Amino Acids as Modulators of Insulin Resistance and the Rate of Glycogen Storage?

New findings are emerging so quickly that I’m compelled to keep writing new posts. I simply have to share them, because they’re very interesting. So, let’s recap the latest understanding — my interpretation of the studies dealing with the regulation of glucose phosphorylation.

Extracellular glucose enters the cell through GLUT1 transporters, and when insulin is present, also through GLUT4 transporters. It reaches the cytosol, where it awaits phosphorylation. If phosphorylation is too slow, cytosolic glucose levels rise and activate the enzyme aldose reductase (AR) and initiate the polyol pathway, i.e. sorbitol → fructose → KHK → H₂O₂ and fructose → AMPD2 → urate — a process moving toward insulin resistance as a protection against rapid flooding of the cytosol with glucose. It’s a mechanism to quickly reduce the rate of glucose entry into the cell because the subsequent processing rate has its limits.

The next step of processing is phosphorylation by the enzymes HK1/HK2. The rate depends on the enzymes’ localization. If they are attached to the mitochondrial membrane and there is enough mitochondrial ATP — that is, sufficient energy — everything proceeds rapidly, and there’s no issue processing large amounts of glucose after insulin stimulation. The product is glucose-6-phosphate (G6P). The level of G6P is remarkably stable and determines what happens next. Lower G6P levels lead to higher glycolytic rates and greater mitochondrial ATP use for glucose phosphorylation. Higher G6P levels cause the enzymes to detach from the mitochondrial membrane, slowing glycolysis and increasing glycogen synthesis. This also raises the likelihood of polyol pathway activation during insulin stimulation.

That was the summary. I recalled that the rate of glycogen synthesis decreases with age. This is a fairly well-known fact, and I wanted to find some details explaining why this happens. But I couldn’t find any mechanism anywhere — apparently no one cares. Older studies clearly show that aging slows glycogen synthesis, but nobody knows why. They simply state that it happens. Strange.

So what could be causing it? I started to look into what process determines the rate of glycogen synthesis. I emphasize that this concerns the rate. Glycogen levels themselves do not change with age — only the rate of its synthesis, and therefore the rate of glucose processing. And I found studies examining an enzyme that is part of the gluconeogenesis (GNG) pathway — the enzyme called glucose-6-phosphatase (G6Pase). It’s the final enzyme of the GNG pathway and not a rate-limiting enzyme for gluconeogenesis. It removes the phosphate group from glucose and, through its activity, lowers G6P levels.

Extracellular amino acids activate the expression of glucose-6-phosphatase (G6Pase), thereby influencing glycolysis and the rate of glycogen storage (my note).

When G6Pase activity changes, something quite different happens — the rate of glycogen synthesis changes. G6Pase is activated, for example, by high glucose levels, which is unusual (since a high product level typically inhibits the reaction). It dephosphorylates G6P back to glucose, lowering G6P levels and slowing glycogen synthesis. In contrast, G6Pase deactivation increases G6P levels and speeds up glycogen synthesis. If we apply my hypothesis about energy intake regulation based on liver glycogen — G6Pase activation increases hunger, while its deactivation reduces it. Lower G6P levels also relieve inhibition of HK1/HK2, increasing phosphorylation rate and glycolysis. By controlling G6Pase activity, one can modulate glycolysis rate — and thus the ability to process glucose efficiently upon insulin stimulation. Therefore, if we want to reduce insulin resistance, it would be useful to activate the enzyme G6Pase. Can we do that? Yes — surprisingly, through certain amino acids.

S4048 blocks the enzyme G6Pase, which rapidly decreases glucose phosphorylation rate (GK) and activates glycogen synthesis (GS) without affecting gluconeogenesis (GNG).

Increased expression of the G6Pase enzyme slows glycogen synthesis and slightly slows glycolysis, but HK1/HK2 enzymes likely remain attached to mitochondria, ready for rapid action upon insulin stimulation.

How does this relate to amino acids? I found a study showing modulation of the expression — i.e. synthesis — of the G6Pase enzyme by extracellular amino acids. That is, by individual components of proteins. This connects to my earlier thoughts about the differing metabolism of glucose and fats depending on the availability of essential and non-essential amino acids (EAA/NEAA). I also proposed the hypothesis that the body must ensure sufficient EAA even at the cost of overeating and storing or burning excesses — meaning that a surplus of NEAA usable for gluconeogenesis could mean signal for further overeating.

And this study shows that it is precisely NEAA and BCAA (branched-chain amino acids) that activate the G6Pase enzyme much more strongly than EAA. It also shows that G6Pase is activated by ornithine, an intermediate of the urea cycle. This cycle processes ammonia produced by removing amino groups during gluconeogenesis from amino acids that didn’t find partners for protein synthesis. It is therefore closely linked with processing excess NEAA and EAA into glucose or fat. What happens when G6Pase is activated by ornithine? Increased G6Pase activity lowers G6P levels, which leads to the positioning of HK1/HK2 on the mitochondrial membrane. Glucose is then preferentially processed via glycolysis — aerobically into CO₂ and water or anaerobically into lactate. However, the rate should be high and insulin resistance low. At the same time, glycogen synthesis is suppressed — which, I believe, elevates daily food intake — leading to greater food consumption to replenish the "missing" essential amino acids.

This is a surprising study that seems unrelated to insulin resistance but is, in fact, very closely connected. All amino acids somehow influence G6Pase enzyme activity — and thus glycolysis, glycogen storage rate, and subsequently the polyol pathway and insulin resistance. Could the amino acid composition in the blood change with age? I think it can. We know that glycine and cysteine levels decrease with age. Returning to the original question — why does the rate of glycogen synthesis decline with age — I would say it may be a manifestation of altered amino acid composition related to changes in their utilization and to the altered quality of food processing in the digestive system in older age.

The amino acid composition of proteins evidently affects not only taste but also how much of a given food we eat — how much surplus accumulates in the body and how it’s processed and stored. The differences are very significant: for example, a mixture of non-essential amino acids (NEAA) activates the G6Pase enzyme about 3× more than a mixture of essential amino acids (EAA). Sulfur-containing (SAA) amino acids cysteine and methionine activate it the least of all amino acids. Conversely, branched-chain (BCAA) amino acids strongly activate G6Pase, similarly to glutamine. Even more interestingly, ornithine — a urea cycle intermediate — also activates G6Pase and therefore probably increases food intake. We see that everything is interconnected — that’s how it is — and it’s difficult to untangle it into simplified mechanisms understandable to humans.

And finally, a brief reminder: an adequate intake of essential amino acids (EAA) with a low intake of non-essential amino acids (NEAA) extends lifespan and prevents mice from overeating. However, a lack of protein does not extend lifespan — remember that!

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References:

A novel amino acid signaling process governs glucose-6-phosphatase transcription

Age-related changes in rat muscle glycogen synthase activity

Glucose-6-phosphatase overexpression lowers glucose 6-phosphate and inhibits glycogen synthesis and glycolysis in hepatocytes without affecting glucokinase translocation. Evidence against feedback inhibition of glucokinase

Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats. A pharmacological study with the chlorogenic acid derivative S4048

Influence of Diets with Varying Essential/Nonessential Amino Acid Ratios on Mouse Lifespan