BHB) would compensate for shortage of glucose.

Not enough fat? That means lower ketones thus more protein (muscle) catabolism to obtain glucose. The brain must have its energy. Being able to convert and store dietary amino acids helps to secure a supply of glucose for the brain without having to break down protein in the body.


2 thoughts on “Hepatic Glucose Metabolism

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