Linking the hepatic glycogen buffer with protein protection

As a short recap of my article on the liver buffer, insulin causes the build-up of glycogen in the liver. When I looked into protein and fructose, I touched the topic of protein protection for the first time.

With this article I wanted to go a bit deeper into this aspect and do this by looking at various diseases showing the link between your glycogen level in the liver and the protein protection that it provides.

We can have a look at a number of conditions but lets first look at an opposite condition to illustrate the interplay between hepatic glucose production and insulin.

NOTE: when the mechanisms are explained below, activity going up or down is not like an on/off switch. It means statistically different enough to note an effect but it doesn’t always mean that for example going down means reducing with 70% or 80% although that can be the case sometimes.

Glycogen Storage Disease (GSD)

Glycogen Storage Disease type 1 is a failure to break down glycogen into glucose resulting in a high glycogen buffer. Insulin still does its job and pushes the conversion of glucose to glycogen when feeding. When fasted, insulin goes down to let glucose come out of the liver but there isn’t much coming out in case of GSD1.

Type 1 of GSD is where G6P (G6P is the step to or from glycogen) cannot be converted to glucose by the enzyme GSPase. As a result we get hypoglycemia. Without a need for insulin to reduce hepatic glucose output, this disease presents itself in all forms possible that result from low insulin levels, including muscle weakness due to catabolism. I’m pointing out muscle weakness because one of the roles that will come back over and over again is that if blood glucose levels cannot be maintained then muscle protein is broken down unless the lack of glucose is compensated somehow with another protective factor.

Affected individuals usually present in the first year of life with severe fasting hypoglycemia, hepatomegaly, failure to thrive, growth retardation, and developmental delay. Other common findings related to hypoglycemia include sweating, irritability, muscle weakness, drowsiness, and seizures.

“Glycogen storage diseases: Diagnosis, treatment and outcome” – https://content.iospress.com/articles/translational-science-of-rare-diseases/trd006

Insulin Resistance (IR)

First a bit of info on IR.

There are 2 ways in which IR can establish itself although both lead to lowered glucose absorption. This is explained in my article on insulin resistance in more detail but to recap… Either 1) fat builds up in the cell and it takes down the insulin receptor so insulin has no signaling effect in the cell or 2) low levels of insulin cause low stimulation through the insulin receptor. Both lower GLUT4 expression, causing lowered glucose uptake.

The first case is a problem that cannot be resolved until the fat is cleared. The second one resolves itself simply by releasing insulin. In this section I’ll be referring to the first case when talking about IR, the problematic case.

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Schematic of how fat accumulation lowers insulin receptor signaling and leads to hyperglycemia. Sourced from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489847/

How can you get fat build up in the liver to cause IR? There are 2 possible ways.

A first one is high fructose containing drink. This causes a fast accumulation of fructose in the liver which gets mostly converted to fat.

A second one is to combine glucose with fat and some protein in a meal. The protein and glucose together will drive up insulin to very high levels. Insulin breaks down the ApoB protein in the liver so the circulating lipids from the meal that reach the liver get stored in the liver and are unable to go out until insulin goes down again and ApoB can start exporting the fat.

Both cases will lead to IR due to accumulating fat. What sets them apart is that the second one is usually happening only at dinner. The first one is happening every time a liquid is taken in which combines glucose with fructose, in other words sugary drinks. Sugary cereals with milk, orange juice, sugar sweetened beverages are all examples of liquids that will feed glucose and fructose into the body with fast supply of fructose to the liver. For most people this will happen during breakfast, lunch and any time in between and towards dinner and even after dinner.

The frequency by which the process of liver fat accumulation is repeated and the volume of fat that is generated is important to establish IR.

Now that we know a bit more on what causes IR, we can get back to the question. Does it also lead to the depletion of glycogen over time and thus muscle atrophy?

Glycogen depletion

A key enzyme in the breakdown of glycogen and output of glucose from the liver is G6Pase which converts G6P to glucose. G6Pase is depending on absence of insulin.

Although not heavily activated, it is more active than expected given the level of insulin that is present in the circulation under IR conditions.

However, the normal activity is inappropriate for the prevailing hyperinsulinemia, indicating predominant hepatic insulin resistance. Thus, sustained G6Pase activity opposes GK (glucokinase) and limits the capacity of the liver to take up glucose

“Pathway-selective Insulin Resistance and Metabolic Disease: The Importance of Nutrient Flux” https://www.jbc.org/content/289/30/20462.full

So we see that the glycogen breakdown is not interrupted by insulin while insulin normally does have that effect.

The quote mentioned glucokinase (GK). This enzyme is responsible for converting glucose into G6P. GK activity is driven by insulin. Also here, without insulin signaling, GK goes down. Putting the 2 together, the newly created glucose will be converted to glycogen at a lower rate and the glycogen breakdown will not fully stop under hyperinsulinemia.

“Metabolic control analysis of hepatic glycogen synthesis in vivo” https://www.pnas.org/content/117/14/8166

What I get from the article is that the flux of the glycogen buffer normally would get depleted. But.. depending on the severity (level and length of time) of the hyperinsulinemia and hyperglycemia, it may still result in a net increase although not as much as would be expected under these severe conditions.

Protein catabolism

With the above info we don’t necessarily expect a loss of protein protection but… Just to briefly touch on this point because it is not about the liver… with the hyperinsulinemia that is associated with liver IR you would expect that this is actually very protective for skeletal muscle. High and prolonged insulin levels right? This may be true in an original phase but IR also establishes itself in the muscle. IR in the muscle further exaggerates the hyperinsulinemia and by not responding to the insulin signaling, the protective effect on skeletal muscle atrophy is uplifted. So as IR worsens in both the liver and skeletal muscle, the hyperinsulinemia and hyperglycemia worsen.

“Skeletal muscle inflammation and insulin resistance in obesity” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199705/

Type 1 diabetes (T1D)

Another scenario we can look at is T1D where insulin production is impaired. When T1D goes untreated, it leads to protein/muscle catabolism. In part this is caused by the lack of insulin which would normally stimulate/protect the skeletal muscle but the role of insulin is 2-fold. When liver glycogen is high, low insulin would lead to a higher glucose output. In order to control this, insulin will raise to maintain homeostatic blood glucose levels.

If the liver glycogen goes down, so will the insulin level. This will gradually uplift the protective effect on skeletal muscle (unless compensated by sufficient BHB). So liver glycogen level and skeletal muscle breakdown are connected through insulin.

High or low liver glycogen, in our T1D case we have insufficient insulin without exogenous insulin supply.

“Protein and Energy Metabolism in Type 1 Diabetes” – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822109/

Although I’ve already written about GNG being a supply driven process, afterwards I found another study showing that a mixed amino acid intake increased glucagon as expected. The resulting hyperglucagonemia caused a reduction of more than 50% in glucogenic amino acids. Glucagon stimulates GNG and GNG is not selective on substrates. Whatever can be converted to glucose will be converted to glucose. This is to highlight again the importance of refilling the liver glycogen buffer.

“Evidence for a catabolic role of glucagon during an amino acid load.” – https://www.ncbi.nlm.nih.gov/pubmed/8690809/

T1 diabetics know they have to compensate for protein in the meal. Without sufficient insulin, the newly created glucose goes out the liver, rising blood glucose. A specific study has been highlighted in the demand or supply article I wrote earlier.

“Protein and fat effects on glucose responses and insulin requirements in subjects with insulin-dependent diabetes mellitus” https://academic.oup.com/ajcn/article-abstract/58/4/555/4716054?redirectedFrom=fulltext

The liver glycogen buffer is very important to prevent protein breakdown. We see that in an overnight fast, T1D already have just 2/3rd of liver glycogen left compared to controls. Their lack of insulin to regulate blood glucose causes a faster depletion of liver glycogen.

“Role of hepatic glycogen breakdown in defective counterregulation of hypoglycemia in intensively treated type 1 diabetes.” – https://www.ncbi.nlm.nih.gov/pubmed/16505228

This is a very difficult situation because without insulin you can’t drive up the glycogen in the liver. Unless handled through insulin administration, this situation can be partially resolved by providing sufficient gluconeogenic substrates and high fat to increase BHB. Overnight fasts will lead to catabolism for T1Ds.

If there is no action of insulin on the liver, the glycogen storage goes down. This is not a case of IR but it is a case where there is no signaling effect triggered by insulin.

It mimics low carb diets whereby the diet itself keeps insulin low in a natural way.

Glycogen-dependent Satiety

If you read my article on the liver buffers and also the article on protein and fructose then you understand that the glycogen buffer is there to protect protein catabolism as I’ve also showed in this article.

In order to stimulate mice to overeat, it is sufficient to reduce the carbs in their diet and replace it with fat. This way they have to increase their food intake. The carbs directly provide protection by safeguarding basal glucose while the fat doesn’t. In order for the fat to provide protection, it has to be converted to BHB first, which mice are not good at.

In a mouse model where more protein is diverted to liver glycogen, we see that the mice do not become obese on the usual high fat (high carb) chow. The model results in higher liver glycogen levels thus no reason to overeat.

“Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model” https://diabetes.diabetesjournals.org/content/64/3/796

Could we have a similar satiety effect with hepatic IR? It is unlikely as it should lead to low glucose levels and we’ve already seen above that IR is associated with high glucose levels.

IR is also characterized by its inability to regulate glucagon secretion in the pancreas leading to higher circulating glucose because there is no response to insulin to store it in the liver and glucagon is responsible for GNG + glycogenolysis, putting out glucose from the liver.

There are many mechanisms through which hunger can be stimulated. A lowered blood glucose could be a direct contributor. However, our mouse example is opposite to the situation in IR where we have elevated glucose.

Insulin = survival

Our evolution has been driven through survival of the best fit. As such, probably nobody will argue that insulin has helped us to survive by storing energy. But most people will only think about storing fat.

After looking into the glycogen buffer, I consider insulin equally as important for survival by regulating replenishment of the liver glycogen. This buffer is not just to supply energy for the brain but by building up the buffer, it also helps to delay the need for protein breakdown.

Some say that we adapted to tolerate carbohydrates. I view carbohydrates as a (not so good) alternative to protein. Normally our liver glycogen buffer would be replenished through meat intake as I’ve shown in the article on supply versus demand.

With meat intake we had both a source for glucose and fat from the animals. With a reduction in meat intake, it became crucial to find an alternative source for glucose because we could not get enough fat and meat so without an alternative, our body protein would be degraded to provide energy to the brain.

This is not to say that protein is only used for the liver glycogen, of course not. No, but what I am saying is that as important as dietary protein is for building/maintaining protein in the body, equally important is its conversion to glycogen to maintain a longer survival.

— THE END —

5 thoughts on “Linking the hepatic glycogen buffer with protein protection

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